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Annals of Clinical and Translational... Jun 2024To define tauopathy-associated changes in the human gray and white matter proteome.
OBJECTIVE
To define tauopathy-associated changes in the human gray and white matter proteome.
METHOD
We applied tandem mass tagged labeling and mass spectrometry, consensus, and ratio weighted gene correlation network analysis (WGCNA) to gray and white matter sampled from postmortem human dorsolateral prefrontal cortex. The sampled tissues included control as well as Alzheimer's disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal degeneration with tau pathology, and chronic traumatic encephalopathy.
RESULTS
Only eight proteins were unique to gray matter while six were unique to white matter. Comparison of the gray and white matter proteome revealed an enrichment of microglial proteins in the white matter. Consensus WGCNA sorted over 6700 protein isoforms into 46 consensus modules across the gray and white matter proteomic networks. Consensus network modules demonstrated unique and shared disease-associated microglial and endothelial protein changes. Ratio WGCNA sorted over 6500 protein ratios (white:gray) into 33 modules. Modules associated with mitochondrial proteins and processes demonstrated higher white:gray ratios in diseased tissues relative to control, driven by mitochondrial protein downregulation in gray and upregulation in white.
INTERPRETATION
The dataset is a valuable resource for understanding proteomic changes in human tauopathy gray and white matter. The identification of unique and shared disease-associated changes across gray and white matter emphasizes the utility of examining both tissue types. Future studies of microglial, endothelial, and mitochondrial changes in white matter may provide novel insights into tauopathy-associated changes in human brain.
PubMed: 38924699
DOI: 10.1002/acn3.52134 -
Neural Regeneration Research Apr 2024Schwann cells are essential for the maintenance and function of motor neurons, axonal networks, and the neuromuscular junction. In amyotrophic lateral sclerosis, where...
Schwann cells are essential for the maintenance and function of motor neurons, axonal networks, and the neuromuscular junction. In amyotrophic lateral sclerosis, where motor neuron function is progressively lost, Schwann cell function may also be impaired. Recently, important signaling and potential trophic activities of Schwann cell-derived exosomal vesicles have been reported. This case report describes the treatment of a patient with advanced amyotrophic lateral sclerosis using serial intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles, marking, to our knowledge, the first instance of such treatment. An 81-year-old male patient presented with a 1.5-year history of rapidly progressive amyotrophic lateral sclerosis. After initial diagnosis, the patient underwent a combination of generic riluzole, sodium phenylbutyrate for the treatment of amyotrophic lateral sclerosis, and taurursodiol. The patient volunteered to participate in an FDA-approved single-patient expanded access treatment and received weekly intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles to potentially restore impaired Schwann cell and motor neuron function. We confirmed that cultured Schwann cells obtained from the amyotrophic lateral sclerosis patient via sural nerve biopsy appeared impaired (senescent) and that exposure of the patient's Schwann cells to allogeneic Schwann cell-derived exosomal vesicles, cultured expanded from a cadaver donor improved their growth capacity in vitro. After a period of observation lasting 10 weeks, during which amyotrophic lateral sclerosis Functional Rating Scale-Revised and pulmonary function were regularly monitored, the patient received weekly consecutive infusions of 1.54 × 1012 (×2), and then consecutive infusions of 7.5 × 1012 (×6) allogeneic Schwann cell-derived exosomal vesicles diluted in 40 mL of Dulbecco's phosphate-buffered saline. None of the infusions were associated with adverse events such as infusion reactions (allergic or otherwise) or changes in vital signs. Clinical lab serum neurofilament and cytokine levels measured prior to each infusion varied somewhat without a clear trend. A more sensitive in-house assay suggested possible inflammasome activation during the disease course. A trend for clinical stabilization was observed during the infusion period. Our study provides a novel approach to address impaired Schwann cells and possibly motor neuron function in patients with amyotrophic lateral sclerosis using allogeneic Schwann cell-derived exosomal vesicles. Initial findings suggest that this approach is safe.
PubMed: 38922880
DOI: 10.4103/NRR.NRR-D-23-01815 -
Toxins Jun 2024Claviceptaceous endophytic fungi in the genus mostly form a symbiotic relationship with cool-season grasses. spp. are capable of producing bioactive alkaloids such as... (Review)
Review
Claviceptaceous endophytic fungi in the genus mostly form a symbiotic relationship with cool-season grasses. spp. are capable of producing bioactive alkaloids such as peramines, lolines, ergot alkaloids, and indole-diterpenes, which protect the host plant from herbivory by animals, insects, and nematodes. The host also benefits from enhanced tolerance to abiotic stresses, such as salt, drought, waterlogging, cold, heavy metals, and low nitrogen stress. The bioactive alkaloids produced can have both direct and indirect effects towards plant parasitic nematodes. Direct interaction with nematodes' motile stages can cause paralysis (nematostatic effect) or death (nematicidal effect). Indirectly, the metabolites may induce host immunity which inhibits feeding and subsequent nematode development. This review highlights the different mechanisms through which this interaction and the metabolites produced have been explored in the suppression of plant parasitic nematodes and also how the specific interactions between different grass genotypes and endophyte strains result in variable suppression of different nematode species. An understanding of the different grass-endophyte interactions and their successes and failures in suppressing various nematode species is essential to enable the proper selection of grass-endophyte combinations to identify the alkaloids produced, concentrations required, and determine which nematodes are sensitive to which specific alkaloids.
Topics: Animals; Alkaloids; Endophytes; Poaceae; Nematoda; Epichloe; Plant Diseases
PubMed: 38922168
DOI: 10.3390/toxins16060274 -
Sports (Basel, Switzerland) May 2024The aim of this systematic review was to assess the effects of plyometric-jump training (PJT) on the physical fitness of youth with cerebral palsy (CP) compared with... (Review)
Review
The aim of this systematic review was to assess the effects of plyometric-jump training (PJT) on the physical fitness of youth with cerebral palsy (CP) compared with controls (i.e., standard therapy). The PRISMA 2020 guidelines were followed. Eligibility was assessed using the PICOS approach. Literature searches were conducted using the PubMed, Web of Science, and SCOPUS databases. Methodological study quality was assessed using the PEDro scale. Data were meta-analyzed by applying a random-effects model to calculate Hedges' g effect sizes (ES), along with 95% confidence intervals (95% CI). The impact of heterogeneity was assessed ( statistic), and the certainty of evidence was determined using the GRADE approach. Eight randomized-controlled studies with low-to-moderate methodological quality were included, involving male (n = 225) and female (n = 138) youth aged 9.5 to 14.6 years. PJT interventions lasted between 8 and 12 weeks with 2-4 weekly sessions. Compared with controls, PJT improved the muscle strength (ES = 0.66 [moderate], 95% CI = 0.36-0.96, < 0.001, = 5.4%), static (ES = 0.69 [moderate], 95% CI= 0.33-1.04, < 0.001, = 0.0%) and dynamic balance (ES = 0.85 [moderate], 95% CI = 0.12-1.58, = 0.023, = 81.6%) of youth with CP. Therefore, PJT improves muscle strength and static and dynamic balance in youth with CP compared with controls. However, more high-quality randomized-controlled trials with larger sample sizes are needed to provide a more definitive recommendation regarding the use and safety of PJT to improve measures of physical fitness.
PubMed: 38921846
DOI: 10.3390/sports12060152 -
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 -
Development of a clinical diagnostic model for Bell's palsy in patients with facial muscle weakness.Biomolecules & Biomedicine Jun 2024Early diagnosis of Bell's palsy is crucial for effective patient management in primary care settings. This study aimed to develop a simplified diagnostic tool to enhance...
Early diagnosis of Bell's palsy is crucial for effective patient management in primary care settings. This study aimed to develop a simplified diagnostic tool to enhance the accuracy of identifying Bell's palsy among patients with facial muscle weakness. Data from 240 patients were analyzed using seven potential clinical evaluation indicators. Two diagnostic benchmarks were established: one based on clinical assessment and the other incorporating magnetic resonance imaging (MRI) findings. A multivariate logistic regression model was developed based on these benchmarks, resulting in the construction of a predictive tool evaluated through latent class models. Both models retained four key clinical indicators: absence of forehead wrinkles, accumulation of food and saliva inside the mouth on the affected side, presence of vesicular rash in the ear or pharynx, and lack of pain or symptoms associated with tick exposure, rash, or joint pain. The first model demonstrated excellent discriminative ability (area under the curve [AUC] = 0.96, 95% confidence interval [CI] 0.94 - 0.99) and calibration (P < 0.001), while the second model also showed good performance (AUC = 0.88, 95% CI 0.83 - 0.92) and calibration (P = 0.005). Bootstrap validation indicated no significant overfitting. The latent class defined by the first model significantly aligned with the clinical diagnosis group, while the second model showed lower consistency.
PubMed: 38920750
DOI: 10.17305/bb.2024.10677 -
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 -
Journal of Anaesthesiology, Clinical... 2024The upper thoracic (T2) erector spinae plane block (UT-ESPB) has been proposed as an alternative to interscalene brachial plexus block for postoperative analgesia in...
The efficacy of ultrasound-guided upper thoracic erector spinae plane block for postoperative analgesia in proximal shoulder surgery and its effect on phrenic nerve function: A prospective exploratory study.
BACKGROUND AND AIMS
The upper thoracic (T2) erector spinae plane block (UT-ESPB) has been proposed as an alternative to interscalene brachial plexus block for postoperative analgesia in shoulder surgery. The current study was conducted to evaluate the same.
MATERIAL AND METHODS
Patients scheduled for shoulder surgery under general anesthesia (GA) received ultrasound-guided UT-ESPB. The outcomes measured were diaphragmatic movements, block characteristics, and quality of recovery at 24 h.
RESULTS
A total of 43 patients were recruited. The incidence of phrenic nerve palsy was 0%. The sensory level achieved by the maximum number of patients at the end of 30 min was C7-T5 level, and none had a motor block. Forty-two percent of patients did not require rescue analgesia till 24 h postoperative. In the rest of the patients, the mean (SD) duration of analgesia was 724.2 ± 486.80 min, and the mean postoperative requirement of fentanyl was 98.80 ± 47.02 μg. The median pain score (NRS) during rest and movement is 2 to 3 and 3 to 4, respectively. The median quality of recovery score at the end of 24 h after the block was 14 (15-14).
CONCLUSION
The upper thoracic ESPB resulted in a sensory loss from C7-T5 dermatomes without any weakness of the diaphragm and upper limb. However, the block was moderately effective in terms of the total duration of analgesia, postoperative pain scores, analgesic requirement, and quality of recovery in patients undergoing proximal shoulder surgeries under GA. Further studies are required to establish its role due to its poor correlation with sensory spread.
PubMed: 38919449
DOI: 10.4103/joacp.joacp_434_22 -
Journal of Anaesthesiology, Clinical... 2024Though permanent vocal cord palsy consequent to recurrent laryngeal nerve (RLN) injury is rare following thyroidectomies, its consequences are grave enough for it to be... (Review)
Review
Though permanent vocal cord palsy consequent to recurrent laryngeal nerve (RLN) injury is rare following thyroidectomies, its consequences are grave enough for it to be the most feared complication postoperatively. Anesthesiologists and surgeons take various precautions to prevent its occurrence and employ various methods for its early detection. They include direct visualization of the nerve intraoperatively, use of intraoperative nerve monitoring, and post-extubation visualization of vocal cord mobility by use of direct or indirect methods. In the present narrative review, we aim to discuss the clinical evidence pertaining to the various methods adopted for the prevention and early detection of RLN palsy during thyroidectomy.
PubMed: 38919442
DOI: 10.4103/joacp.joacp_346_22 -
The Iowa Orthopaedic Journal 2024Walking is a vital activity often compromised in individuals with neuropathic conditions. Charcot-Marie-Tooth (CMT) disease and Cerebral Palsy (CP) are two common...
BACKGROUND
Walking is a vital activity often compromised in individuals with neuropathic conditions. Charcot-Marie-Tooth (CMT) disease and Cerebral Palsy (CP) are two common neurodevelopmental disabilities affecting gait, predisposing to the risk of falls. With guiding scientific evidence limited, there is a critical need to better understand how surgical correction affects mobility, balance confidence, and gait compared to ankle foot orthosis (AFO) bracing. A systematic approach will enable rigorous collaborative research to advance clinical care.
METHODS
Key elements of this vision include 1) prospective studies in select patient cohorts to systematically compare conservative vs. surgical management, 2) objective laboratory-based evaluation of patient mobility, balance, and gait using reliable methods, and 3) use of patient-centric outcome measures related to health and mobility.
RESULTS
Valid and reliable standardized tests of physical mobility and balance confidence have been described in the literature. They include 1) the four-square step test, a widely used test of balance and agility that predicts fall risk, 2) the self-selected walking velocity, a measure of general mobility able to detect function change with orthosis use, and 3) the activity specific balance confidence scale, a survey instrument that assesses an individual's level of balance confidence during activity. Additionally, motion capture and ground reaction force data can be used to evaluate whole-body motion and loading, with discriminative biomechanical measures including toe clearance during the swing phase of gait, plantarflexion at 50% of swing, peak ankle plantarflexor moment, and peak ankle push-off power.
CONCLUSION
The tools needed to support evidence-based practice and inform clinical decision making in these challenging patient populations are all available. Research must now be conducted to better understand the potential benefits and limitations of AFO use in the context of mobility and balance during gait for individuals with neuropathic conditions, particularly relative to those offered by surgical correction.
CLINICAL RELEVANCE
Following this path of research will provide comparative baseline data on mobility, balance confidence, and gait that can be used to inform an objective criterion-based approach to AFO prescription and the impact of surgical intervention.
Topics: Humans; Postural Balance; Charcot-Marie-Tooth Disease; Foot Orthoses; Cerebral Palsy; Orthotic Devices; Gait Disorders, Neurologic; Gait; Walking
PubMed: 38919344
DOI: No ID Found