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Brain : a Journal of Neurology Jun 2024Charcot-Marie-Tooth (CMT) disease is a neuromuscular disorder affecting the peripheral nervous system. The diagnostic yield in demyelinating CMT (CMT1) is typically...
Charcot-Marie-Tooth (CMT) disease is a neuromuscular disorder affecting the peripheral nervous system. The diagnostic yield in demyelinating CMT (CMT1) is typically ∼80-95%, of which at least 60% is due to the PMP22 gene duplication. The remainder of CMT1 is more genetically heterogeneous. We used whole exome and whole genome sequencing data included in the GENESIS database to investigate novel causal genes and mutations in a cohort of ∼2,670 individuals with CMT neuropathy. A recurrent heterozygous missense variant p.Thr1424Met in the recently described CMT gene ITPR3, encoding IP3R3 (inositol 1,4,5-trisphosphate receptor 3) was identified. This previously reported p.Thr1424Met change was present in 33 affected individuals from nine unrelated families from multiple populations, representing an unusual recurrence rate at a mutational hotspot, strengthening the gene-disease relationship (GnomADv4 allele frequency 1.76e-6). Sanger sequencing confirmed the co-segregation of the CMT phenotype with the presence of the mutation in autosomal dominant and de novo inheritance patterns, including a four-generation family with multiple affected second-degree cousins. Probands from all families presented with slow nerve conduction velocities, matching the diagnostic category of CMT1. Remarkably, we observed a uniquely variable clinical phenotype for age at onset and phenotype severity in p.Thr1424Met carrying patients, even within families. Finally, we present data supportive of a dominant-negative effect of the p.Thr1424Met mutation with associated changes in protein expression in patient-derived cells.
PubMed: 38938188
DOI: 10.1093/brain/awae206 -
BMC Medical Education Jun 2024Clinical teaching during encounters with real patients lies at the heart of medical education. Mixed reality (MR) using a Microsoft HoloLens 2 (HL2) offers the potential... (Observational Study)
Observational Study
BACKGROUND
Clinical teaching during encounters with real patients lies at the heart of medical education. Mixed reality (MR) using a Microsoft HoloLens 2 (HL2) offers the potential to address several challenges: including enabling remote learning; decreasing infection control risks; facilitating greater access to medical specialties; and enhancing learning by vertical integration of basic principles to clinical application. We aimed to assess the feasibility and usability of MR using the HL2 for teaching in a busy, tertiary referral university hospital.
METHODS
This prospective observational study examined the use of the HL2 to facilitate a live two-way broadcast of a clinician-patient encounter, to remotely situated third and fourth year medical students. System Usability Scale (SUS) Scores were elicited from participating medical students, clinician, and technician. Feedback was also elicited from participating patients. A modified Evaluation of Technology-Enhanced Learning Materials: Learner Perceptions Questionnaire (mETELM) was completed by medical students and patients.
RESULTS
This was a mixed methods prospective, observational study, undertaken in the Day of Surgery Assessment Unit. Forty-seven medical students participated. The mean SUS score for medical students was 71.4 (SD 15.4), clinician (SUS = 75) and technician (SUS = 70) indicating good usability. The mETELM Questionnaire using a 7-point Likert Scale demonstrated MR was perceived to be more beneficial than a PowerPoint presentation (Median = 7, Range 6-7). Opinion amongst the student cohort was divided as to whether the MR tutorial was as beneficial for learning as a live patient encounter would have been (Median = 5, Range 3-6). Students were positive about the prospect of incorporating of MR in future tutorials (Median = 7, Range 5-7). The patients' mETELM results indicate the HL2 did not affect communication with the clinician (Median = 7, Range 7-7). The MR tutorial was preferred to a format based on small group teaching at the bedside (Median = 6, Range 4-7).
CONCLUSIONS
Our study findings indicate that MR teaching using the HL2 demonstrates good usability characteristics for providing education to medical students at least in a clinical setting and under conditions similar to those of our study. Also, it is feasible to deliver to remotely located students, although certain practical constraints apply including Wi-Fi and audio quality.
Topics: Humans; Feasibility Studies; Prospective Studies; Students, Medical; Female; Male; Self Report; Education, Medical, Undergraduate; Adult; Young Adult; Augmented Reality; Education, Distance; Surveys and Questionnaires
PubMed: 38937764
DOI: 10.1186/s12909-024-05591-z -
Scientific Reports Jun 2024Research to improve and expand treatment options for motor impairment after stroke remains an important issue in rehabilitation as the reduced ability to move affected...
Research to improve and expand treatment options for motor impairment after stroke remains an important issue in rehabilitation as the reduced ability to move affected limbs is still a limiting factor in the selection of training content for stroke patients. The combination of action observation and peripheral nerve stimulation is a promising method for inducing increased excitability and plasticity in the primary motor cortex of healthy subjects. In addition, as reported in the literature, the use of action observation and motor imagery in conjunction has an advantage over the use of one or the other alone in terms of the activation of motor-related brain regions. The aim of the pilot study was thus to combine these findings into a multimodal approach and to evaluate the potential impact of the concurrent application of the three methods on dexterity in stroke patients. The paradigm developed accordingly was tested with 10 subacute patients, in whom hand dexterity, thumb-index pinch force and thumb tapping speed were measured for a baseline assessment and directly before and after the single intervention. During the 10-min session, patients were instructed to watch a repetitive thumb-index finger tapping movement displayed on a monitor and to imagine the sensations that would arise from physically performing the same motion. They were also repeatedly electrically stimulated at the wrist on the motorically more affected body side and asked to place their hand behind the monitor for the duration of the session to support integration of the displayed hand into their own body schema. The data provide a first indication of a possible immediate effect of a single application of this procedure on the dexterity in patients after stroke.
Topics: Humans; Pilot Projects; Male; Female; Middle Aged; Aged; Stroke; Stroke Rehabilitation; Motor Cortex; Peripheral Nerves; Imagery, Psychotherapy; Adult; Motor Skills; Electric Stimulation
PubMed: 38937566
DOI: 10.1038/s41598-024-65911-7 -
Biochimica Et Biophysica Acta.... Jun 2024Three-dimensional (3D) organoids derived from human pluripotent stem cells (hPSCs) have revolutionized in vitro tissue modeling, offering a unique opportunity to...
BACKGROUND
Three-dimensional (3D) organoids derived from human pluripotent stem cells (hPSCs) have revolutionized in vitro tissue modeling, offering a unique opportunity to replicate physiological tissue organization and functionality. This study investigates the impact of radiation on skeletal muscle response using an innovative in vitro human 3D skeletal muscle organoids (hSMOs) model derived from hPSCs.
METHODS
The hSMOs model was established through a differentiation protocol faithfully recapitulating embryonic myogenesis and maturation via paraxial mesodermal differentiation of hPSCs. Key skeletal muscle characteristics were confirmed using immunofluorescent staining and RT-qPCR. Subsequently, the hSMOs were exposed to a clinically relevant dose of 2 Gy of radiation, and their response was analyzed using immunofluorescent staining and RNA-seq.
RESULTS
The hSMO model faithfully recapitulated embryonic myogenesis and maturation, maintaining key skeletal muscle characteristics. Following exposure to 2 Gy of radiation, histopathological analysis revealed deficits in hSMOs expansion, differentiation, and repair response across various cell types at early (30 min) and intermediate (18 h) time points post-radiation. Immunofluorescent staining targeting γH2AX and 53BP1 demonstrated elevated levels of foci per cell, particularly in PAX7 cells, during early and intermediate time points, with a distinct kinetic pattern showing a decrease at 72 h. RNA-seq data provided comprehensive insights into the DNA damage response within the hSMOs.
CONCLUSIONS
Our findings highlight deficits in expansion, differentiation, and repair response in hSMOs following radiation exposure, enhancing our understanding of radiation effects on skeletal muscle and contributing to strategies for mitigating radiation-induced damage in this context.
PubMed: 38936620
DOI: 10.1016/j.bbamcr.2024.119792 -
Biomedicine & Pharmacotherapy =... Jun 2024Injury of a peripheral nerve (PNI) leads to both ischemic and inflammatory alterations. Sciatic nerve injury (SNI) represents the most widely used model for PNI....
Injury of a peripheral nerve (PNI) leads to both ischemic and inflammatory alterations. Sciatic nerve injury (SNI) represents the most widely used model for PNI. Mesenchymal stem cell-based therapy (MSCs) has convenient properties on PNI by stimulating the nerve regeneration. Melatonin has cytoprotective activity. The neuroprotective characteristics of MSCs and melatonin separately or in combination remain a knowledge need. In the rats-challenged SNI, therapeutic roles of intralesional MSCs and intraperitoneal melatonin injections were evaluated by functional assessment of peripheral nerve regeneration by walking track analysis involving sciatic function index (SFI) and two electrophysiological tests, electromyography and nerve conduction velocity, as well as measurement of antioxidant markers in serum, total antioxidant capacity (TAC) and malondialdehyde, and mRNA expression of brain derived neurotrophic factor (BDNF) in nerve tissues in addition to the histopathological evaluation of nerve tissue. Both individual and combination therapy with MSCs and melatonin therapies could effectively ameliorate this SNI and promote its regeneration as evidenced by improving the SFI and two electrophysiological tests and remarkable elevation of TAC with decline in lipid peroxidation and upregulation of BDNF levels. All of these led to functional improvement of the damaged nerve tissues and good recovery of the histopathological sections of sciatic nerve tissues suggesting multifactorial synergistic approach of the concurrent usage of melatonin and MSCs in PNI. The combination regimen has the most synergistic neuro-beneficial effects in PNI that should be used as therapeutic option in patients with PNI to boost their quality of life.
PubMed: 38936196
DOI: 10.1016/j.biopha.2024.117015 -
Acta Histochemica Jun 2024We previously reported the presence of P2X3 purinoceptors (P2X3)-expressing subserosal afferent nerve endings consisting of net- and basket-like nerve endings in the rat...
Immunohistochemical localization of proteins involved in exocytosis of glutamate from P2X3 purinoceptor-expressing subserosal afferent nerve endings in the rat gastric antrum.
We previously reported the presence of P2X3 purinoceptors (P2X3)-expressing subserosal afferent nerve endings consisting of net- and basket-like nerve endings in the rat gastric antrum. These nerve endings may morphologically be vagal mechanoreceptors activated by antral peristalsis. The present study investigated immunoreactivities for vesicular glutamate transporter (VGLUT) 1 and VGLUT2 as well as exocytosis-related proteins, i.e., core components of the SNARE complex (SNAP25, Stx1, and VAMP2) and synaptotagmin-1 (Syt1), in whole-mount preparations of the rat gastric antrum using double immunofluorescence. VGLUT1 immunoreactivity was not detected, whereas VGLUT2 immunoreactivity was observed in P2X3-immunoreactive subserosal nerve endings composed of both net- and basket-like endings. In net-like nerve endings, intense VGLUT2 immunoreactivity was localized in polygonal bulges of reticular nerve fibers and peripheral axon terminals. Furthermore, intense immunoreactivities for SNAP25, Stx1, and VAMP2 were localized in net-like nerve endings. Intense immunoreactivities for VAMP2 and Syt1 were observed in VGLUT2-immunoreactive net-like nerve endings. In basket-like nerve endings, VGLUT2 immunoreactivity was localized in pleomorphic terminal structures and small bulges surrounding the subserosal ganglion, whereas immunoreactivities for SNAP25, Stx1, and VAMP2 were weak in these nerve endings. VGLUT2-immunoreactive basket-like nerve endings were weakly immunoreactive for VAMP2 and Syt1. These results suggest that subserosal afferent nerve endings release glutamate by exocytosis mainly from net-like nerve endings to modulate their mechanoreceptor function.
PubMed: 38936136
DOI: 10.1016/j.acthis.2024.152170 -
Peripheral nerve transfers for dysfunctions in central nervous system injuries: a systematic review.International Journal of Surgery... Jun 2024The review highlights recent advancements and innovative uses of nerve transfer surgery in treating dysfunctions caused by central nervous system (CNS) injuries, with a...
BACKGROUND
The review highlights recent advancements and innovative uses of nerve transfer surgery in treating dysfunctions caused by central nervous system (CNS) injuries, with a particular focus on spinal cord injury (SCI), stroke, traumatic brain injury, and cerebral palsy.
METHODS
A comprehensive literature search was conducted regarding nerve transfer for restoring sensorimotor functions and bladder control following injuries of spinal cord and brain, across PubMed and Web of Science from January 1920 to May 2023. Two independent reviewers undertook article selection, data extraction, and risk of bias assessment with several appraisal tools, including the Cochrane Risk of Bias Tool, the JBI Critical Appraisal Checklist, and SYRCLE's ROB tool. The study protocol has been registered and reported following PRISMA and AMSTAR guidelines.
RESULTS
Nine hundred six articles were retrieved, of which 35 studies were included (20 on SCI and 15 on brain injury), with 371 participants included in the surgery group and 192 in the control group. These articles were mostly low-risk, with methodological concerns in study types, highlighting the complexity and diversity. For SCI, the strength of target muscle increased by 3.13 of Medical Research Council grade, and the residual urine volume reduced by more than 100 ml in 15 of 20 patients. For unilateral brain injury, the Fugl-Myer motor assessment (FMA) improved 15.14-26 score in upper extremity compared to 2.35-26 in the control group. The overall reduction in Modified Ashworth score was 0.76-2 compared to 0-1 in the control group. Range of motion (ROM) increased 18.4-80° in elbow, 20.4-110° in wrist and 18.8-130° in forearm, while ROM changed -4.03°-20° in elbow, -2.08°-10° in wrist, -2.26°-20° in forearm in the control group. The improvement of FMA in lower extremity was 9 score compared to the presurgery.
CONCLUSION
Nerve transfer generally improves sensorimotor functions in paralyzed limbs and bladder control following CNS injury. The technique effectively creates a 'bypass' for signals and facilitates functional recovery by leveraging neural plasticity. It suggested a future of surgery, neurorehabilitation and robotic-assistants converge to improve outcomes for CNS.
Topics: Humans; Nerve Transfer; Spinal Cord Injuries; Brain Injuries, Traumatic; Peripheral Nerves; Cerebral Palsy
PubMed: 38935818
DOI: 10.1097/JS9.0000000000001267 -
PLoS Biology Jun 2024Loss of synapses between spiral ganglion neurons and inner hair cells (IHC synaptopathy) leads to an auditory neuropathy called hidden hearing loss (HHL) characterized...
Loss of synapses between spiral ganglion neurons and inner hair cells (IHC synaptopathy) leads to an auditory neuropathy called hidden hearing loss (HHL) characterized by normal auditory thresholds but reduced amplitude of sound-evoked auditory potentials. It has been proposed that synaptopathy and HHL result in poor performance in challenging hearing tasks despite a normal audiogram. However, this has only been tested in animals after exposure to noise or ototoxic drugs, which can cause deficits beyond synaptopathy. Furthermore, the impact of supernumerary synapses on auditory processing has not been evaluated. Here, we studied mice in which IHC synapse counts were increased or decreased by altering neurotrophin 3 (Ntf3) expression in IHC supporting cells. As we previously showed, postnatal Ntf3 knockdown or overexpression reduces or increases, respectively, IHC synapse density and suprathreshold amplitude of sound-evoked auditory potentials without changing cochlear thresholds. We now show that IHC synapse density does not influence the magnitude of the acoustic startle reflex or its prepulse inhibition. In contrast, gap-prepulse inhibition, a behavioral test for auditory temporal processing, is reduced or enhanced according to Ntf3 expression levels. These results indicate that IHC synaptopathy causes temporal processing deficits predicted in HHL. Furthermore, the improvement in temporal acuity achieved by increasing Ntf3 expression and synapse density suggests a therapeutic strategy for improving hearing in noise for individuals with synaptopathy of various etiologies.
Topics: Animals; Hair Cells, Auditory, Inner; Synapses; Neurotrophin 3; Mice; Auditory Threshold; Evoked Potentials, Auditory; Reflex, Startle; Auditory Perception; Spiral Ganglion; Female; Male; Hearing Loss, Hidden
PubMed: 38935589
DOI: 10.1371/journal.pbio.3002665 -
Radiologie (Heidelberg, Germany) Jun 2024Soft tissue tumors are a very heterogeneous group of tumors. Their classification is regularly updated by the World Health Organization (WHO), most recently in 2020....
Soft tissue tumors are a very heterogeneous group of tumors. Their classification is regularly updated by the World Health Organization (WHO), most recently in 2020. The current classification of soft tissue tumors emphasizes molecular biological tumor characteristics, which enable tumor-specific treatment. In addition to Ewing's sarcoma, which occurs as bone as well as extra-skeletal soft tissue tumors as a small round cell sarcoma, three other subtypes of undifferentiated, small and round cell sarcomas have been introduced. Some names of the new sarcomas can be derived from the gene mutations. The groups of adipocytic and (myo)fibroblastic tumors have been extended by three further entities. There were further additions to vascular soft tissue tumors, smooth muscle cell tumors, peripheral nerve sheath tumors and tumors of uncertain differentiation. A distinction is made between benign, intermediate locally aggressive, intermediate rarely metastatic and malignant soft tissue tumors.
PubMed: 38935287
DOI: 10.1007/s00117-024-01332-x -
Current Pain and Headache Reports Jun 2024This review aims to summarize current knowledge on the pathophysiology of pain and the role of neuro-immune crosstalk in the development of acute and chronic pain (CP).... (Review)
Review
PURPOSE OF REVIEW
This review aims to summarize current knowledge on the pathophysiology of pain and the role of neuro-immune crosstalk in the development of acute and chronic pain (CP). Specifically, the review focuses on the role of immune cells involved in the innate and acquired immune response, emphasizing their bidirectional interactions with the nervous systems and discussing the implications of this crosstalk on acute and CP management.
RECENT FINDINGS
In the last two decades, multiple studies have uncovered the important role of the immune system in initiating, maintaining, and resolving pain stimuli. Furthermore, researchers discovered that the immune system interacts tightly with the nervous system, creating a bidirectional crosstalk in which immune cells influence the response of peripheral and central nerve fibers while neurotransmitters and neuropeptides released by nociceptors directly and indirectly modulate the immune response. The neuro-immune crosstalk in acute and CP is a complex and not fully understood process that comprise the interactions of multiple diverse molecules, bidirectional interferences, and numerous redundant processes. Despite the complexity, important steps have been taken in recent years toward explaining the specific roles of each immune cell type and molecule in the initiation, maintenance and resolution of pain. These findings may set the basis for innovative therapeutic options that target the immune system, overcoming the limitations of current treatments in providing pain relief and the disadvantages associated with opioid therapy.
PubMed: 38935243
DOI: 10.1007/s11916-024-01282-y