Normal Nerve Research Articles

Quantitative Assessment of Collagen Architecture to Determine Role of Tumor Stroma During Vestibular Schwannoma Progression.

The primary objective was to characterize the abundance and architecture of collagen in the extracellular matrix in vestibular schwannoma (VS). The secondary objective was to investigate the association between collagen architecture and tumor size. Retrospective cohort study. Academic referral center. Tumor samples were obtained from patients with sporadic VS undergoing microsurgical resection. Histological analyses were performed including picrosirius red (PSR) staining under polarized light. Collagen architecture was quantified using an automated fiber detection software. Second Harmonic Generation (SHG) microscopy and immunofluorescence (IF) were utilized to characterize collagen architecture. Eleven tumor specimens were included (mean tumor diameter = 2.80 cm, range 1.5-4.0 cm), and were divided into large (mean diameter = 3.5 ± 0.4 cm) and small (mean tumor diameter = 2.0 ± 0.4 cm) cohorts based on size. The large VS cohort showed significantly higher collagen density (27.65% vs 12.73%, P = .0043), with more thick fibers (mature Type I, 24.54% vs 12.97%, P = .0022) and thin fibers (immature Type I or mature Type III, 23.55% vs 12.27%, P = .026). Tumor volume correlated with greater degree of collagen fiber disorganization (P = .0413, r2 = 0.298). Specifically, collagen type I intensity was significantly higher in large VS compared to small tumors (P < .001) and peripheral nerve (P = .028). Larger VS exhibit increased collagen abundance in the tumor stroma, and a more disorganized collagen architecture compared to smaller VS and normal peripheral nerve tissue. This finding indicates that collagen organization may play a significant role in extracellular matrix remodeling and the progression of VS.

Randomized Clinical Study of Nano-Cerium Oxide and its Efficacy in Sciatic Nerve Regeneration: A Histopathological Evaluation

Background: Peripheral nerve damage is a frequent clinical condition. peripheral nerve injuries are variable, and these injuries are mostly caused by trauma. Blunt trauma has many types, including contusion, laceration, stretching, traction, penetrating and perforating injuries, abnormal sleeping positions, external pressure, internal compression, ischemia. Cerium oxide nanoparticles are used widely in the materials field. Besides their material applications. Objective: this study was examining how cerium oxide nanoparticles impact axonal regeneration of the sciatic nerve in rats. Materials and Methods: 24 adult animals used, weighing average (M±SD: 230 ± 20 g). The animals were separated into two group. The first group (control) was left without treatment, The second group (Nano cerium Oxide) was treated orally with 50 mg of Nano cerium oxide daily for 7 days. Right Sciatic nerve was completely transected in all animals. The result evaluated at 4th, 8th and 12th weeks post-operative. Results: The histopathological results, indicated that the high effective result in the second group, then the control group. The control group has a significant nerve damage and some regenerative signs over time. While there are indications of severe damage particularly at 4 and 8 weeks, then presence of almost normal nerve fibers at 12 weeks suggests partial recovery. Conclusion: Nano Cerium Oxide accelerated the regeneration of the peripheral nerves These findings suggest that this nanoparticle could can be seen as a novel therapy for promoting the regeneration of the nervous system.

Exploring the Role of Inflammatory Genes and Immune Infiltration in Vestibular Schwannomas Pathogenesis.

Vestibular schwannomas (VSs) exhibit a range of tumor behaviors, such as growth patterns and auditory dysfunction. Recent research has offered insights into the inflammatory microenvironment in modulating tumor dynamics. This study investigates the role of inflammatory genes and immune infiltration in VS pathogenesis. We retrieved mRNA microarray data of VSs and normal nerves from the GEO database (GSE141801, GSE108524, and GSE56597), focusing on bioinformatic analysis of inflammatory response genes. Based on the evidence provided by bioinformatics analysis, we assessed the expression levels of Iba-1, IL-10, IL-10RA, and IL-18 in 31 VS patients via immunohistochemistry and delved into their association with tumor size and auditory dysfunction. We identified 1117 differentially expressed genes (DEGs) in VSs compared to normal nerves, showing an upregulation in inflammatory pathways. Intersection with inflammatory response genes (IRG) yielded 41 significant IRG-DEGs. Network analysis identified a core module of 10 IRG-DEGs and 11hub genes, most of which were inflammatory cytokines. Immune infiltration analysis showed macrophage activation and M2 polarization. These findings were validated in an independent dataset (GSE39645). To further explore the association between inflammation and tumor behaviors, immunohistochemistry analysis was conducted on VS samples and the results exhibited notable associations between the macrophage marker (Iba1) and inflammatory cytokines (IL-10, IL-10RA, and IL-18) with both tumor size and auditory dysfunction. In particular, the multiple regression analysis of inflammatory cytokines demonstrated that IL-10 and IL-10RA were statistically significant predictors of tumor size, while IL-18 was associated with hearing loss. Our study underscores the role of inflammation in VS pathogenesis, showing that macrophage activation with M2 polarization and the expression of inflammatory cytokines, especially IL-10/IL-10RA and IL-18, are linked to tumor size and auditory function. This study highlights the inflammatory landscape's impact on VS behaviors, providing a basis for targeted therapeutic strategies.

Spatial lipidomics reveals myelin defects and pro-tumor macrophage infiltration in MPNST adjacent nerves

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas arising from peripheral nerves, accounting for 3-5% of soft tissue sarcomas. MPNSTs often recur locally, leading to poor survival. Achieving tumor-free surgical margins is essential to prevent recurrence, but current methods for determining tumor margins are limited, highlighting the need for improved biomarkers. In this study we investigated the degree to which MPNST extends into nerves adjacent to tumors. Alterations to the lipidome of MPNST and adjacent peripheral nerves were assessed using spatial lipidomics. Tissue samples from 5 MPNST patients were analyzed, revealing alterations of the lipid profile extending into the peripheral nerves beyond what was expected based on macroscopic and histological observations. Integration of spatial lipidomics and high-resolution accurate mass profiling identified distinct lipid profiles associated with healthy nerves, connective tissue, and tumors. Notably, histologically normal nerves exhibited myelin degradation and infiltration of pro-tumoral M2 macrophages, particularly near the tumor. Furthermore, aberrant osmium staining patterns and loss of H3K27me3 staining in absence of atypia were observed in a case with tumor recurrence. This exploratory study thereby highlights the changes occurring in the nerves affected by MPNST beyond what is visible on H&E, and provides leads for further biomarker studies, including aberrant osmium staining, to assess resection margins in MPNST

A neuromuscular clinician's guide to magnetic resonance neurography.

Magnetic resonance neurography (MRN) is increasingly used in clinical practice for the evaluation of patients with a wide spectrum of peripheral nerve disorders. This review article discusses the technical aspects of MRN highlighting the core sequences performed for clinical care. A robust, high-resolution, heavily T2-weighted fluid-sensitive sequence performed on a 3.0 Tesla magnet system remains the main workhorse MRN sequence. In specific clinical scenarios, adjunct techniques such as diffusion-weighted imaging can be added to a protocol for disease characterization. In addition, gadolinium-based contrast material can also be administered for the purposes of image optimization (suppress adjacent vascular signal) and disease characterization. Technical modifications to field of view and planes of imaging can be made based on the clinical question and discussion with the radiologist(s). On fluid-sensitive MRN sequences, a normal peripheral nerve exhibits iso- to minimally hyperintense signal relative to skeletal muscle with a predictable trajectory, preserved "fascicular" architecture, and tapered caliber from proximal to distal. Peripheral nerve abnormalities on MRN include alterations in signal, caliber, architecture, diffusion characteristics as well as enhancement and provide information regarding the underlying etiology. Although some MRN findings including nerve hyperintensity and long-segmental enlargement are nonspecific, there are certain diagnoses that can be made with high certainty based on imaging including benign peripheral nerve tumors, high-grade peripheral nerve injury, and intraneural ganglia. The purpose of this article is to familiarize a neuromuscular clinician with fundamentals of MRN acquisition and interpretation to facilitate communication with the neuromuscular radiologist and optimize patient care.

Chronic Immune Sensory Polyradiculopathy (CISP): A Systematic Review of the Literature

Chronic immune sensory polyradiculopathy (CISP) is a rare inflammatory immune disorder affecting the nervous system, primarily targeting the proximal sensory nerve roots. The condition was first described by Sinreich in 2004. We conducted a systematic review of CISP cases published on PubMed to identify common clinical presentations, along with neurophysiological, radiological, cerebrospinal fluid (CSF), and other findings. Our review included a total of 22 patients from 8 articles. Many patients presented with gait difficulties and sensory ataxia and were found to have normal nerve conduction studies (NCS) and electromyography (EMG) but exhibited characteristic abnormalities in somatosensory evoked potentials (SSEP), elevated CSF protein levels, thickened nerve roots on contrast-enhanced lumbar spine MRIs, and histological changes on nerve root biopsies. Clinical improvement was observed following treatment with steroids and/or intravenous immunoglobulin (IVIG). The study concluded that while CISP is rare, it is an important clinical entity to consider, as accurate diagnosis and appropriate treatment can lead to significant improvements in neurological symptoms and disabilities.

Role of Ultrasonography in the Evaluation of Peripheral Nerve Pathologies: A Study of 200 Cases.

The aim of this study is to ascertain the role of ultrasonography in appraising the structural intricacies of peripheral nerve pathologies. (1) To scrutinize the anatomy of both normal and abnormal peripheral nerves. (2) Assess different parameters like continuity of the nerve, echotexture, vascularity, cross-sectional area, and thickness of the nerve in various pathologies. In a prospective observational study conducted at the Department of Radio Diagnosis, Tertiary Care Centre, the study design focused on the examination of 200 cases utilizing a high-resolution 9-14 Mhz and 17 Mhz linear array transducer, integrated into the Aplio 400 Canon Ultrasound System. Among the total cases, 62 were identified as traumatic neuropathy cases, 52 as entrapment neuropathy cases, 14 as infective neuropathy cases, 54 as thermal neuropathy cases, 14 as metabolic neuropathy cases, and 4 as nerve-tumor cases. In conclusion, this investigation illuminates the dynamic role of ultrasonography as an invaluable diagnostic instrument in appraising peripheral nerve pathologies. The noninvasive attributes, widespread availability, and economic viability of ultrasonography render it a pragmatic choice for clinicians. This inquiry buttresses the escalating significance of ultrasonography within neurology, emphasizing its potential to revolutionize the terrain of peripheral nerve pathology assessment.

Advancements and mechanisms of stem cell-based therapies for spinal cord injury in animals.

Spinal cord injury (SCI) is a neurodegenerative disorder of the central nervous system (CNS) that can lead to permanent loss of sensation and voluntary movement beyond the affected area. Extensive preclinical and clinical trials have been conducted to evaluate the safety and effectiveness of stem cells for the treatment of various CNS diseases or disorders, including SCI. However, several challenges hinder nerve cell regeneration in the injured spinal cord, such as extensive cell loss, limited neural cell regeneration capacity, axonal disruption, and the presence of growth-inhibiting molecules, particularly astroglial scarring or glial scars at the injury site in chronic cases. These obstacles pose significant challenges for physicians in restoring normal motor and sensory nerve function in both humans and animals following SCI. This review focuses on SCI pathogenesis, the mechanisms underlying the therapeutic potential of Mesenchymal Stem Cells (MSCs) in SCI, and the potential of stem cell-based therapies as promising avenues for treatment. This review article also included relevant preclinical and clinical data from animal studies.

A revised electrodiagnosis-based severity classification for carpal tunnel syndrome

BACKGROUND: An electrodiagnostic evaluation is conducted to diagnose carpal tunnel syndrome (CTS) and evaluate its severity. OBJECTIVE: This study proposes a revised approach for classifying the severity of electrophysiological findings for patients with CTS. METHODS: This retrospective cross-sectional study included patients with CTS confirmed through electrodiagnostic evaluations. Based on the Stevens’ classification, the patients were divided into three groups (mild/moderate/severe). A new intermediate group was defined to identify patients with normal motor nerve conduction studies and abnormal electromyographic results. CTS pain was evaluated using a numeric rate scale. Physical examinations and sonographic evaluation were performed to detect anatomical abnormalities. RESULTS: Overall, 1,069 CTS hands of 850 CTS patients were included. The mean age was 57.9 ± 10.8 years, and 336 (39.5%) were men. There were 522 (48.8%) mild cases; 281 (26.3%) moderate cases; and 266 (24.9%) severe cases. In the severe group, 49 cases were reclassified into the intermediate group. The median cross-sectional area in the intermediate group significantly differed from that in the severe group. However, the pain score significantly differed from that of the moderate group. CONCLUSION: The intermediate CTS group showed clinical features that were intermediate to those of the moderate and severe CTS groups.

New phenotyping questionnaire for diagnosing sarcoidosis-associated small fiber neuropathy.

Small fiber neuropathy is a common complication in patients with sarcoidosis and its prevalence is estimated at 40-86%. The underlying mechanism influences the presentation of small fiber neuropathy. For example, patients with metabolic diseases are often associated with a classic length-dependent small fiber neuropathy pattern, while patients with inflammatory diseases are more often present with a non-length-dependent small fiber neuropathy. Detailed phenotyping may be useful to improve diagnostic efficiency, as a clue to underlying mechanisms and as a precondition for personalized medicine. This study examined four phenotypes distinguishing between length-dependent and non-length-dependent presentation with a new subdivision for continuous and intermittent presentation. Forty-eight sarcoid patients with symptoms and at least two clinical signs of small fiber neuropathy and normal nerve conduction studies were classified as having probable small fiber neuropathy. A new small fiber neuropathy phenotyping questionnaire has been developed that allows patients to mark the anatomical locations of pain at three different levels: the skin, muscles, and joints. The location of symptoms was used to define length dependence, and two colors were used to distinguish continuous (red) from intermittent (blue) symptoms. In addition, skin biopsy, corneal confocal microscopy, Sudoscan and water immersion skin wrinkling were used to investigate a correlation between the four phenotypes, sensory function, nerve fiber density, and autonomic nerve function. Overall, 35% of patients with probable small fiber neuropathy showed length-dependent symptoms and 44% showed non-length-dependent symptoms while 21% suffered from non-neuropathic musculoskeletal pain. The distinction between intermittent and continuous symptoms showed significantly less continuous than intermittent non-length-dependent symptoms (odds ratio = 0.3, P = 0.01). Moreover, continuous length-dependent symptoms were the only phenotype that correlated with thermal threshold testing (R = 0.3; P = 0.02) and the small fiber neuropathy screening list (R = 0.3; P = 0.03). In addition, thermal threshold testing (TTT) also correlated with the small fiber neuropathy (SFN) screening list (R = 0.3; P = 0.03). Other diagnostic methods showed no correlation with any of the four defined phenotypes. A novel finding is that TTT is only associated with continuous length-dependent pain, suggesting that TTT could result in more false negatives in patients with other pain phenotypes. Determining the pathophysiologic mechanisms could help develop new diagnostic methods. If patients suspected of SFN show symptoms without a length-dependent continuous presentation, the diagnosis should focus less on the diagnostic methods used.

Diaphragmatic Myopathy Associated with Dual Immune Checkpoint Inhibitors in a Patient with Renal Cell Carcinoma

ABSTRACT Immune-related adverse events (irAEs) have become increasingly prevalent with immune checkpoint inhibitor (ICI) cancer treatment. We present a 79-year-old man with metastatic renal cell carcinoma who developed shortness of breath and hypercapnic respiratory insufficiency after his first cycle of nivolumab and ipilimumab. Laboratory data showed elevated creatinine kinase, troponins, and transaminases. Computed tomography of the chest demonstrated bilateral lower lobe atelectasis. Heart catheterization and endomyocardial biopsy were unremarkable. Electromyogram (EMG) and nerve conduction studies (NCS) of the limb muscles revealed mild diffuse myopathy, normal sensory nerve conductions, and low-amplitude motor responses. Subsequent diaphragmatic EMG and NCS demonstrated severe myopathy. ICI-mediated myopathy predominantly affecting diaphragmatic muscles was diagnosed. Treatment included intravenous methylprednisolone, infliximab, abatacept, rituximab, and plasmapheresis. He underwent tracheostomy placement on hospital day 11 due to minimal improvement. He was discharged to a long-term acute care hospital, but unfortunately, he died less than 1 month later due to recurrent infections. irAEs can affect any organ system, but diaphragmatic dysfunction is uncommon. Use of diaphragmatic EMG, NCS, ultrasound study, or biopsy can support the diagnosis. Treatment includes systemic steroids, plasmapheresis, immunosuppressive medications, respiratory support, and cessation of causative medications. ICI-related diaphragmatic dysfunction should be suspected in those patients at risk with hypoxia, hypercapnia, or prolonged invasive or noninvasive ventilation without a distinct etiology. This case report exemplifies the importance of multidisciplinary workup and management of respiratory symptoms and insufficiency to identify and ameliorate irAEs. Diaphragmatic involvement can be associated with significant morbidity and mortality despite early aggressive multimodal therapy.

Comparison of Glaucoma Diagnosis by Telemedicine, In-Person Ophthalmologist, and Optometrist.

Diagnosis of glaucoma through telemedicine demonstrates moderate agreement with in-person ophthalmologist (MD) and in-person optometrist (OD) diagnosis, providing evidence that telemedicine is a timely, accurate screening method in settings where an in-person visit may not be feasible. To compare diagnostic agreement of glaucoma between in-person MD, in-person OD, and a simulated telemedicine program. A cross-sectional study of patients with normal optic nerve structural and functional imaging and new patients referred for glaucoma evaluation examined in-person by an MD for glaucoma with a dilated examination and structural and functional optic nerve testing (optical coherence tomography, photos, and visual field); examined in person by an OD with a dilated examination and optic nerve testing; and structural and functional optic nerve testing reviewed separately by 2 ophthalmologists [telemedicine ophthalmologist reviewer 1 (TMD1), telemedicine ophthalmologist reviewer 2 (TMD2)] with masking of prior MD and OD diagnoses. Interrater agreement between each diagnostic method (MD, OD, TMD1, and TMD2) of normal versus disease (open angle glaucoma, normal tension glaucoma, other types of glaucoma, other optic nerve disorders, ocular hypertension, and glaucoma suspect) for each eye was calculated (Cohen unweighted kappa). A total of 100 patients with a median age of 66 years (interquartile range: 59-72), male (40%) and white (62%) were analyzed. There was moderate agreement between MD and telemedicine [TMD1 kappa 0.49 (95% CI: 0.37-0.61), TMD2 kappa 0.44 (95% CI: 0.32-0.56)] and between MD and OD diagnosis [0.41 (95% CI: 0.28-0.54)] and fair-moderate agreement between OD and telemedicine [TMD1: 0.46 (95% CI: 0.34-0.58), TMD2: 0.61 (95% CI: 0.50-0.72)]. The simulated telemedicine approach had comparable levels of agreement in glaucoma diagnosis with in-person fellowship-trained ophthalmologists, presenting a crucial complementary role in screening and increasing access to care, particularly in rural or underserved settings.

Facial Nerve Preserving Subtotal Excision for Large Vestibular Schwannoma: An Institution-Based Functional Outcome Study.

The ideal goal of treatment for medium to large vestibular schwannoma is complete tumor removal with preservation of all cranial nerves. However, despite the advancements in microsurgery and intraoperative monitoring, the risk of facial nerve dysfunction following total resection varies between 31% and 57%. Currently, the goal of treatment for large tumors is shifting from total excision to facial nerve preservation. To evaluate the facial nerve outcome in patients who underwent subtotal excision with or without subsequent gamma knife radiosurgery for large vestibular schwannomas in our institute. All patients who underwent primary surgery for large vestibular schwannomas between January 2012 and December 2016 were analyzed retrospectively. Cases where total excision was not done and a residue was left behind to prevent facial nerve injury during surgery were included in the study. A total of 52 patients who met the inclusion criteria were analyzed. At final follow-up, 70% of patients had good facial nerve function (H-B grade 1 and 2). In patients with normal facial nerve function preoperatively, 81% (25/31) of them had good facial nerve outcomes (H-B grade 1 and 2), whereas in patients with preexisting facial nerve deficits, nearly 62% (13/21) of them either maintained or had improvement in their facial nerve grades. Good facial nerve outcomes and tumor control rate is obtained by subtotal excision of VS followed by upfront or delayed GKRS; however, there is a need for long-term follow-up to detect recurrences in these slow-growing tumors.

Normal Sonographic Peripheral Nerve Cross-Sectional Area Based on the Results of Meta-Analysis Studies

Normal Sonographic Peripheral Nerve Cross-Sectional Area Based on the Results of Meta-Analysis Studies

Development of a major histocompatibility complex class II conditional knockout mouse to study cell-specific and time-dependent adaptive immune responses in peripheral nerves.

The precise relationship between molecular mimicry and tissue-specific autoimmunity is unknown. Major histocompatibility complex (MHC) class II antigen presenting cell-CD4+ T-cell receptor complex interactions are necessary for adaptive immunity. This study aimed to determine the role of endoneurial endothelial cell MHC class II in autoimmune polyneuropathy. Cryopreserved Guillain-Barré syndrome (GBS) patient sural nerve biopsies and sciatic nerves from the severe murine experimental autoimmune neuritis (sm-EAN) GBS model were studied. Cultured conditional ready MHC Class II antigen A-alpha chain (H2-Aa) embryonic stem cells were used to generate H2-Aaflox/+ C57BL/6 mice. Mice were backcrossed and intercrossed to the SJL background to generate H2-Aaflox/flox SJL mice, bred with hemizygous Tamoxifen-inducible von Willebrand factor Cre recombinase (vWF-iCre/+) SJL mice to generate H2-Aaflox/flox; vWF-iCre/+ mice to study microvascular endothelial cell adaptive immune responses. Sm-EAN was induced in Tamoxifen-treated H2-Aaflox/flox; vWF-iCre/+, H2-Aaflox/flox; +/+, H2-Aa+/+; vWF-iCre/+ and untreated H2-Aaflox/flox; vWF-iCre/+ adult female SJL mice. Neurobehavioral, electrophysiological and histopathological assessments were performed at predefined time points. Endoneurial endothelial cell MHC class II expression was observed in normal and inflamed human and mouse peripheral nerves. Tamoxifen-treated H2-Aaflox/flox; vWF-iCre/+ mice were resistant to sm-EAN despite extensive MHC class II expression in lymphoid and non-lymphoid tissues. A conditional MHC class II knockout mouse to study cell- and time-dependent adaptive immune responses in vivo was developed. Initial studies show microvascular endothelial cell MHC class II expression is necessary for peripheral nerve specific autoimmunity, as advocated by human in vitro adaptive immunity and ex vivo transplant rejection studies.

New Heterostilbene and Triazole Oximes as Potential CNS-Active and Cholinesterase-Targeted Therapeutics.

New furan, thiophene, and triazole oximes were synthesized through several-step reaction paths to investigate their potential for the development of central nervous systems (CNS)-active and cholinesterase-targeted therapeutics in organophosphorus compound (OP) poisonings. Treating patients with acute OP poisoning is still a challenge despite the development of a large number of oxime compounds that should have the capacity to reactivate acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The activity of these two enzymes, crucial for neurotransmission, is blocked by OP, which has the consequence of disturbing normal cholinergic nerve signal transduction in the peripheral and CNS, leading to a cholinergic crisis. The oximes in use have one or two pyridinium rings and cross the brain-blood barrier poorly due to the quaternary nitrogen. Following our recent study on 2-thienostilbene oximes, in this paper, we described the synthesis of 63 heterostilbene derivatives, of which 26 oximes were tested as inhibitors and reactivators of AChE and BChE inhibited by OP nerve agents-sarin and cyclosarin. While the majority of oximes were potent inhibitors of both enzymes in the micromolar range, we identified several oximes as BChE or AChE selective inhibitors with the potential for drug development. Furthermore, the oximes were poor reactivators of AChE; four heterocyclic derivatives reactivated cyclosarin-inhibited BChE up to 70%, and cis,trans-5 [2-((Z)-2-(5-((E)-(hydroxyimino)methyl)thiophen-2-yl)vinyl)benzonitrile] had a reactivation efficacy comparable to the standard oxime HI-6. In silico analysis and molecular docking studies, including molecular dynamics simulation, connected kinetic data to the structural features of these oximes and confirmed their productive interactions with the active site of cyclosarin-inhibited BChE. Based on inhibition and reactivation and their ADMET properties regarding lipophilicity, CNS activity, and hepatotoxicity, these compounds could be considered for further development of CNS-active reactivators in OP poisoning as well as cholinesterase-targeted therapeutics in neurodegenerative diseases such as Alzheimer's and Parkinson's.

Evaluation of suitability and biodegradability of the organophosphate insecticides to mitigate insecticide pollution in onion farming

Organophosphates constitute a major class of pesticides widely employed in agriculture to manage insect pests. Their toxicity is attributed to their ability to inhibit the functioning of acetylcholinesterase (AChE), an essential enzyme for normal nerve transmission. Organophosphates, especially chlorpyrifos, have been a key component of the integrated pest management (IPM) in onions, effectively controlling onion maggot Delia antiqua, a severe pest of onions. However, the growing concerns over the use of this insecticide on human health and the environment compelled the need for an alternative organophosphate and a potential microbial agent for bioremediation to mitigate organophosphate pesticide pollution. In the present study, chloropyrifos along with five other organophosphate insecticides, phosmet, primiphos-methyl, isofenphos, iodofenphos and tribuphos, were screened against the target protein AChE of D. antiqua using molecular modeling and docking techniques. The results revealed that iodofenphos showed the best interaction, while tribuphos had the lowest interaction with the AChE based on comparative binding energy values. Further, protein-protein interaction analysis conducted using the STRING database and Cytoscap software revealed that AChE is linked with a network of 10 different proteins, suggesting that the function of AChE is disrupted through interaction with insecticides, potentially leading to disruption within the network of associated proteins. Additionally, an in silico study was conducted to predict the binding efficiency of two organophosphate degrading enzymes, organophosphohydrolase (OpdA) from Agrobacterium radiobacter and Trichoderma harzianum paraoxonase 1 like (ThPON1-like) protein from Trichoderma harzianum, with the selected insecticides. The analysis revealed their potential to degrade the pesticides, offering a promising alternative before going for cumbersome onsite remediation.

Dose-Painting Proton Radiotherapy Guided by Functional MRI in Non-enhancing High-Grade Gliomas

AimsThis study aimed to demonstrate the feasibility and evaluate the dosimetric effect and clinical impact of dose-painting proton radiotherapy (PRT) guided by functional MRI in non-enhancing high-grade gliomas (NE-HGGs). Materials and methodsThe 3D-ASL and T2 FLAIR MR images of ten patients with NE-HGGs before radiotherapy were studied retrospectively. The hyperintensity on T2 FLAIR was used to generate the planning target volume (PTV), and the high-perfusion volume on 3D-ASL (PTV-ASL) was used to generate the simultaneous integrated boost (SIB) volume. Each patient received pencil beam scanning PRT and photon intensity-modulated radiotherapy (IMRT). There were five plans in each modality: (1) Uniform plans (IMRT60 vs. PRT60): 60Gy in 30 fractions to the PTV. (2)–(5) SIB plans (IMRT72, 84, 96, 108 vs. PRT72, 84, 96, 108): Uniform plan plus additional dose boost to PTV-ASL in 30 fractions to 72, 84, 96, 108 Gy. The dosimetric differences between various plans were compared. The clinical effects of target volume and organs at risk (OARs) were assessed using biological models for both tumor control probability (TCP) and normal tissue complication probability (NTCP). ResultsCompared with the IMRT plan, the D2 and D50 of the PRT plans with the same prescription dose increased by 1.27–4.12% and 0.64–2.01%, respectively; the R30 decreased by > 32%; the dose of brainstem and chiasma decreased by > 27% and >32%; and the dose of normal brain tissue (Br-PTV), optic nerves, eyeballs, lens, cochlea, spinal cord, and hippocampus decreased by > 50% (P < 0.05). The maximum necessary dose was 96GyE to achieve >98% TCP for PRT, and it was 84Gy to achieve >91% TCP for IMRT. The average NTCP of Br-PTV was 1.30% and 1.90% for PRT and IMRT at the maximum dose escalation, respectively. The NTCP values of the remaining OARs approached zero in all PRT plans. ConclusionThe functional MRI-guided dose escalation using PRT is feasible while sparing the OARs constraints and demonstrates a potential clinical benefit by improving TCP with no or minimal increase in NCTP for tissues outside the PTV. This retrospective study suggested that the use of PRT-based SIB guided by functional MRI may represent a strategy to provide benefits for patients with NE-HGGs.

A Novel &lt;i&gt;NDUFV2&lt;/i&gt; Variant in an Asymptomatic Adolescent Girl with Progressive Cavitating Leukoencephalopathy

&lt;b&gt;&lt;i&gt;Introduction:&lt;/i&gt;&lt;/b&gt; Pathogenic variants in several genes encoding components of the mitochondrial respiratory chain have been linked to various clinical phenotypes such as progressive cavitating leukoencephalopathy (PCL). The association between PCL, previously linked to numerous gene mutations in the literature, and the &lt;i&gt;NDUFV2&lt;/i&gt; gene mutations has emerged as a recent and noteworthy discovery. PCL is generally diagnosed in symptomatic patients during the early years of life, mostly in infancy. &lt;b&gt;&lt;i&gt;Case Presentation:&lt;/i&gt;&lt;/b&gt; In a previously healthy 12-year-old Turkish girl, a computed tomography scan taken for minor head trauma incidentally revealed suspicious hypodense areas in the periventricular white matter. Subsequently, a magnetic resonance imaging evaluation was performed. There was no history of motor regression, irritability, or seizures up to the age of 12. The case exhibited normal neurological and cranial nerve examinations. Magnetic resonance imaging detected bilateral periventricular T2/FLAIR hyperintensities with cystic areas suggestive of PCL. Whole-exome sequencing revealed the presence of a homozygous p.R222C missense variant in the &lt;i&gt;NDUFV2&lt;/i&gt; gene. Over a 6-year follow-up period, the patient remained asymptomatic, and there were no discernible changes in the magnetic resonance imaging findings. &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; This case underscores the association between a potentially causal variant at the &lt;i&gt;NDUFV2&lt;/i&gt; locus and PCL. It is worth noting that this novel variation in PCL can not only manifest with symptoms in the infantile period but also remain asymptomatic into adolescence.

SoxB family genes delay regeneration and cause abnormal movement in Dugesia japonica.

SoxB subfamily is an important branch of Sox family and plays a key role in animal physiological process, but little is known about their function in planarian regeneration. This study aims to evaluate the function of DjSoxB family genes in intact and regenerating planarians Dugesia japonica. Here, we amplify the full-length cDNA of DjSoxB1 and DjSoxB2 in D. japonica by rapid amplification of the cDNA ends (RACE), detect the expression of DjSoxB family genes in planarian. The results show that DjSoxBs are expressed in parenchymal tissue and the hybridization signals partially disappear after irradiation indicates DjSoxB family genes are expressed in neoblasts. After the RNA interference (RNAi) of DjSoxB1, DjSoxB2 and DjSoxB3 separately, the numbers of proliferative cells are all reduced that causes planarians show slower growth of blastema in the early stage of regeneration, and nerves of planarians are affected that the movement speed of planarians decreases in varying degrees. Specially, planarians in the DjSoxB3 RNAi group show shrinkage and twisting. Overall, this study reveals that DjSoxB family genes play a role in cell proliferation during regeneration. They also play an important role in the maintenance of normal nerve function and nerve regeneration. These results provide directions for the functional study of SoxB family genes and provide an important foundation for planarian regeneration.