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The most common mutation in southern Chinese individuals with late-onset multiple acyl-coenzyme A dehydrogenase deficiency (MADD; a fatty acid metabolism disorder) is c.250G > A (p.Ala84Thr) in the electron transfer flavoprotein dehydrogenase gene (ETFDH). Various phenotypes, including episodic weakness or rhabdomyolysis, exercise intolerance, and peripheral neuropathy, have been reported in both muscular and neuronal contexts. Our cellular models of MADD exhibit neurite growth defects and excessive apoptosis. Given that axonal degeneration and neuronal apoptosis may be regulated by B-cell lymphoma (BCL)-2 family proteins and mitochondrial outer membrane permeabilization through the activation of proapoptotic molecules, we measured the expression levels of proapoptotic BCL-2 family proteins (e.g., BCL-2-associated X protein and p53-upregulated modulator of apoptosis), cytochrome c, caspase-3, and caspase-9 in NSC-34 cells carrying the most common ETFDH mutation. The levels of these proteins were higher in the mutant cells than in the wide-type cells. Subsequent treatment of the mutant cells with coenzyme Q10 downregulated activated protein expression and mitigated neurite growth defects. These results suggest that the activation of the BCL-2/mitochondrial outer membrane permeabilization/apoptosis pathway promotes apoptosis in cellular models of MADD and that coenzyme Q10 can reverse this effect. Our findings aid the development of novel therapeutic strategies for reducing axonal degeneration and neuronal apoptosis in MADD., (© 2024. The Author(s).)

Research has shown that obesity is a low-grade inflammatory disease that is often associated with comorbidities, such as diabetes and chronic pain. Recent data have indicated that chemokines may play a role in these conditions due to their pronociceptive and chemotactic properties, which promote hypersensitivity and inflammation. Accumulating evidence suggests that CCR2, CCR5, and their ligands (CCL2, CCL3, CCL4, CCL5, CCL7, CCL8, CCL11 CCL12, and/or CCL13) play a role in rodent models of pain and obesity, as well as in patients with diabetes and obesity. It was proven that the blockade of CCR2 and CCR5, including the simultaneous blockade of both receptors by dual antagonists, effectively reduces hypersensitivity to thermal and mechanical stimuli in chronic pain states, including diabetic neuropathy. The present review discusses these chemokine receptors and the role of their ligands in diabetes and obesity, as well as their involvement in diabetic neuropathy and obesity-induced hypersensitivity.

This report describes five cases of urinary incontinence in Quarter Horse mares associated with the development of sabulous cystitis. The animals in this study had a history of persistent urinary incontinence for eight months, with clinical signs of continuous dribbling urine during rest and movement. The initial treatment with antibiotics and anti-inflammatory drugs was ineffective. Clinical examination revealed severe scalding in the perineal region and on the medial aspect of the hind limbs, along with neurological signs such as ataxia, hind limb paresis, and diminished perineal reflexes. Transrectal ultrasonography confirmed bladder distension and the presence of hyperechoic particles in the urine. Urinalysis revealed typical features of sabulous cystitis, including abundant calcium carbonate crystals. Despite treatment with corticosteroids, antibiotics, and daily bladder lavage with physiological saline, no substantial clinical improvement was observed. The limited therapeutic response and guarded prognosis were discussed with the owner, who opted to monitor the mares without altering their clinical condition for two years. This report highlights the complexity of managing urinary incontinence associated with sabulous cystitis in horses and emphasizes the importance of accurate diagnosis and early recognition of clinical signs for effective treatment., Competing Interests: Conflict of interests: The authors have no conflict of interest to declare.

Aims: Diabetic patients are at elevated risk of neuropathy; early detection is desirable to minimise the risk of complications. The Medipin pin-prick device was appraised as a screening tool for diabetic neuropathy., Methods: Prospective cross-sectional comparative screening study in primary care setting, involving 389 participants with type 2 diabetes mellitus. The Medipin pin-prick method, involving dorsal application on the hallux of both feet, was compared to 10 g monofilament testing., Results: The ternary and semi-quantitative approach for scoring Medipin pin-prick sensation give very similar results (Spearman rho 0.67, P < 0.001). A total of 59 % patients had no signs of neuropathy (sharp sensation), 38 % reported impaired sensation (dull sensation), and an absence of sensation occurred in 3 % of patients. For the monofilament dorsal method, the figures were 79 % no neuropathy, 14 % elevated risk, and 7 % neuropathy respectively, and with the monofilament plantar method 87 % of patients had no neuropathy and 13 % did. Correlation analyses showed that taller patients and those with existing neuropathic pain are at very modest increased risk of neuropathy., Conclusions: The Medipin pin-prick device can identify diabetic neuropathy and detects (first signs of) neuropathy in relatively more patients than 10 g monofilament testing. The differential targeting of nerve types, namely predominant small (Medipin) versus large (monofilament) fibre, likely underpins the difference in outcomes., Competing Interests: Declaration of Competing Interest None to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Purpose: Critical illness polyneuropathy (CIP) has been linked to neurocardiac dysfunction mediated by autonomic nervous system dysregulation, which increases mortality. We aimed to assess if heart rate variability (HRV) biofeedback could improve neurocardiac function in CIP., Methods: We randomly allocated (1:1) patients with electrophysiologically confirmed CIP undergoing early inpatient neurological rehabilitation to additional HRV or sham biofeedback over 14 days. We evaluated neurocardiac function via standard deviation of normal-to-normal intervals (SDNN) as the primary outcome, as well as HRV frequency domains, sympathetic cutaneous sudomotor and vasomotor functions and disability at baseline, post intervention and 4 weeks later. The study is registered on the German Clinical Trials Register (DRKS00028911)., Results: We included 30 patients with CIP (40% females, median [interquartile range] age 64.6 [56, 72] years). We observed an increase in SDNN and the predominantly parasympathetic high frequency domain post intervention (ß = 16.4, 95% confidence interval [CI] 0.2, 32.6 [p = 0.047] and ß = 1179.2, 95% CI 119.9, 2158.5 [p = 0.018]), which was sustained at the 4-week follow-up (ß = 25.7, 95% CI 6.0, 45.4 [p = 0.011] and ß = 25.7, 95% CI 6.0, 45.4 [p = 0.011]). Patients who underwent HRV biofeedback displayed a higher adjusted Barthel index, indicating less severe disability 4 weeks after the intervention compared to those in the sham group (ß = 23.3, 95% CI 5.5, 41.1 [p = 0.014]). Low frequency and sympathetic skin functions did not differ between groups (p = nonsignificant)., Conclusions: Our study provides pilot data suggesting that, in patients with CIP, HRV biofeedback can improve neurocardiac function with a predominant effect on the parasympathetic nervous system and has a beneficial effect on functional recovery., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Purpose: Cardiovascular autonomic neuropathy (CAN) is a common diabetic complication associated with excess morbidity and mortality. CAN is also seen in conditions such as Parkinson's disease. Normative reference data for cardiovascular autonomic function are used to stratify individuals into those with and without CAN. However, reference thresholds for both cardiovascular autonomic reflex tests (CARTs) and heart rate variability (HRV) are scarce and based on small sample sizes. The aim of the study was to establish contemporary normative reference thresholds based on a large non-diabetic population free of cardiovascular disease (CVD)., Methods: Cardiovascular autonomic function, CARTs and 5-min HRV indices were assessed in individuals without diabetes and CVD from the Lolland-Falster Health Study (2018-2020) by applying the point-of-care device Vagus™. Age-specific normative reference thresholds were estimated by using log-transformed quantile regression models at the 5th and 10th percentile, with adjustments made for sex. Models assessing the association between age and HRV indices were further adjusted for heart rate., Results: We present age-specific normative reference thresholds for cardiovascular autonomic function, including CARTs and HRV, for 875 individuals (48% females) aged 15-85 years. The reference thresholds are presented for both the 5th and 10th lower percentile. Higher age was inversely associated with all outcomes. Females tended to have a higher parasympathetic drive compared to males. Pre-test conditions did not affect CARTs significantly., Conclusions: The presented age-related normative reference thresholds for both CARTs and HRV indices based on a large Danish cohort may facilitate improved quality of research and treatment., (© 2024. The Author(s).)

Inherited peripheral neuropathies (IPNs) encompass a clinically and genetically heterogeneous group of disorders causing length-dependent degeneration of peripheral autonomic, motor and/or sensory nerves. Despite gold-standard diagnostic testing for pathogenic variants in over 100 known associated genes, many patients with IPN remain genetically unsolved. Providing patients with a diagnosis is critical for reducing their 'diagnostic odyssey', improving clinical care, and for informed genetic counselling. The last decade of massively parallel sequencing technologies has seen a rapid increase in the number of newly described IPN-associated gene variants contributing to IPN pathogenesis. However, the scarcity of additional families and functional data supporting variants in potential novel genes is prolonging patient diagnostic uncertainty and contributing to the missing heritability of IPNs. We review the last decade of IPN disease gene discovery to highlight novel genes, structural variation and short tandem repeat expansions contributing to IPN pathogenesis. From the lessons learnt, we provide our vision for IPN research as we anticipate the future, providing examples of emerging technologies, resources and tools that we propose that will expedite the genetic diagnosis of unsolved IPN families., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Toll-like receptor 4 (TLR4) and the transient receptor potential vanilloid subtype 1 (TRPV1) are both upregulated and play key roles in the induction and expression of paclitaxel-related chemotherapy-induced peripheral neuropathy (CIPN). Using Apolipoprotein A-I binding protein, non-specific cholesterol depletion, TLR4 mis-sense rats and a TLR4 inhibitor, we demonstrate that co-localization of TRPV1 with TLR4 to cholesterol-rich lipid membrane rafts in nociceptors is essential for its normal activation as well as for its exaggerated activation that underlies the development and expression of CIPN. The findings suggest that TLR4-lipid rafts may have an essential role in numerous neuroinflammatory and neuropathic pain conditions. This mechanism is also generalized to female rats for the first time., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This article presents a unique diagnostic test for the neurogenic thoracic outlet syndrome (nTOS). nTOS is one of the most misdiagnosed and controversial medical problems; the diagnosis is clinical, and there are few specific diagnostic criteria for this condition. We would like to share this unique diagnostic modality, the Tafler test, with medical professionals. The Tafler test helps diagnose nTOS, differentiate it from cervical radiculopathy and carpal tunnel syndrome, and effectively tailor treatment for its symptoms. The following case series aims to describe several patients with nTOS who had failed previous treatment with surgery, physical therapy, and analgesics. The implementation of the Tafler test as a treatment modality in combination with osteopathic manipulative treatment (OMT) and physical therapeutic modalities led to significant improvements in treatment efficiency., Competing Interests: Human subjects: All authors have confirmed that this study did not involve human participants or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Tafler et al.)

Prolonged squatting is a well-documented cause of common peroneal neuropathy, wherein the common peroneal nerve is thought to be compressed between the biceps femoris tendon and the lateral head of the gastrocnemius muscle or the fibular head. However, deep peroneal neuropathy resulting from prolonged squatting has not been previously reported. We present the case of a tile installer who developed unilateral deep peroneal neuropathy following extended squatting, diagnosed through ultrasonography, which identified the bilateral division of the common peroneal nerves between the knee joint and the fibular head. This case underscores the value of ultrasonography, particularly when electrodiagnostic results are inconsistent with clinical expectations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Jo, Kim, Song, Park, Choi and Han.)

We report a case of SYNE1 -associated autosomal recessive spinocerebellar ataxia (SCAR8) presenting with a complex multisystemic phenotype, including highly elevated creatine kinase levels and lower-leg muscle atrophy. In addition to identifying two novel pathogenic variants in the SYNE1 gene, whole-exome sequencing revealed three variants of uncertain significance in the DYSF gene. Electromyography and muscle magnetic resonance imaging indicated a neurogenic pattern of muscle involvement. These findings, along with the segregation analysis of the variants, allowed us to exclude DYSF -associated muscular dystrophy; however, we cannot entirely rule out the possibility that the DYSF gene variants may act as modifiers of the patient's phenotype.

Diabetic neuropathy (DN) is a common complication of long-lasting type 1 and type 2 diabetes, with no curative treatment available. Here, we tested the effect of the incretin mimetic liraglutide in DN in mice with early-stage type 1 diabetes bred in a standard laboratory or enriched environment. With a single i.p. injection of streptozotocin 150 mg/kg, we induced murine diabetes. Liraglutide (0.4 mg/kg once daily, i.p. for ten days since the eighth post-streptozotocin day) failed to decrease the glycemia in the diabetic mice; however, it alleviated their antinociceptive behavior, as tested with formalin. The second phase of the formalin test had significantly lower results in liraglutide-treated mice reared in the enriched environment vs. liraglutide-treated mice under standard conditions [2.00 (0.00-11.00) vs. 29.00 (2.25-41.50) s, p = 0.016]. Liraglutide treatment, however, decreased the threshold of reactivity in the von Fray test. A significantly higher neopterin level was demonstrated in the diabetic control group compared to treatment-naïve controls and the liraglutide-treated diabetic mice ( p < 0.001). The glutamine/glutamate ratio in both liraglutide-treated groups, either reared under standard conditions ( p = 0.003) or an enriched environment ( p = 0.002), was significantly higher than in the diabetic controls. This study demonstrates an early liraglutide effect on pain sensation in two streptozotocin-induced diabetes mouse models by reducing some inflammatory and oxidative stress parameters.

Vitamin B 12 , cobalamin, is indispensable for humans owing to its participation in two biochemical reactions: the conversion of l-methylmalonyl coenzyme A to succinyl coenzyme A, and the formation of methionine by methylation of homocysteine. Eukaryotes, encompassing plants, fungi, animals and humans, do not synthesise vitamin B 12 , in contrast to prokaryotes. Humans must consume it in their diet. The most important sources include meat, milk and dairy products, fish, shellfish and eggs. Due to this, vegetarians are at risk to develop a vitamin B 12 deficiency and it is recommended that they consume fortified food. Vitamin B 12 behaves differently to most vitamins of the B complex in several aspects, e.g. it is more stable, has a very specific mechanism of absorption and is stored in large amounts in the organism. This review summarises all its biological aspects (including its structure and natural sources as well as its stability in food, pharmacokinetics and physiological function) as well as causes, symptoms, diagnosis (with a summary of analytical methods for its measurement), prevention and treatment of its deficiency, and its pharmacological use and potential toxicity.

Introduction: Autoimmune nodopathy (AN) is a new entity in the field of peripheral neuropathies and is defined by the presence of auto-antibodies against structures of the node of Ranvier combined with specific clinico-pathophysiological features and therapy response in affected patients. The target-specific antibodies do not only serve as diagnostic biomarkers but also for treatment evaluation during follow-up., Case Report: We report a 66-year-old female patient with various autoimmune diseases, including a history of membranous glomerulonephritis which presented with acute-onset, sensorimotor tetraparesis, cranial nerve involvement, and mild respiratory insufficiency. Under the suspicion of Guillain-Barré syndrome, she received intravenous immunoglobulins (IVIg) and achieved remission. At 8 months later, she relapsed with now a poor response to IVIg and developed additional features such as severe sensory ataxia, tremor, and neuropathic pain. Anti-contactin-1 IgG2 antibodies were detected, and the diagnosis was reverted to AN. Plasma exchange and rituximab treatment led to a serological remission and corresponding significant clinical improvement, and the therapy was paused. At 2 years after symptom onset, her condition worsened again with sensorimotor symptoms and severe neuropathic pain despite seronegativity for contactin-1. However, serum binding assays to teased nerve fiber staining showed recurring antibody reactivity against paranodal structures. Caspr-1 was identified as a new target antigen via cell-based assay, and high-titer antibodies of the IgG4 subclass were confirmed via ELISA. Hence, a new cycle of plasma exchange and regular rituximab treatment was initiated, with subsequent clinical improvement and serological remission. The serum neurofilament light chain (sNFL) levels were assessed retrospectively and rose and fell together with the antibody titer., Discussion: This case demonstrates that autoimmunity to (para)nodal structures can reoccur especially in patients prone to autoimmune disorders and can switch its target antigen and subclass in the course of disease. The presence of auto-antibodies against different targets at the node of Ranvier has direct implications for therapeutic management. We suggest a close follow-up of patients with AN after successful therapy. In case of deterioration despite seronegativity, non-specific tests such as teased fiber assays and repeated screening for different target antigens should be considered., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Author CV declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Appeltshauser, Glenewinkel, Rohrbacher, Wessely, Villmann, Sommer and Doppler.)

The aim of this meta-analysis is to compare the clinical outcomes in patients with and without residual osteomyelitis (ROM) after surgical bone resection for diabetic foot osteomyelitis (DFO). We completed a systematic literature search using PubMed, Scopus, and Embase using keywords DFO, Residual OM (ROM), and positive bone margins. The study outcomes included wound healing, antibiotic duration, amputation, and re-infection. Five hundred and thirty patients were included in the analysis; 319 had no residual osteomyelitis (NROM), and 211 had ROM. There was not a significant difference in the proportion of wounds that healed 0.6 (p = 0.1, 95% confidence intervals [95% CI] 0.3-1.3). The risk of infection was 2.0 times higher (OR = 2.0, p = 0.02, 95% CI 1.1-3.4), and the risk of amputation was 4.3 times higher (OR = 4.3, p = 0.0001, 95% CI 2.4-7.6) in patients with ROM. Patients with ROM received antibiotics significantly longer. The mean difference was 16.3 days (p = 0.02, 95% CI 11.1-21.1)., (© 2024 The Author(s). Wound Repair and Regeneration published by Wiley Periodicals LLC on behalf of The Wound Healing Society.)

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common and dose-limiting chemotoxicity caused by oxaliplatin. This study investigated the relationship between dietary quality and the development of moderate and/or severe CIPN in colon cancer survivors using data from the Focus on Reducing Dose-Limiting Toxicities in Colon Cancer with Resistance Exercise trial (ClinicalTrials.gov identifier NCT03291951)., Methods: Diet quality was collected using a 127-item food-frequency questionnaire and was scored using the Alternative Healthy Eating Index-2010 (AHEI-2010). CIPN was assessed with the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events at each chemotherapy cycle. The association of dietary quality with time to the first moderate-to-severe (moderate-severe) or severe event of CIPN was estimated using Cox proportional hazards models. Only participants who received oxaliplatin were included in this analysis (n = 132)., Results: Seventy-four participants (56.1%) reported moderate-severe CIPN. Higher dietary quality was associated with a significantly decreased risk of moderate-severe CIPN (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.93-0.99) and severe CIPN (HR, 0.91; 95% CI, 0.85-0.98). Consumption of red and processed meat (HR, 1.78; 95% CI, 1.07-2.83) and sugar-sweetened beverages (HR, 1.33; 95% CI, 1.10-1.59) was associated with an increased risk of moderate-severe CIPN. Consumption of sugar-sweetened beverages also was associated with an increased risk of severe CIPN (HR, 1.57; 95% CI, 1.14-2.18), whereas vegetable consumption was associated with a reduced risk of severe CIPN (HR, 0.29; 95% CI, 0.09-0.73)., Conclusions: Among patients with colon cancer who received oxaliplatin-based chemotherapy, higher baseline dietary quality was associated with a reduced risk of moderate-severe CIPN., (© 2024 American Cancer Society.)

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a heterogeneous but clinically well-described disease within circumscribed parameters. It is immunologically mediated through several poorly understood mechanisms. First-line therapies with steroids, intravenous immunoglobulin (IVIG) or plasma exchange are each effective in about two-thirds of patients. These treatments are seldom associated with complete resolution or cure, and often pose considerable practical, financial and medical implications.Our understanding of many of the key pathological processes in autoimmune diseases is expanding, and novel targeted therapeutics are being developed with promise in several autoimmune neurological disorders.This narrative review looks first at detailing key pathogenic mechanisms of disease in CIDP, followed by an in-depth description of potential novel therapies and the current evidence of their application in clinical practice., Competing Interests: Competing interests: FE has received funding in grants from CSL Behring, Grifols, Terumo BCT, Takeda, Kendion and the GBS/CIDP foundation. He has also received consultation fees (paid to institution) from Takeda, Dianthus, Sanofi and Argenx. MPL has given advice on ad hoc advisory boards particularly on trial design to Roche, AstraZeneca, Sanofi, UCB, Sanofi, Takeda, Polyneuron and BeiGene (conference expenses and advisory board). Unrestricted conference expenses have been received from Beigene and CSL Behring. He has received research grants from Charitable Foundations: Patrick Berthoud Charitable Trust, ABN, Guarantors of Brain, National Brain Appeal, UCLH Charities, Leonard Wolfson Foundation, Medical Research Council, GBS CIDP Foundation International, New Zealand Medical Foundation, GAIN UK. SK has received conference expenses from CSL Behring., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Peripheral neuropathies of the foot and ankle can be challenging to diagnose clinically due to concomitant traumatic and nontraumatic or degenerative orthopedic conditions. Although clinical history, physical examination, and electrodiagnostic testing comprised of nerve conduction velocities and electromyography are used primarily for the identification and classification of peripheral nerve disorders, MR neurography (MRN) can be used to visualize the peripheral nerves as well as the skeletal muscles of the foot and ankle for primary neurogenic pathology and skeletal muscle denervation effect. Proper knowledge of the anatomy and pathophysiology of peripheral nerves is important for an MRN interpretation., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Withania somnifera (W. somnifera) has a long history of safety in the amelioration of neuro-active ailments. The current study aims to explore Withania somnifera phyto-active principle anti-microbial, ant-neuropathic, and anti-inflammatory activities, and to modify these activities utilizing nano-cubosomes exploiting their mechanisms of action. Bio-guided fractionation technique was utilized, to identify the most phyto-active compound, using LC-MS-NMR online technique and biological models of diabetes, neuropathy, and inflammation. In-vitro antibacterial activity was also monitored. The HbA1c, in-vivo antioxidant (serum-catalase, TBARS, and GSH), serum insulin, and pro-inflammatory serum cytokines (TNF alpha, IL-six, and IL-ten) levels have been assessed to establish the anti-neuropathic and anti-inflammatory mechanisms. The nano-cubosomal formulations (CUB 1-3) were utilized to improve the W. somnifera most active compound efficacy. W. somnifera has shown ten major peaks; coagulin Q (10.2 %), dihydrowithanolide A (2.4 %), dihydrowithaferin D (1.8 %), physagulin D (7.6 %), withanoside V (2.3 %), withanolide A (WDA, 10.3 %), withafrin A (4.9 %), withaferin D (7.7 %), withanone 9 (9.9 %), withanolide D (4.8 %). The bio-guided fractionation technique utilizing LC-MS-NMR technique has proved that withanolide A (WDA) is the most phyto-active compound in W. somnifera. The latter has shown better results than WDA, which might be due to other effective compounds in Ws. However, CUB 3 (WDA nano-cubosomes dispersion) has shown more prominent anti-diabetic, anti-neuropathic, anti-inflammatory, and anti-bacterial potentials than Ws and WDA. Thus, CUB 3 modified WDA activity, and improved its efficacy. The normalization of HbA1c levels, increased insulin secretagogue potential, and the amelioration of the oxidative-stress may be the underlying Ws, WDA, and CUB 3 antidiabetic neuropathy mechanism. Moreover, the Ws, WDA, and CUB 1-3 anti-inflammatory mechanism might be due to the amelioration of the pro-inflammatory serum cytokines (decreasing TNF alpha and IL-six levels and increasing IL-ten). Thus, CUB 3 might be a powerful tool in augmenting Withania somnifera activity as an oral drug-delivery system and improving its efficacy against neuropathy and inflammation., Competing Interests: Declaration of competing interest The three authors declare no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Hydrodissection is becoming increasingly recognized as a treatment for nerve entrapment syndromes in the orthopedic and rehabilitation world. Carpal Tunnel Syndrome (CTS) is the most prevalent nerve entrapment neuropathy, characterized by compression of the median nerve as it passes through the carpal tunnel. Initial management includes NSAIDs and wrist splints, but surgical intervention is often necessary when these measures fail. Ultrasound-guided hydrodissection of the median nerve is both safe and effective and presents a minimally invasive option when first-line treatments fail to provide adequate symptom relief. This case report demonstrates the potential for an alternative approach to analgesia in the Emergency Department (ED) for patients presenting with pain related to CTS. Here we discuss a case of a 26-year-old female presenting with CTS symptoms and her successful treatment with ultrasound-guided hydrodissection in the ED., Competing Interests: Declaration of competing interest None of the listed authors have any financial conflicts of interest or any other disclosures., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Diabetes-induced hyperglycemia leads to excessive production of oxygen free radicals, inflammatory cytokines, and oxidative stress, which initiates diabetic peripheral neuropathy (DPN). Currently, this condition affects 20% of adults with diabetes. Despite significant advances in the treatment of diabetes, the incidence of its complications, including DPN, is still high. Thus, there is a growing research interest in developing more effective and treatment approaches with less side effects for diabetes and its complications. Nigella sativa L. (NS) has received much research attention as an antioxidant, anti-yperglycemic factor, and anti-inflammatory agent. This natural compound demonstrates its antidiabetic neuropathy effect through various pathways, including the reduction of lipid peroxidation, the enhancement of catalase and superoxide dismutase enzyme activity, and the decrease in inflammatory cytokine levels. The present review focuses on the bioactive and nutraceutical components of black cumin (Nigella sativa L.) and their effects on DPN. In addition, we have also summarized the findings obtained from several experimental and clinical studies regarding the antidiabetic neuropathy effect of NS in animal models and human subjects., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Nanotechnology has emerged as a promising approach for the targeted delivery of therapeutic agents while improving their efficacy and safety. As a result, nanomaterial development for the selective targeting of cancers, with the possibility of treating off-target, detrimental sequelae caused by chemotherapy, is an important area of research. Breast and ovarian cancer are among the most common cancer types in women, and chemotherapy is an essential treatment modality for these diseases. However, chemotherapy-induced neurotoxicity, neuropathy, and cardiomyopathy are common side effects that can affect breast and ovarian cancer survivors quality of life. Therefore, there is an urgent need to develop effective prevention and treatment strategies for these adverse effects. Nanoparticles (NPs) have extreme potential for enhancing therapeutic efficacy but require continued research to elucidate beneficial interventions for women cancer survivors. In short, nanotechnology-based approaches have emerged as promising strategies for preventing and treating chemotherapy-induced neurotoxicity, neuropathy, and cardiomyopathy. NP-based drug delivery systems and therapeutics have shown potential for reducing the side effects of chemotherapeutics while improving drug efficacy. In this article, the latest nanotechnology approaches and their potential for the prevention and treatment of chemotherapy-induced neurotoxicity, neuropathy, and cardiomyopathy in breast and ovarian cancer survivors are discussed., (© 2023 The Authors. Small published by Wiley‐VCH GmbH.)

Background: Diabetes mellitus (DM) is associated with increased risk of morbidity and premature mortality due to its various complications. In an Indian study, the prevalence of diabetic peripheral neuropathy (DPN) in type 2 diabetic subjects was shown to be 29.2%. There is increasing evidence that a deficiency of nerve growth factor (NGF) in diabetes, as well as the calcitonin gene-related peptide (CGRP), may also contribute to the development of DPN. The aim of the current study was to evaluate nerve growth factor levels with neuropathy in type 2 DM., Materials and Methods: Forty healthy controls and 40 patients with type 2 DM were recruited; they were asked to report to Dept. of Physiology for initial history taking, general examination and neuropathy examination. A total of 5 mL of blood was collected for neurotrophic factor estimation as well as glycemic profile estimation., Results: The brain-derived neurotrophic factor (BDNF) values were significantly lower in the DM group whereas the insulin levels were also quite high in DM. The hot thresholds for both the upper limb and lower limb were greater in the DM group suggesting the impending neuropathy. Similarly, the Michigan scores were also greater in the DM group. The neuropathy parameters especially the Michigan A and B and the hot thresholds were positively correlated with duration of DM and glucose profile., Conclusion: The neurotrophic factors especially BDNF are drastically reduced in DM patients and are negatively associated with neuropathy, and hence, BDNF can be utilized as a therapeutic target to treat and prevent neuropathy., (© 2024. The Author(s), under exclusive licence to Royal Academy of Medicine in Ireland.)

Objectives: Duloxetine, the only American Society of Clinical Oncology (ASCO) treatment recommended for chemotherapy-induced peripheral neuropathy (CIPN) in cancer survivors, is not effective for 40% of survivors. This study examined the ability of a duloxetine-prazosin combination to prevent the development of allodynia and hyperalgesia in a rat model of oxaliplatin-induced peripheral neuropathy (OPIN)., Methods: Female (n = 24) and male (n = 41) rats were started on duloxetine (15 mg), prazosin (2 mg), or a duloxetine-prazosin combination one week prior to administration of the chemotherapy drug, oxaliplatin, and continued the duloxetine-prazosin combination for 32 days. Behavioral testing for mechanical allodynia and mechanical hyperalgesia was done with selected von Frey filaments over the course of the study., Results: Overall percent paw withdrawal for rats that received the duloxetine-prazosin combination was significantly lower in female (p < .001 for both conditions) and male (p = .029 for allodynia; p < .001 for hyperalgesia) than those that received water. No significant posttreatment differences were found for allodynia or hyperalgesia between rats treated with duloxetine and rats that received the duloxetine-prazosin combination in either sex., Conclusions: These finding provide preliminary evidence that a duloxetine-prazosin combination can prevent the posttreatment development of allodynia and hyperalgesia in both male and female rats; however, the results suggest that the duloxetine-prazosin combination is no more efficacious than duloxetine alone in preventing chronic OIPN., Implications for Nursing Practice: The profession of nursing is built on clinical practice supported by scientific research. The current study addressed the clinical practice problem of prevention and management of painful OIPN, which is a priority area in oncology nursing., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a serious therapy-limiting side effect of commonly used anticancer drugs. Previous studies suggest that lipids may play a role in CIPN. Therefore, the present study aimed to identify the particular types of lipids that are regulated as a consequence of paclitaxel administration and may be associated with the occurrence of post-therapeutic neuropathy., Methods: High-resolution mass spectrometry lipidomics was applied to quantify d=255 different lipid mediators in the blood of n=31 patients drawn before and after paclitaxel therapy for breast cancer treatment. A variety of supervised statistical and machine-learning methods was applied to identify lipids that were regulated during paclitaxel therapy or differed among patients with and without post-therapeutic neuropathy., Results: Twenty-seven lipids were identified that carried relevant information to train machine learning algorithms to identify, in new cases, whether a blood sample was drawn before or after paclitaxel therapy with a median balanced accuracy of up to 90%. One of the top hits, sphinganine-1-phosphate (SA1P), was found to induce calcium transients in sensory neurons via the transient receptor potential vanilloid 1 (TRPV1) channel and sphingosine-1-phosphate receptors.SA1P also showed different blood concentrations between patients with and without neuropathy., Conclusions: Present findings suggest a role for sphinganine-1-phosphate in paclitaxel-induced biological changes associated with neuropathic side effects. The identified SA1P, through its receptors, may provide a potential drug target for co-therapy with paclitaxel to reduce one of its major and therapy-limiting side effects., Funding: This work was supported by the Deutsche Forschungsgemeinschaft (German Research Foundation, DFG, Grants SFB1039 A09 and Z01) and by the Fraunhofer Foundation Project: Neuropathic Pain as well as the Fraunhofer Cluster of Excellence for Immune-Mediated Diseases (CIMD). This work was also supported by the Leistungszentrum Innovative Therapeutics (TheraNova) funded by the Fraunhofer Society and the Hessian Ministry of Science and Arts. Jörn Lötsch was supported by the Deutsche Forschungsgemeinschaft (DFG LO 612/16-1)., Competing Interests: JL, KG, SM, LH, CA, YS, ST, SW, DT, NF, CB, BS, CS, GG, MS No competing interests declared, (© 2024, Lötsch, Gasimli et al.)

Background: Many of the current treatments for chronic neuropathic pain have variable effectiveness and known side effects. Given the prevalence of this type of intractable pain (3-17% of general population), additional therapeutic non-invasive approaches are desired. Magnetic Peripheral Nerve Stimulation (mPNS) delivered at 0.5Hz provides an effective pain relief without side effects. The objective of this randomized, controlled, multi-site clinical trial was to compare long-term safety and efficacy of mPNS in patients with chronic, intractable, post-traumatic or post-surgical neuropathic pain to comprehensive Conventional Medical Management (CMM)., Methods: A total of 65 patients with post-traumatic, post-surgical neuropathy were treated within a multicenter, randomized, clinical trial comparing the safety and effectiveness of mPNS + CMM to CMM alone. Patients were randomized 1:1 and followed through 90 days. The primary endpoint is a proportion of responders, 50% or greater reduction in pain at Day 90. The secondary endpoints included the European Quality of Life 5 Dimensions 3 Level (EQ-5D-3L) and Patient Global Impression of Change (PGIC)., Results: At 3 months, 71% of subjects were considered responders (>50% pain relief) in the mPNS + CMM group vs 13% of subjects in the CMM group. The mPNS + CMM group had a mean reduction in VAS scores at Day 90 of 3.8 points (>50% reduction), while CMM showed less than a 1-point (0.7 point) mean reduction or ~10% reduction (p < 0.0001). The EQ-5D-3L score increased in the mPNS + CMM study group, whereas the CMM group showed no improvement in EQ-5D-3L at Day 90. PGIC responder rates were 80.6% and 4.3% at Day 90 for mPNS + CMM and CMM groups, respectively., Conclusion: mPNS + CMM was superior to CMM in a randomized prospective study when used for treatment of post-traumatic, post-surgical neuropathy. Due to the lack of other effective non-invasive treatments for neuropathic pain, mPNS should be considered much earlier in the treatment algorithm., Competing Interests: LK serves on advisory boards for Biotronik, Gimer, Neuralace, PainTEQ, and Presidio and has research agreements with Neuros, Nevro, FUS Mobile, Saluda, and Nalu. KA is a consultant for Nevro, Saluda, Biotronik, Boston Scientific, and Presidio. JR is a consultant for Neuralace Medical. Dr. Li serves as a consultant for Abbott, Avanos, Averitas Pharm, Biotronik, Boston Scientific, Nalu Medical, Nevro, PainTEQ, Saluda Medical, SPR Therapeutics, Vertos Medical, and is on the Speaker’s Bureau for Scilex Pharm, and has Stock Options in Nalu Medical. He has received research support from Avanos, Biotronik, Boston Scientific, SGX Medical, Nalu Medical, PainTEQ, Saluda Medical, and SPR Therapeutics. MB is a consultant for Neuralace Medical and Boston Scientific. He Chairs the Advisory Board for Neuralace Medical. The authors report no other conflicts of interest in this work., (© 2024 Kapural et al.)

Background: Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS), a relatively common cause of late-onset progressive ataxia, is a genetic disease characterised by biallelic pentanucleotide AAGGG repeat expansion in intron 2 of the replication factor complex subunit 1 gene. Herein, we describe the first molecularly confirmed CANVAS family with five affected siblings from Turkey., Case Presentation: The family comprised seven siblings born from healthy non-consanguineous parents. CANVAS phenotype was present in five of them; two were healthy and asymptomatic. Chronic cough was the first symptom reported in all five siblings, followed by the development of sensory symptoms, oscillopsia and imbalance. Clinical head impulse test (HIT) was positive in all cases and video HIT performed on three patients revealed very low vestibulo-ocular reflex gains bilaterally. Magnetic resonance imaging and nerve conduction studies revealed cerebellar atrophy and sensory neuronopathy, respectively. RP-PCR confirmed the homozygous presence of the AAGGG repeat expansion in all five cases., Conclusion: Genetic screening for CANVAS should be considered in all patients with late-onset ataxia, sensory disturbances and vestibular involvement, especially in the presence of chronic cough., (© 2024. The Author(s).)

The chemotherapeutic agent vincristine is commonly used for a variety of hematologic cancers, as well as solid tumors of the head and neck, bronchial carcinoma, as part of the procarbazine, lomustine and vincristine (PCV) regimen, for glioma. Damage to nerve tissue (neuropathy) is often dose-limiting and restricts treatment. Nimodipine is a calcium antagonist that has also shown neuroprotective properties in preliminary studies. In this approach here, we investigated the effects of the combination of vincristine and nimodipine on three cancer cell lines (A549, SAS and LN229) and neuronal cells (RN33B, SW10). Fluorescence microscopy, lactate dehydrogenase (LDH) assays and Western blot analyses were used. Nimodipine was able to enhance the cell death effects of vincristine in all tumor cells, while neuronal cells were protected and showed less cell death. There was an opposite change in the protein levels of Ak strain transforming/protein kinase B (AKT) in tumor cells (down) and neuronal cells (up), with simultaneous increased protein levels of cyclic adenosine monophosphate response element-binding protein (CREB) in all cell lines. In the future, this approach may improve tumor response to chemotherapy and reduce unwanted side effects such as neuropathy.

Objective: The impact of fine motor impairment among adult survivors of childhood acute lymphoblastic leukemia on life after treatment is unknown., Methods: This study evaluated prevalence and utilized multivariate logistic regression to identify risk factors for fine motor impairment among survivors of acute lymphoblastic leukemia, and associations with educational attainment and social independence. Latent class analysis defined social independence (independent, moderately independent, dependent), using employment, independent living, personal care assistance, routine need assistance, driver's license status, and marital status inputs., Results: Among 875 survivors who were ≥ 25 years old (age when most adults achieve independence) and ≥ 5 years from diagnosis (mean = 28.97 years), 33.6% had fine motor impairment, with scores at or below the 10th percentile of the scores of community controls (n = 460) on fine motor components of the Physical Performance Test and the Grooved Peg-Board Test. Survivors exposed to cranial radiation had more fine motor impairment than those without (45.8% vs 20.2%). Male sex (exposed: odds ratio [OR] = 2.55, 95.0% CI = 1.65-3.92; unexposed: OR = 3.02, 95.0% CI = 1.69-5.38), and lower scores on the Wechsler Abbreviated Scale of Intelligence (exposed: OR = 0.46, 95.0% CI = 0.36-0.58; unexposed: OR = 0.43, 95.0% CI = 0.31-0.58) were risk factors for neuropathy. A 1-point-higher total neuropathy score was associated with 8% (95.0% CI = 1%-17%) increased odds of fine motor impairment. Fine motor impairment was associated with less than a college education (less than high school: OR = 2.23, 95.0% CI = 1.20-4.14; high school diploma/general equivalency diploma: OR = 2.66, 95.0% CI = 1.65-4.30; vocational education: OR = 2.07, 95.0% CI = 1.38-3.13), and less social independence (moderately independent: OR = 1.80, 95.0% CI = 1.15-2.83; dependent: OR = 2.65, 95.0% CI = 1.25-5.64)., Conclusion: Fine motor impairment in survivors of childhood acute lymphoblastic leukemia may interfere with optimal educational attainment and social independence., Impact: Early identification of survivors at risk for fine motor impairment, with timely intervention, may improve long-term outcomes., (© 2024 American Physical Therapy Association. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To assess the associations between active CMV infection and patient-reported symptoms of cancer-related cognitive impairment (CRCI) and peripheral neuropathy in ovarian cancer survivors., Methods: We conducted a cross-sectional study among individuals with a diagnosis of ovarian cancer, primary peritoneal cancer, or fallopian tube cancer from academic and community cancer clinics at any time point after completion of front-line chemotherapy. Participants completed a one-time survey and provided a blood sample. Plasma virus DNA levels were measured using digital PCR, with ≥100 copies/mL of plasma considered active infection (CMV+, EBV+ as a control). We measured symptoms of CRCI and peripheral neuropathy using the Patient-Reported Outcomes Measurement Information System (PROMIS) Cognitive Function short form 8a and Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity (FACT/GOG-NTX) subscale measurements, respectively. Symptoms were compared by active CMV infection status in the full group and among the subgroup receiving active treatment using t-tests and linear regression models., Results: 152 participants were included. A total of 59 (38.8 %) participants were CMV+. After adjustment for potential confounding variables, individuals who were CMV+ self-reported significantly more symptoms of peripheral neuropathy that those who were CMV- (p = 0.04). In the subgroup of participants currently receiving chemotherapy, individuals who were CMV+ had significantly lower perceived cognitive functioning compared to individuals who were CMV- (p = 0.03); this was not observed in the full cohort. No associations were observed between outcomes and EBV infection., Conclusions: Active CMV infection is common in this survivor population and may be associated with more symptoms of CRCI and neuropathy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Numerous factors can contribute to the incidence or exacerbation of peripheral neuropathy induced by oxaliplatin (OXA). Recently, platinum accumulation in the spinal cord of mice after OXA exposure, despite the efficient defenses of the central nervous system, has been demonstrated by our research group, expanding the knowledge about its toxicity. One hypothesis is platinum accumulation in the spinal cord causes oxidative damage to neurons and impairs mitochondrial function. Thus, the main aim of this study was to investigate the relationship between aging and OXA-induced neuropathic pain and its comorbidities, including anxious behavior and cognitive impairment. By using an OXA-induced peripheral neuropathy model, platinum and bioelement concentrations and their influence on oxidative damage, neuroprotection, and neuroplasticity pathways were evaluated in Swiss mice, and our findings showed that treatment with OXA exacerbated pain and anxious behavior, albeit not age-induced cognitive impairment. Platinum deposition in the spinal cord and, for the first time, in the brain of mice exposed to OXA, regardless of age, was identified. We found that alterations in bioelement concentration, oxidative damage, neuroprotection, and neuroplasticity pathways induced by aging contribute to OXA-induced peripheral neuropathy. Our results strive to supply a basis for therapeutic interventions for OXA-induced peripheral neuropathy considering age specificities., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Natural language processing (NLP) techniques can be used to analyze large amounts of electronic health record texts, which encompasses various types of patient information such as quality of life, effectiveness of treatments, and adverse drug event (ADE) signals. As different aspects of a patient's status are stored in different types of documents, we propose an NLP system capable of processing 6 types of documents: physician progress notes, discharge summaries, radiology reports, radioisotope reports, nursing records, and pharmacist progress notes., Objective: This study aimed to investigate the system's performance in detecting ADEs by evaluating the results from multitype texts. The main objective is to detect adverse events accurately using an NLP system., Methods: We used data written in Japanese from 2289 patients with breast cancer, including medication data, physician progress notes, discharge summaries, radiology reports, radioisotope reports, nursing records, and pharmacist progress notes. Our system performs 3 processes: named entity recognition, normalization of symptoms, and aggregation of multiple types of documents from multiple patients. Among all patients with breast cancer, 103 and 112 with peripheral neuropathy (PN) received paclitaxel or docetaxel, respectively. We evaluate the utility of using multiple types of documents by correlation coefficient and regression analysis to compare their performance with each single type of document. All evaluations of detection rates with our system are performed 30 days after drug administration., Results: Our system underestimates by 13.3 percentage points (74.0%-60.7%), as the incidence of paclitaxel-induced PN was 60.7%, compared with 74.0% in the previous research based on manual extraction. The Pearson correlation coefficient between the manual extraction and system results was 0.87 Although the pharmacist progress notes had the highest detection rate among each type of document, the rate did not match the performance using all documents. The estimated median duration of PN with paclitaxel was 92 days, whereas the previously reported median duration of PN with paclitaxel was 727 days. The number of events detected in each document was highest in the physician's progress notes, followed by the pharmacist's and nursing records., Conclusions: Considering the inherent cost that requires constant monitoring of the patient's condition, such as the treatment of PN, our system has a significant advantage in that it can immediately estimate the treatment duration without fine-tuning a new NLP model. Leveraging multitype documents is better than using single-type documents to improve detection performance. Although the onset time estimation was relatively accurate, the duration might have been influenced by the length of the data follow-up period. The results suggest that our method using various types of data can detect more ADEs from clinical documents., (©Tomohiro Nishiyama, Ayane Yamaguchi, Peitao Han, Lis Weiji Kanashiro Pereira, Yuka Otsuki, Gabriel Herman Bernardim Andrade, Noriko Kudo, Shuntaro Yada, Shoko Wakamiya, Eiji Aramaki, Masahiro Takada, Masakazu Toi. Originally published in JMIR Medical Informatics (https://medinform.jmir.org), 24.09.2024.)

Some therapeutic agents have been found to have effects beyond their primary indications. Peripheral neuropathy, a common side effect of chemotherapy, remains inadequately treated. Identifying additional properties of existing medications could thus uncover novel therapeutic avenues. Previous studies have identified an additional effect of simvastatin in reducing neuropathy; however, the mechanism underlying this effect remains unclear. We investigated the novel effects of statins on chemotherapy-induced peripheral neuropathy in mice. Mice treated with oxaliplatin or paclitaxel did not show exacerbation or improvement in cold sensations upon acetone testing with statin administration. However, concurrent oral statin treatment mitigated the nociceptive response to mechanical stimuli induced by each anti-tumor agent. Co-administration of a glutathione S-transferase inhibitor, which modulates redox reactions, abolished the ameliorative effect of statins on mechanical nociceptive behavior. Additionally, the glutathione S-transferase inhibitor did not affect normal sensory perception or impair the anti-tumor effect of chemotherapy agents. A search for GST-associated molecules and pathways using artificial intelligence revealed that GST regulates inflammatory cytokines as a regulatory or causative gene. Our findings suggest that statins have class effects that ameliorate cytotoxic anti-cancer drug-induced mechanical allodynia via GST pathway activation., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier Ltd.)

Purpose: Chemotherapy-induced peripheral neurotoxicity (CIPN) is a prevalent, dose-limiting, tough-to-treat toxicity involving numbness, tingling, and pain in the extremities with enigmatic pathophysiology. This randomized controlled pilot study explored the feasibility and preliminary efficacy of exercise during chemotherapy on CIPN and the role of the interoceptive brain system, which processes bodily sensations., Methods: Nineteen patients (65 ± 11 years old, 52% women; cancer type: breast, gastrointestinal, multiple myeloma) starting neurotoxic chemotherapy were randomized to 12 weeks of exercise (home-based, individually tailored, moderate intensity, progressive walking, and resistance training) or active control (nutrition education). At pre-, mid-, and post-intervention, we assessed CIPN symptoms (primary clinical outcome: CIPN-20), CIPN signs (tactile sensitivity using monofilaments), and physical function (leg strength). At pre- and post-intervention, we used task-free ("resting") fMRI to assess functional connectivity in the interoceptive brain system, involving the salience and default mode networks., Results: The study was feasible (74-89% complete data across measures) and acceptable (95% retention). We observed moderate/large beneficial effects of exercise on CIPN symptoms (CIPN-20, 0-100 scale: - 7.9 ± 5.7, effect size [ES] =  - 0.9 at mid-intervention; - 4.8 ± 7.3, ES = - 0.5 at post-intervention), CIPN signs (ES =  - 1.0 and - 0.1), and physical function (ES = 0.4 and 0.3). Patients with worse CIPN after neurotoxic chemotherapy had lower functional connectivity within the default mode network (R 2  = 40-60%) and higher functional connectivity within the salience network (R 2  = 20-40%). Exercise tended to increase hypoconnectivity and decrease hyperconnectivity seen in CIPN (R 2  = 12%)., Conclusion: Exercise during neurotoxic chemotherapy is feasible and may attenuate CIPN symptoms and signs, perhaps via changes in interoceptive brain circuitry. Future work should test for replication with larger samples., Trial Registration: Registered Jan 2017 on ClinicalTrials.gov as NCT03021174., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating condition affecting an increasing number of cancer survivors worldwide. However, insights into its pathophysiology and availability of effective therapies remain lacking. Dorsal root ganglia (DRG) have been studied as a key component of chemotherapeutic drug toxicity and a potential therapeutic target for CIPN treatment. This comprehensive review aims to synthesize, summarize, and correlate the results of both preclinical and clinical studies relevant to the pathophysiology and management of CIPN in relation to the DRG. Design: Review. A thorough literature search was conducted using the terms 'dorsal root ganglion' and 'chemotherapy-induced peripheral neuropathy', along with appropriate variations. Searched databases included PubMed, EMBASE, Medline, Cochrane Library, Wiley Library, and Web of Science. Inclusion criteria targeted all English language, peer-reviewed original research from the inception of these databases to the present year. Review articles, book chapters, and other nonoriginal publications were excluded. Of 134 relevant studies identified, the majority were preclinical studies elucidating how various chemotherapeutic agents, especially taxanes, disrupt neurotransmission, inflammatory processes, and apoptotic pathways within sensory neurons of DRG. Not only do these effects correlate with the presentation of CIPN, but their disruption has also been shown to reduce CIPN symptoms in preclinical models. However, clinical studies addressing DRG interventions are very limited in number and scope at this time. These results reveal various pathways within DRG that may be effective targets for CIPN treatment. While limited, clinical studies do offer promise in the utility of DRG neuromodulation in managing painful CIPN. In the future, clinical trials are needed to assess interventions aimed at these neuronal and nonneuronal pathological targets to better treat this complex condition., (© The Author(s), 2024.)

Interpreting intramuscular electromyography (iEMG) signals for diagnosing and quantifying the severity of lumbosacral radiculopathy is challenging due to the subjective evaluation of signals. To address this limitation, a clinical decision support system (CDSS) was developed for the diagnosis and quantification of the severity of lumbosacral radiculopathy based on intramuscular electromyography (iEMG) signals. The CDSS uses the EMG interference pattern method (QEMG IP) to directly extract features from the iEMG signal and provide a quantitative expression of injury severity for each muscle and overall radiculopathy severity. From 126 time and frequency domain features, a set of five features, including the crest factor, mean absolute value, peak frequency, zero crossing count, and intensity, were selected. These features were derived from raw iEMG signals, empirical mode decomposition, and discrete wavelet transform, and the wrapper method was utilized to determine the most significant features. The CDSS was trained and tested on a dataset of 75 patients, achieving an accuracy of 93.3%, sensitivity of 93.3%, and specificity of 96.6%. The system shows promise in assisting physicians in diagnosing lumbosacral radiculopathy with high accuracy and consistency using iEMG data. The CDSS's objective and standardized diagnostic process, along with its potential to reduce the time and effort required by physicians to interpret EMG signals, makes it a potentially valuable tool for clinicians in the diagnosis and management of lumbosacral radiculopathy. Future work should focus on validating the system's performance in diverse clinical settings and patient populations., (© 2024. International Federation for Medical and Biological Engineering.)

There have been several methods established for immunohistochemical labeling of the PGP 9.5 antigen in human tissue for the assessment of epidermal nerve fiber density, none of which uses neutral-buffered formalin as the preferred fixative for paraffin-embedded tissue. The literature maintains that formalin-fixed paraffin embedded tissues are unable to be used for this purpose and that other fixatives must be used due to the cross-linkages caused by formalin fixation. This study was undertaken to develop a standardized method for the use of formalin-fixed paraffin embedded tissues for immunohistochemical labeling and assessment of epidermal nerve fiber density. Formalin-fixed paraffin embedded tissues from the punch biopsies of patients suspected to have small fiber neuropathy were prepared for immunohistochemical labeling using heat-induced epitope retrieval for one hour at 92°C. The tissues were then stained with a polyclonal rabbit anti-human PGP 9.5 primary antibody. The resulting stains were then evaluated by a licensed pathologist who counted the number of epidermal nerve fibers stained and recorded the epidermal length in millimeters. Human foreskin was used as the tissue control in these studies. Satisfactory immunohistochemical labeling of epidermal nerve fibers was achieved from formalin-fixed paraffin embedded tissues through the use of heat-induced epitope retrieval. The authors of this paper have concluded that formalin-fixed paraffin embedded tissues may be used to achieve satisfactory immunohistochemical labeling for the assessment of epidermal nerve fiber density.

Background: Oxaliplatin, a major drug in metastatic colorectal cancer (mCRC), is responsible for cumulative, dose-limiting peripheral neuropathy (PN). Whether the hepatic arterial infusion (HAI) route can limit oxaliplatin-induced PN in comparison with the intravenous (IV) route has not been specifically explored so far., Methods: We compared the frequency and severity of PN in oxaliplatin-naive patients with mCRC included in trials that evaluated treatment with oxaliplatin administered either by HAI (ACCORD 04, CHOICE, OSCAR, and PACHA-01 trials) or by IV route (FFCD 2000-05 trial). We retrieved anonymized, prospectively collected data from trial databases for the ACCORD 04, CHOICE, and FFCD 2000-05 trials and through a review of Gustave Roussy patients' electronic medical records for PACHA-01 and OSCAR trials. The primary endpoint was the incidence of clinically significant PN (grades 2 to 4) according to the cumulative dose of oxaliplatin received. Secondary endpoints were time to onset of neuropathy as a function of the cumulative dose of oxaliplatin, discontinuation of oxaliplatin for neurotoxicity, and safety., Results: A total of 363 patients were included (IV, 300; HAI, 63). In total, 180 patients in the IV group (60%) and 30 patients in the HAI group (48%) developed clinically significant PN, with no significant difference between the two groups (p = 0.23). No difference was shown in the time to onset of PN either (p = 0.23)., Conclusion: The administration of oxaliplatin HAI rather than IV in the treatment of mCRC does not reduce the incidence, precocity, and severity of PN., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Competing Interests: Competing interests: None declared.

Background: Research on Qi Gong (QG) supports promising health benefits. Both interest and use of QG in U.S. adults has increased over the past decade. Shared Medical Appointments (SMAs) are a novel, cost-effective, and time efficient health care delivery approach associated with patient and clinician satisfaction., Objectives: A telehealth delivered QG SMA was pilot tested among a diverse demographic population within an integrative medicine practice at an academic medical center to assess feasibility and acceptability., Methods: This was a feasibility/acceptability pilot study conducted at a large New York City academic medical center's Integrative Health and Wellness center from January to July 2023. A QG instructor-acupuncturist and an integrative medicine physician-acupuncturist co-led 3 separate series (5 Element QG, Eight-Section Brocade, and Joint-Mobilizing/Sinew Strengthening exercises) of weekly 30-45-minute sessions of QG SMA on a weekday afternoon via telemedicine. The first session included an overview of QG and Traditional Chinese Medicine (TCM) research while follow-up sessions included a check-in, didactic demonstration followed by QG practice, and a debrief to answer questions. Video links were provided for home practice. Surveys assessing satisfaction were sent pre/post series., Results: 18 sessions of QG SMA were offered over a 6-month period. A total of 40 unique participants from diverse demographics (gender, race/ethnicity, primary residence) attended, for a total of 197 virtual visits. A total of 20 participants enrolled in Series 1 (8 weeks), 23 enrolled in Series 2 (7 weeks), and 16 enrolled in Series 3 (3cweeks). For each session, group attendance ranged from 8-16 with an average of 11 participants. Attendance was high with participants attending an average of 72% of the sessions. Participants attended 88% of the first 8-week series, 54% of the second 7-week series, and 60% of the third series. Participant interest persisted over time with 35% of the 40 participants attending more than 1 series, and 12.5% attending all 3 series. Participants' diagnoses and health symptoms included pain (62.5%), cancer (45%) anxiety/depression (40%), cardiovascular disease (CVD) or metabolic conditions (32.5%), gastrointestinal (GI) symptoms/diagnoses (27.5%), stress (22.5%), osteopenia/osteoporosis (17.5%), and insomnia (17.5%). Pre-series [n = 27] participants endorsed symptoms including sleep disturbances, fatigue, pain, stress, weakness, GI symptoms, psychological symptoms, hot flashes, and brain fog. Post-program survey results [n = 11] suggested QG program addressed common symptoms including fatigue, insomnia, anxiety, stress, pain, weakness, and gastrointestinal symptoms. Participants reported incorporating QG, breathing techniques, and meditation into their daily routine. All participants reported their goals were met and that they would recommend the program to others. Regarding delivery preferences, 73% preferred telehealth, 27% hybrid, and none preferred in-person. Participants appreciated the format, new skills, community, and instructors., Conclusion: While the Virtual QG SMA series provided to diverse demographic population with mixed diagnoses is feasible, acceptable, and shows promising positive impact in this pilot, caution in interpreting the data is advised due to the low response rate of the post-program survey. Robust studies with longer follow-ups are recommended., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Background: Peripheral neuropathy is a common complication of diabetes, impacting many patients with type 1 or 2 diabetes. Acute-onset peripheral neuropathy after diabetic ketoacidosis (DKA) is rare yet serious, and reports on long-term functional outcomes and rehabilitation for this condition are limited. We present a case of bilateral foot drop caused by acute-onset peripheral neuropathy following DKA. The case was effectively managed through prompt and continuous intervention., Case: A 21-year-old male university student with no notable medical history who was seeking employment presented with impaired consciousness. DKA associated with type 1 diabetes was diagnosed. As blood glucose and acidosis improved, he rapidly regained consciousness. On Day 3 post-onset, bilateral foot drop and lower leg sensory impairment emerged, with nerve conduction studies indicating lower extremity peripheral neuropathy on Day 8. Improvement during hospitalization was modest, so ankle-foot orthoses were prescribed on Day 10. He could walk independently with the orthoses on Day 12 and was discharged home on Day 15. Outpatient follow-up was continued to support the patient's efforts to gain employment. Needle electromyography in the tibialis anterior muscles bilaterally showed denervation at 2 months and polyphasic potentials at 8 months. In the 2 years post-onset, bilateral lower limb muscle strength progressively improved, and the patient successfully secured clerical employment., Discussion: Successful rehabilitation for employment was achieved in the rare condition of acute-onset neuropathy after DKA through effective management based on early orthotic prescription, clinical and electrophysiological examinations, and continuous follow-up., Competing Interests: CONFLICTS OF INTEREST: The authors declare no conflict of interest., (2024 The Japanese Association of Rehabilitation Medicine.)

Familial dysautonomia (FD) is a rare sensory and autonomic neuropathy that results from a mutation in the ELP1 gene. Virtually all patients report gastrointestinal (GI) dysfunction and we have recently shown that FD patients have a dysbiotic gut microbiome and altered metabolome. These findings were recapitulated in an FD mouse model and moreover, the FD mice had reduced intestinal motility, as did patients. To understand the cellular basis for impaired GI function in FD, the enteric nervous system (ENS; both female and male mice) from FD mouse models was analyzed during embryonic development and adulthood. We show here that not only is Elp1 required for the normal formation of the ENS, but it is also required in adulthood for the regulation of both neuronal and non-neuronal cells and for target innervation in both the mucosa and in intestinal smooth muscle. In particular, CGRP innervation was significantly reduced as was the number of dopaminergic neurons. Examination of an FD patient's gastric biopsy also revealed reduced and disoriented axons in the mucosa. Finally, using an FD mouse model in which Elp1 was deleted exclusively from neurons, we found significant changes to the colon epithelium including reduced E-cadherin expression, perturbed mucus layer organization, and infiltration of bacteria into the mucosa. The fact that deletion of Elp1 exclusively in neurons is sufficient to alter the intestinal epithelium and perturb the intestinal epithelial barrier highlights a critical role for neurons in regulating GI epithelium homeostasis., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Neuropathy is a disturbance of function or a pathological change in nerves causing poor health and quality of life. A proportion of chronic pain patients in the community suffer persistent neuropathic pain symptoms because current drug therapies may be suboptimal so there is a need for new therapeutic modalities. This study investigated the neuroprotective flavonoid, 6-methoxyflavone (6MF), as a potential therapeutic agent and gabapentin as the standard comparator, against neuropathic models. Thus, neuropathic-like states were induced in Sprague-Dawley rats using sciatic nerve chronic constriction injury (CCI) mononeuropathy and systemic administration of streptozotocin (STZ) to induce polyneuropathy. Subsequent behaviors reflecting allodynia, hyperalgesia, and vulvodynia were assessed and any possible motoric side-effects were evaluated including locomotor activity, as well as rotarod discoordination and gait disruption. 6MF (25-75 mg/kg) antagonized neuropathic-like nociceptive behaviors including static- (pressure) and dynamic- (light brushing) hindpaw allodynia plus heat/cold and pressure hyperalgesia in the CCI and STZ models. 6MF also reduced static and dynamic components of vulvodynia in the STZ induced polyneuropathy model. Additionally, 6MF reversed CCI and STZ suppression of locomotor activity and rotarod discoordination, suggesting a beneficial activity on motor side effects, in contrast to gabapentin. Hence, 6MF possesses anti-neuropathic-like activity not only against different nociceptive modalities but also impairment of motoric side effects., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Diabetic neuropathy (DN) is one of the major microvascular complications of diabetes mellitus affecting 50% of the diabetic population marred by various unmet clinical needs. There is a need to explore newer pathological mechanisms for designing futuristic regimens for the management of DN. There is a need for post-transcriptional regulation of gene expression by non-coding RNAs (ncRNAs) to finetune different cellular mechanisms with significant biological relevance. MicroRNAs (miRNAs) are a class of small ncRNAs (~ 20 to 24 nucleotide length) that are known to regulate the activity of ~ 50% protein-coding genes through repression of their target mRNAs. Differential expression of these miRNAs is associated with the pathophysiology of diabetic neuropathy via regulating various pathways such as neuronal hyperexcitability, inflammation, axonal growth, regeneration, and oxidative stress. Of note, the circulating and extracellular vesicular miRNAs serve as potential biomarkers underscoring their diagnostic potential. Recent pieces of evidence highlight the potential of miRNAs in modulating the initiation and progression of DN and the possibility of developing miRNAs as treatment options for DN. In this review, we have elaborated on the role of different miRNAs as potential biomarkers and emphasized their druggable aspects for promising future therapies for the clinical management of DN., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Guillain-Barré syndrome (GBS) is a neurological disorder characterized by peripheral, autoimmune-mediated demyelinating polyneuropathy, which can cause muscle weakness and paralysis. While most cases are triggered by respiratory or gastrointestinal infections, vaccinations have also been linked to GBS pathogenesis. The association of the influenza vaccine and GBS, notably prevalent during the 1976 United States swine flu pandemic, has significantly decreased with contemporary seasonal influenza vaccines. At the same time, cases of GBS have been reported with newer vaccines, like the recently approved respiratory syncytial virus (RSV) vaccines. However, their exact relationship with autoimmune demyelinating polyneuropathy remains unknown. In this report, we present a case of a 60-year-old man who developed GBS two weeks after receiving the new Pfizer's RSV vaccine in conjunction with the influenza vaccine for the first time., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Huynh et al.)