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AbstractDiabetic peripheral neuropathy (DPN) is a debilitating complication of diabetes mellitus, affecting nearly 50% of diabetic patients and leading to chronic pain, numbness, and progressive sensory and motor function loss. This study investigates the potential of siRNA-mediated silencing of poly (ADP-ribose) polymerase 1 (PARP1) to alleviate DPN in a rat model. PARP1 overactivation, driven by hyperglycemia-induced oxidative stress, exacerbates neuronal damage in DPN. Using chitosan nanoparticles (ChNPs) to deliver PARP1-targeting siRNA intrathecally in diabetic rats induced with streptozotocin (STZ) 55 mg/kg intraperitoneally, we conducted behavioral and physiological assessments, including Sciatic Functional Index (SFI), motor nerve conduction velocity (MNCV), grip strength, and pain sensitivity tests, alongside qRT-PCR analyses, to evaluate therapeutic outcomes. Our findings indicate statistically significant improvements, with siRNA ChNPs-mediated PARP1 silencing alleviating neuropathic symptoms in DPN rats (p < 0.001 for SFI and MNCV improvements). Biochemical analyses revealed reductions in oxidative stress markers, such as MDA, and increased antioxidant levels, including GSH, CAT, and SOD (p < 0.001). Pro-inflammatory cytokines and apoptotic markers, including NF-κB, IL6, IL1β, TNFa, TGF-β, CAS3, CAS9, BAK, and BAX, also showed significant reductions (p < 0.01), confirming the neuroprotective effects of PARP1 inhibition. These results highlight the potential of siRNA-based therapies targeting PARP1 as a promising therapeutic approach for DPN, paving the way for future research with clinical applications. [ABSTRACT FROM AUTHOR]

Summary Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal disorders, manifesting multiple clinical autoimmune inflammatory phenomena, including rarely peripheral neuropathy. Twenty‐four patients diagnosed with MDS and 29 healthy subjects were enrolled in this prospective study in a 5‐year period. Every subject was assessed by symptoms questionnaire and clinical neurological examination followed by nerve conduction studies, quantitative sensory testing and skin biopsy. Peripheral neuropathy was diagnosed in 12 subjects (50%). Our study indicated that peripheral neuropathy involving large and small nerve fibres, with a symmetrical length‐dependent pattern, is not uncommon between patients with MDS. [ABSTRACT FROM AUTHOR]

Background and Aims Methods Results Interpretation Charcot–Marie–Tooth (CMT) type 1 neuropathies are the most common inherited diseases of the peripheral nervous system. Although more than 100 causative genes have been identified so far, therapeutic options are still missing. We could previously identify that early‐onset physical exercise (voluntary wheel running, VWR) dampens peripheral nerve inflammation, improves neuropathological alterations, and clinical outcome in Cx32def mice, a model for CMT1X. We here investigate the clinical and histopathological effect of late‐onset exercise in Cx32def mice at an advanced disease stage.Nine‐month‐old Cx32def mice were allowed to run for 4 days/week on a commercially available running wheel for 3 months, with timely limited access to running wheels, representing a running distance of ~2000 m. Control mutants had no access to running wheels. Afterward, mice were investigated by distinct functional tests and by immunohistochemical and electron microscopical techniques.We found that late‐onset physical exercise (late VWRlim) prevented the robust functional decline in 12‐month‐old Cx32def mice. This was accompanied by improved neuromuscular innervation of distal muscles and axonal preservation in femoral quadriceps nerves. In contrast to a “pre‐symptomatic” start of physical exercise in Cx32def mice, late‐onset VWR did not alter nerve inflammation and myelin thickness at 12 months of age.We conclude that VWR has robust beneficial effects on nerve function in Cx32def mice, even when applied at a progressed disease stage. These results have important translational implications, suggesting that physical exercise might be an effective treatment option for CMT1 patients, even when disease symptoms have already progressed. [ABSTRACT FROM AUTHOR]

AbstractNeuropathic pain is the crucial dose-limiting side effect of paclitaxel in chemotherapy patients that negatively impacts the quality of life and survival. Currently, no effective treatment option is available. Aprepitant, a well-established chemotherapy antiemetic performing neurokinin-1 receptor antagonism, shows analgesic effects in some pain models. We studied aprepitant analgesic effects on the paclitaxel-induced neuropathic pain model in rats besides inflammatory markers assessment. Rats intraperitoneally received paclitaxel, reaching the cumulative paclitaxel dose of 8 mg/kg. Aprepitant was orally administered every alternate day between days 2 and 14, with a prescribed dosage of 10 or 20 mg/kg. The evaluation of mechanical allodynia and cold hyperalgesia involved the measurement of paw withdrawal threshold and acetone test score on days 0, 7, and 14. On day 14, paw licking latency was measured using a hot plate test before scarification and tissue collection for interleukin 1β, tumor necrosis factor α, and nuclear factor kappa B (NF-kB) evaluation. Paclitaxel induced neuropathy as indicated by a lowered hind paw withdrawal threshold in the Von Frey test, a higher score in the acetone test, and shortened hot plate latency. Aprepitant effectively alleviated cold and thermal hyperalgesia as well as mechanical allodynia. Moreover, aprepitant administration significantly reversed paclitaxel-mediated elevation of proinflammatory cytokines levels in dorsal root ganglia. In addition, aprepitant application suppressed the protein expression of NF-kB in the dorsal root ganglia of paclitaxel-treated rats, as revealed by western blot analysis. Aprepitant treatment ameliorates neuropathy induced by paclitaxel, which is associated with decreasing proinflammatory cytokines and NF-kB expression. [ABSTRACT FROM AUTHOR]

Background and Aims Methods Results Interpretation Peripheral neuropathy (PN) is a common neurological condition in elderly adults. Vitamin D deficiency has been associated with diabetic and chemotherapy‐induced neuropathy, but its role in idiopathic PN, in which no underlying cause of neuropathy can be identified, has not been investigated.Two hundred thirty patients with idiopathic PN enrolled in the Peripheral Neuropathy Research Registry (PNRR) at Johns Hopkins University School of Medicine had vitamin D testing information on record. Linear and logistic regressions were used to investigate the relationship between absolute vitamin D level or vitamin D insufficiency (<20 ng/mL) and both the severity of neuropathy as measured by the reduced total neuropathy score (TNSr) and severity of neuropathic pain.Sixteen (7%) patients were vitamin D insufficient (<20 ng/mL). Controlling for factors known to correlate with severity of neuropathy, there was no correlation between absolute vitamin D levels and TNSr (correlation coefficient 0.01, 95% CI −0.03 to 0.07, p = .59) and no association between vitamin D insufficiency and TNSr (correlation coefficient 0.3, 95% CI −2.8 to 3.4, p = .86). Vitamin D insufficiency was not associated with the presence of neuropathic pain (OR 4.1, 95% CI 0.6–26.0, p = .13), and there was no correlation between vitamin D levels and pain score (correlation coefficient 0.01, 95% CI −0.02 to 0.03, p = .59).In a single‐center cohort of patients with idiopathic PN, there was no correlation between vitamin D levels and the severity of neuropathy or neuropathic pain. [ABSTRACT FROM AUTHOR]

This study demonstrates that adverse events (AEs) extracted using natural language processing (NLP) from clinical texts reflect the known frequencies of AEs associated with anticancer drugs. Using data from 44,502 cancer patients at a single hospital, we identified cases prescribed anticancer drugs (platinum, PLT; taxane, TAX; pyrimidine, PYA) and compared them to non-treatment (NTx) group using propensity score matching. Over 365 days, AEs (peripheral neuropathy, PN; oral mucositis, OM; taste abnormality, TA; appetite loss, AL) were extracted from clinical text using an NLP tool. The hazard ratios (HRs) for the anticancer drugs were: PN, 1.15–1.95; OM, 3.11–3.85; TA, 3.48-4.71; and AL, 1.98–3.84; the HRs were significantly higher than that of the NTx group. Sensitivity analysis revealed that the HR for TA may have been underestimated; however, the remaining three types of AEs extracted from clinical text by NLP were consistently associated with the three anticancer drugs. [ABSTRACT FROM AUTHOR]

Objective Methods Results Interpretation Krabbe disease is due to deficiency of galactocerebrosidase, resulting in progressive neurodegeneration due to demyelination. The purpose of this study is to document disease progression in the newly classified infantile‐onset (0–12 months). We evaluated the outcomes of hematopoietic stem cell transplantation (HSCT) and described meaningful clinical endpoints.Patients with infantile Krabbe disease were prospectively evaluated between 2000 and 2022. All patients underwent comprehensive and standardized protocols. Descriptive statistics and Kaplan–Meier survival curves were used for analysis.One hundred and thirty‐seven children with infantile Krabbe disease were included (68 males and 69 females). Of the 137, 96 were not treated and 41 underwent hematopoietic stem cell transplantation. Twenty‐three were asymptomatic and 18 symptomatic. Initial symptoms included irritability, developmental delay or loss of milestones, feeding difficulties, spasticity, and reflux with an average survival of 2.2. Abnormalities in nerve conduction studies, auditory brainstem responses, and brain MRIs were evident in both groups of patients. Age at transplantation and signs and symptoms determined functional outcomes. Symptomatic and asymptomatic transplanted patients showed an increase in galactocerebrosidase and a decrease in psychosine, but did not reach the normal range. The median survival for transplanted symptomatic patients was 5 years while asymptomatic was extended to 15.5 years.Infantile Krabbe disease with onset before 12 months is rapidly progressive. Irreversible brain damage occurs unless timely HSCT is performed. HSCT does not prevent the progression of peripheral nerve disease. This study can be used to monitor patients and evaluate the effects of future therapies. [ABSTRACT FROM AUTHOR]

Background: Both age‐associated hearing loss (AAHL) and peripheral neuropathy (PN) are common in older patients, and both are associated with impaired balance, falls, and premature mortality. The objectives of this study were to document the prevalence and severity of AAHL in older primary care patients, and to explore associations between AAHL, PN, balance, falls, and mortality. Methods: We analyzed information obtained in 1999 from 793 primary care patients recruited from practices participating in the Oklahoma Longitudinal Assessment of the Health Outcomes of Mature Adults (OKLAHOMA) Studies. Available data included demographic and health information, history of falls and hospitalizations, audiometry, balance testing, examination of the peripheral nerves, 50 foot timed gait, and dates of death up to 22 calendar years and 8106 person‐years of follow‐up. Proportionate hazards (PH) and structural equation modeling (SEM) were used to examine associations between AAHL, PN, balance, gait time, and mortality. Results: 501 of the 793 participants (63%) had AAHL. Another 156 (20%) had low frequency and 32 (4%) had unilateral deficits. Those with moderate or severe AAHL and the 255 (32%) with PN had impaired balance (p < 0.0001), increased gait time (p = 0.0001), and reduced survival time (p < 0.0001). In the PH model, both AAHL and PN were associated with earlier mortality (H.Rs. [95% C.I.]: 1.36 [1.13–1.64] and 1.32 [1.10–1.59] respectively). The combination of moderate or severe AAHL and PN, present in 24% of participants, predicted earlier mortality than predicted by either deficit alone (O.R. [95% C.I.I] 1.55 [1.25–1.92]). In the SEM models, the impacts of both moderate or severe AAHL and PN on survival were mediated, in part, through loss of balance. Conclusions: Hearing loss and PN, both common in older patients, appear to be independently and additively associated with premature mortality. Those associations may be mediated in part by impaired balance. The Mechanisms are likely multiple and complex. [ABSTRACT FROM AUTHOR]

The eye, and the cornea in particular, is a common site of chemotherapy induced toxicity, and ocular side effects of both traditional and novel agents have been reported. Corneal confocal microscopy (CCM) is an in vivo technique that allows for the study of all the corneal layers in an easy, non-invasive and reproducible way via the direct visualization of corneal cell morphologies as well as of sub-basal nerve plexus. Thus, it represents a useful way to identify and monitor chemotherapy induced corneal alterations. This work aims to review the use of CCM in identifying corneal toxicity secondary to chemotherapy treatment, as regards both corneal nerves alterations in the setting of chemotherapy induced peripheral neuropathy (CIPN) and other corneal structure changes, particularly involving the corneal epithelium. [ABSTRACT FROM AUTHOR]

Simple Summary: Surgical treatment of rectal cancer with a low anterior resection allows patients to maintain normal anatomy. Despite this, many patients can postoperatively develop symptoms related to bowel dysfunction known as low anterior resection syndrome (LARS). Systemic therapy for rectal cancer treatment often includes platinum-based chemotherapy agents with peripheral neuropathy as a common side effect. LARS and chemotherapy-induced peripheral neuropathy (CIPN) may greatly affect a patient's quality of life. Thus, the purpose of this study was to evaluate a potential relationship between CIPN and LARS. We found there was an association between CIPN and the development of LARS. Thus, further studies should look to evaluate the possible biological mechanisms behind this relationship. Introduction: Low anterior resection syndrome (LARS) can be a debilitating condition that develops after undergoing sphincter-preserving surgery for rectal cancer. Chemotherapy-induced peripheral neuropathy is a common side effect of platinum-based chemotherapy agents used as systemic therapy for rectal cancer treatment. The purpose of this study was to determine the potential relationship between CIPN and LARS. Methods: This was a retrospective review of patients who underwent a low anterior resection for rectal cancer and received systemic therapy contacted at least six months from the most recent surgery. Eligible patients were called and completed the relevant surveys over the phone or email. Results: There was a total of 42 patients who completed the surveys with 33 (79%) having major LARS. Presence of a diverting ileostomy was the only significantly differentcharacteristic in those with major LARS versus those without. CIPN was independently associated with LARS (p = 0.046) on linear regression when controlling for neoadjuvant chemoradiation, diverting ileostomy and tumor distance from the anal verge. Conclusions: Developing severe CIPN is associated with developing LARS. Further studies evaluating the etiology behind this relationship should be conducted. [ABSTRACT FROM AUTHOR]

Purpose: Regulatory guidance suggests capturing patient-reported overall side effect impact in cancer trials. We examined whether the Functional Assessment of Cancer Therapy (FACT) GP5 item ("I am bothered by side effects of treatment") post-neoadjuvant chemotherapy/radiotherapy differed between oxaliplatin vs. non- oxaliplatin arms in the National Surgical Adjuvant Breast and Bowel Project (NSABP) R-04 trial of stage II–III rectal cancer patients. Methods: The R-04 neoadjuvant trial compared local-regional tumor control between patients randomized to receive 5-fluorouracil or capecitabine with radiation, with or without oxaliplatin (4 treatment arms). Participants completed surveys at baseline and immediately after chemoradiotherapy. GP5 has a 5-point response scale: "Not at all" (0), "A little bit" (1), "Somewhat" (2), "Quite a bit" (3), and "Very much" (4). Logistic regression compared the odds of reporting moderate-high side effect impact (GP5 2–4) between patients receiving oxaliplatin or not after chemoradiotherapy, controlling for relevant patient characteristics. We examined associations between GP5 and other patient-reported outcomes reflecting side effects. Results: Analyses were performed among 1132 study participants. Participants receiving oxaliplatin were 1.58 times (95% CI: 1.22–2.05) more likely to report moderate-high side effect bother at post-chemotherapy/radiation. In both arms, worse overall side effect impact was associated with patient-reported diarrhea, nausea, vomiting, and peripheral sensory neuropathy (p < 0.01 for all). Conclusion: This secondary analysis of R-04 found that GP5 distinguished between patients receiving oxaliplatin or not as part of their post-neoadjuvant chemoradiotherapy, adding patient-centric evidence on the reduced tolerability of oxaliplatin and demonstrating that GP5 is sensitive to known toxicity differences between treatments. ClinicalTrials.gov: NCT00058474. [ABSTRACT FROM AUTHOR]

Objectives The aim of our study was to identify the potential distinct phenotypes within a broad SpA population. Methods We conducted a cross-sectional study using the REGISPONSER registry, which has data from 31 specialist centres in Spain, including patients with SpA who have fulfilled the ESSG criteria. A latent class analysis (LCA) was performed to identify the latent classes underlying SpA according to a set of predefined clinical and radiographic features, independently of expert opinion. Results In a population of 2319 SpA patients, a five-classes LCA model yielded the best fit. Classes named 'Axial with spine involvement' and 'Axial with isolated SI joint involvement' showed a primarily axial SpA phenotype defined by inflammatory back pain and high HLA-B27 prevalence. Patients in class 'Axial + peripheral' showed a similar distribution of manifest variables to previous classes but also had a higher likelihood of peripheral involvement (peripheral arthritis/dactylitis) and enthesitis, therefore representing a mixed (axial and peripheral) subtype. Classes 'Peripheral + psoriasis' and 'Axial + peripheral + psoriasis' were indicative of peripheral SpA (and/or PsA) with high likelihood of psoriasis, peripheral involvement, dactylitis, nail disease, and low HLA-B27 prevalence, while class 'Axial + peripheral + psoriasis' also exhibited increased probability of axial involvement both clinically and radiologically. Conclusion The identification of five latent classes in the REGISPONSER registry with significant overlap between axial and peripheral phenotypes is concordant with a unifying concept of SpA. Psoriasis and related features (nail disease and dactylitis) influenced the phenotype of both axial and peripheral manifestations. [ABSTRACT FROM AUTHOR]

Vincristine-induced peripheral neuropathy (VIPN) is an adverse effect of regimens used for the treatment of aggressive B-cell non-Hodgkin lymphoma (B-NHL). A single-nucleotide polymorphism (SNP) in the promotor region of the CEP72 gene has been identified as risk factor for the development of VIPN in children. To validate these results in adults we aimed to determine the association of the high-risk CEP72 (rs924607 TT genotype) with the occurrence and severity of VIPN. Analysis of SNP rs924607 (TT, CC or CT) was performed in all enrolled patients with available blood samples with a TaqMan genotyping assay. Rates and grades of VIPN were assessed prospectively as part of the RICOVER-60 trial. CEP72 genotype could be assessed in 519 patients. VIPN data was available for 499/519 patients who were included in the final analysis. 286 (57%) patients developed VIPN of any grade during treatment. Grade 2–4 VIPN occurred in 33% (166/499) of patients. The high-risk CEP72 TT genotype at rs924607 was identified in 97/499 (19%) patients. The TT genotype was not correlated with VIPN in the overall study population compared to patients with either CC or CT genotypes (p = 0.748). However, in the subgroup of female patients, the TT genotype was associated with increased occurrence of any-grade VIPN as well as grade 2–4 VIPN as compared to patients with either CC or CT genotypes (p = 0.016 and p = 0.020, respectively). Thus, the SNP rs924607 in the CEP72 gene is associated with increased VIPN incidence in female patients with aggressive B-NHL treated with CHOP chemotherapy. Trial registration ClinicalTrials.gov identifier: NCT00052936, submission date: 2005-06-23, EudraCT Number: 2010-019587-36. [ABSTRACT FROM AUTHOR]

Purpose: Preliminary data suggest that gait abnormalities in Parkinson disease (PD) may be associated with sympathetic cardiac denervation. No kinematic gait studies were performed to confirm this observation. We aimed to correlate spatiotemporal kinematic gait parameters with cardiac sympathetic denervation as determined by cardiac [11C]HED PET in PD. Methods: Retrospective database analysis of 27 PD patients with cardiac sympathetic denervation. All patients underwent spatiotemporal kinematic gait assessment (medication 'off' state), cardiac [11C]HED and dopaminergic brain [11C]DTBZ PET scans. We employed a hierarchical regression approach to examine associations between the extent of cardiac denervation, dopaminergic nigrostriatal neurodegeneration, and three gait parameters - velocity, step length and cadence. Results: More extensive cardiac denervation was associated with slower velocity (estimate: -1.034, 95% CI [-1.65, -0.42], p = 0.002), shorter step length (estimate: -0.818, 95% CI [-1.43, -0.21], p = 0.011) and lower cadence (estimate: -0.752, 95% CI [-1.28, -0.23], p = 0.007) explaining alone 30% (Adjusted-R²: 0.297), 20% (Adjusted-R²: 0.202) and 23% (Adjusted-R²: 0.227) of the variability, respecivetly. These associations remained independent of striatal dopaminergic impairment and confounding factors such as age, Hoehn and Yahr (HY) stages, peripheral neuropathy, cognition, and autonomic symptoms. In contrast, striatal dopaminergic denervation was significantly associated with step length (estimate: 0.883, 95% CI [0.29, 1.48], p = 0.005), explaining about 24% of the variability but was dependent of HY stage. Conclusions: More severe cardiac noradrenergic denervation was associated with lower gait velocity, independent of striatal dopaminergic denervation and HY stage, impacting both step length and cadence. These results suggest independent contributions of the peripheral autonomic system degeneration on gait dynsfunction in PD. [ABSTRACT FROM AUTHOR]

Diabetic neuropathy is one of the most serious and common complications of diabetes with a wide spectrum, affecting 30–50% of diabetic patients. However, the current treatments of this disorder, mainly based on controlling blood glucose level, show an inadequate clinical outcome. Better approaches are needed. In this fashion, it is noted that promoting nerve regeneration and preventing nerve degeneration should be focused on equally and appropriately. In this mini review, how more effective approaches are in targeting PI3K/AKT and MEK/ERK pathways in the treatment of peripheral diabetic neuropathy is discussed. Future treatment of peripheral diabetic neuropathy should consider these approaches. [ABSTRACT FROM AUTHOR]

Adjuvant oxaliplatin plus capecitabine (XELOX) therapy is recommended for patients with curatively resected colon cancer. However, prospective data on its practical application in Japanese patients are limited. Therefore, we aimed to conduct a long-term clinical evaluation of the efficacy and safety of adjuvant XELOX in patients with curatively resected stage III colon cancer (MCSCO-1024). This prospective, multi-center, open-label, single-arm, phase II study enrolled patients with curatively resected stage III colon cancer. The treatment protocol consisted of a 120-minute intravenous infusion of oxaliplatin (130 mg/m2) on day 1 and two divided doses oral capecitabine (2000 mg/m2/day) for 14 days in a 3-week cycle, totaling eight cycles (24 weeks). The primary endpoint was 3-year disease-free survival (DFS), and the secondary endpoints were 5-year overall survival and long-term prognosis of peripheral sensory neuropathy. A total of 196 patients were enrolled between November 2011 and August 2014 (34 months). The 3-year DFS rate was 73%, and the 5-year overall survival rate was 87%. The overall incidence of peripheral sensory neuropathy was 17%, with a 1% rate of grade 3 neuropathy after 5 years. Adjuvant XELOX demonstrated utility and safety in the clinical management of Japanese patients with stage III colon cancer. [ABSTRACT FROM AUTHOR]

Diabetic peripheral neuropathy (DPN) affects ∼50% of the 500 million people with type 2 diabetes worldwide and is considered disabling and irreversible. The current study was undertaken to assess the effect of metformin on peripheral neuropathy outcomes in type 2 diabetes. Participants with type 2 diabetes (n = 69) receiving metformin were recruited and underwent clinical assessment, peripheral nerve ultrasonography, nerve conduction studies, and axonal excitability studies. Also concurrently screened were 318 participants who were not on metformin, and 69 were selected as disease control subjects and matched to the metformin participants for age, sex, diabetes duration, BMI, HbA1c, and use of other diabetes therapies. Medical record data over the previous 20 years were analyzed for previous metformin use. Mean tibial nerve cross-sectional area was lower in the metformin group (metformin 14.1 ± 0.7 mm2, nonmetformin 16.2 ± 0.9 mm2, P = 0.038), accompanied by reduction in neuropathy symptom severity (P = 0.021). Axonal excitability studies demonstrated superior axonal function in the metformin group, and mathematical modeling demonstrated that these improvements were mediated by changes in nodal Na+and K+conductances. Metformin treatment is associated with superior nerve structure and clinical and neurophysiological measures. Treatment with metformin may be neuroprotective in DPN. Article Highlights: We aimed to assess whether peripheral neuropathy outcomes for patients with type 2 diabetes were better on metformin treatment. Metformin and nonmetformin groups with type 2 diabetes were matched for demographic and metabolic factors. Clinical neuropathy scores, peripheral nerve ultrasonography, nerve conduction studies, axonal excitability, and mathematical modeling findings were all superior in the metformin group. Mathematical modeling suggested this was due to superior nodal Na+and K+conductances. Treatment with metformin may be neuroprotective in diabetic peripheral neuropathy. [ABSTRACT FROM AUTHOR]

Splicing is a posttranscriptional RNA processing mechanism that enhances genomic complexity by creating multiple isoforms from the same gene. We aimed to characterize the isoforms expressed in the human peripheral nervous system, with the goal of creating a resource to identify novel isoforms of functionally relevant genes associated with somatosensation and nociception. We used longread sequencing to document isoform expression in the human dorsal root ganglia from 3 organ donors and validated in silico by confirming expression in short-read sequencing from 3 independent organ donors. Nineteen thousand five hundred forty-seven isoforms of protein-coding genes were detected and validated. We identified 763 isoforms with at least one previously undescribed splice junction. Previously unannotated isoforms of multiple pain-associated genes, including ASIC3, MRGPRX1, and HNRNPK, were identified. In the novel isoforms of ASIC3, a region comprising approximately 35% of the 5’UTR was excised. By contrast, a novel splice junction was used in isoforms of MRGPRX1 to include an additional exon upstream of the start codon, consequently adding a region to the 5’UTR. Novel isoforms of HNRNPK were identified, which used previously unannotated splice sites to both excise exon 14 and include a sequence in the 3’ end of exon 13. This novel insertion is predicted to introduce a tyrosine phosphorylation site potentially phosphorylated by SRC. We also independently confirm a recently reported DRG-specific splicing event in WNK1 that gives insight into how painless peripheral neuropathy occurs when this gene is mutated. Our findings give a clear overview of mRNA isoform diversity in the human dorsal root ganglia obtained using long-read sequencing. [ABSTRACT FROM AUTHOR]

Purpose: Isoniazid, a first-line antitubercular drug, is associated with nervous system adverse drug reactions such as seizures, peripheral neuropathy, and psychosis. This systematic review of case reports and case series aimed to characterize the demographic, social, and clinical factors associated with isoniazid-induced psychosis in patients with active tuberculosis (TB) and those who received isoniazid for latent TB infection (LTBI). Methods: We comprehensively searched the Embase, PubMed, and Scopus databases to identify relevant studies published between the date of inception of the database and June 2024. Results: A total of 28 studies, including 21 case reports and 7 case series involved 37 patients who developed isoniazid-induced psychosis. A higher frequency of isoniazid-induced psychosis was observed during the first 2 months of treatment, with a relatively early onset observed among patients aged 18 years or less. Delusions and/or hallucinations are the common symptoms of isoniazid-induced psychosis. Psychomotor disturbances, disorganized speech or formal thought disorder, disorganized or abnormal behaviour, and neuropsychiatric symptoms (sleep disturbances, hostility or aggression, confusion, affective symptoms, anxiety symptoms, and cognitive difficulties) were the other symptoms observed in the included studies. More than 80% of cases rechallenged with isoniazid resulted in the recurrence of psychotic symptoms. Conclusion: Patients with TB and LTBI should be assessed for psychotic and neuropsychiatric symptoms during isoniazid therapy, mainly in the first 2 months. Further research is required to understand the impact of underlying risk factors, such as genetic predisposition and isoniazid pharmacokinetics, as well as the clinical utility and dosage recommendations of pyridoxine for managing isoniazid-induced psychosis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Diabetic peripheral neuropathy (DPN), a complication of diabetes mellitus (DM), is a neurodegenerative disorder that results from hyperglycemic damage and deficient insulin receptor (IR) signaling in peripheral nerves, triggered by failure of insulin production and insulin resistance. IR signaling plays an important role in nutrient metabolism and synaptic formation and maintenance in peripheral neurons. Although several animal models of DPN have been developed to identify new drug candidates using cytotoxic reagents, nutrientrich diets, and genetic manipulations, a model showing beneficial effects remains to be established. In this study, we aimed to develop a DPN animal model using zebrafish to validate the effects of drug candidates on sensory neuropathy through in vivo imaging during the early larval stage. To achieve this, we generated Tg (ins:gal4p16);Tg (5uas:epNTR-p2a-mcherry) zebrafish using an enhanced potency nitroreductase (epNTR)-mediated chemogenetic ablation system, which showed highly efficient ablation of pancreatic β-cells following treatment with low-dose metronidazole (MTZ). Using in vivo live imaging, we observed that sensory nerve endings and postsynaptic formation in the peripheral lateral line (PLL) were defective, followed by a disturbance in rheotaxis behavior without any locomotory behavioral changes. Despite defects in sensory nerves and elevated glucose levels, both reactive oxygen species (ROS) levels, a primary cause of DPN, and the number of ganglion cells, remained normal. Furthermore, we found that the activity of mTOR, a downstream target of IR signaling, was decreased in the PLL ganglion cells of the transgenic zebrafish. Our data indicates that peripheral neuropathy results from the loss of IR signaling due to insulin deficiency rather than hyperglycemia alone. [ABSTRACT FROM AUTHOR]

Peripheral neuropathy is a common cause for neurological consultation, especially among those with diabetes mellitus. However, research on peripheral neuropathy among the general population is lacking in Malaysia. This study aimed to determine the prevalence and factors associated with peripheral neuropathy in a setting of retail pharmacies. This cross-sectional study of 1283 participants was conducted at retail pharmacies in Selangor. Peripheral neuropathy was defined as the final score in the mild to severe category in the severity rating scale using a biothesiometer. SPSS version 26 was used to perform the analysis. Multiple logistic regressions were used to determine the factors associated with peripheral neuropathy. The prevalence of peripheral neuropathy based on the biothesiometer was 26.5%. According to multiple logistic regression, the predictors of peripheral neuropathy were those who have diabetes (AOR = 3.901), aged more than 50 years (AOR = 3.376), have secondary education or below (AOR = 2.330), are male (AOR = 1.816), and have underlying hypertension (AOR = 1.662). Peripheral neuropathy is a reasonably prevalent condition, affecting a quarter of the general population, and often goes undiagnosed. It is crucial for healthcare providers to proactively screen for peripheral neuropathy, particularly in high-risk populations, to prevent potential complications. [ABSTRACT FROM AUTHOR]

Chemotherapy-induced peripheral neuropathy (CIPN) affects a significant majority of cancer patients, with up to 80% experiencing this severe and dose-limiting side effect while undergoing anti-cancer treatment. CIPN can be induced by a variety of drugs commonly employed in the management of both solid tumors and hematologic cancers. The inadequacies in comprehending the pharmacological interventions associated with CIPN and the subsequent signaling pathways have significantly contributed to the disappointing outcomes of several drugs in clinical trials. Recent investigations in pain research have demonstrated a growing inclination toward addressing neuro-inflammation as a strategy for managing chronic pain conditions. Notably, toll-like receptor-4 (TLR-4) has emerged as a key player in immune system activation and is undergoing extensive research. In this review, we emphasize the potential role of TLR-4 in neuropathic pain, highlighting its promise as a target for CIPN treatment. Furthermore, we explore and analyse the intricate interplay between TLR-4, diverse immune cells, downstream pathways, and receptors within the context of CIPN. A comprehensive exploration of these interactions provides valuable insights into the central role of TLR-4 in CIPN development, paving the way for potential ground-breaking therapeutic approaches to alleviate this debilitating condition. [ABSTRACT FROM AUTHOR]

Charcot-Marie-Tooth disease (CMT) is a hereditary peripheral neuropathy involving approximately 80 pathogenic genes. Whole-exome sequencing (WES) and confirmatory Sanger sequencing analysis was applied to identify the diseasecausing mutations in a Chinese patient with lower limb weakness. We present an 18-year-oldmalewith a 2.5-year history of progressive lower limbweakness and an unsteady gait. Upon admission, a physical examination revealed hands tremulousness, bilateral calf muscle wasting and weakness, pes cavus, and elevated serum creatine kinase (CK) levels. Electromyography demonstrated axonal neuropathy affecting both upper and lower limbs. A de novo heterozygous missense mutation was identified in the MORC2 gene, NM_ 001303256.3: c.1199A>G, NP_001290186.1: p.Gln400Arg. Consequently, these clinical and genetic findings suggested a diagnosis of hereditary peripheral neuropathy, CMT type 2Z. Oral mecobalamin and coenzyme Q10 was initiated as subsequent treatment. Our study firstly reports theMORC2 c.1199A>Gmutation occurring de novo, highlighting its causal association with CMT2Z, and prompting its reclassification as likely pathogenic. Oral mecobalamin and coenzyme Q10 might be a potential treatment approach for early-stage CMT2Z. We recommend genetic testing for CMT patients to identify the genetic etiology, thereby improving clinical management and facilitating genetic counseling. [ABSTRACT FROM AUTHOR]

Aim: To describe treatment-induced toxicities (TITs) and associated factors in Zimbabwean cancer patients receiving cisplatin. Methods: In total, 252 Zimbabwean women with cervical cancer, receiving cisplatin were followed up over 12 months for TITs and disease status. Results: Peripheral neuropathy (70%) and ototoxicity (53%) were most prevalent. Advanced disease (OR = 1.3; 95% CI = 1.1–1.5; p = 0.02), pain comedications (OR = 1.3; 95% CI = 1.1–1.5; p = 0.03), alcohol (OR = 2.8; 95% CI = 1.1–7.5; p = 0.04) and comorbidities (OR = 1.2; 95% CI = 1.1–1.4; p = 0.04) increased peripheral neuropathy and ototoxicity risk. Older age increased risk of disease progression (OR = 1.9; 95% CI = 1.4–3.0; p = 0.033). Conclusion: High peripheral neuropathy and ototoxicity prevalence were observed, which are not routinely monitored in Zimbabwe. There is a need for capacity building to incorporate comprehensive TIT testing and optimize cancer care in Zimbabwe. Plain Language Summary Cancer treatment has side effects, also known as treatment-induced toxicities (TITs), that can lead to death if not management properly. African populations are more likely to develop TITs, however, not many studies research on TITs in Africans and why they are more prone to TITs. This study followed up 252 Zimbabwean women with cervical cancer, over 12 months for TITs and found that loss of sensation and ear complications most commonly occurred after treatment. Advanced disease, prescribed pain medication, alcohol consumption history and underlying diseases such as diabetes increased likelihood of TITs, while older age increased risk of unresponsive cancer. This study highlights a need to incorporate comprehensive monitoring for TITs for at-risk individuals toward improving cancer care. Article highlights Peripheral neuropathy and ototoxicity are common in Zimbabwean cancer patients, even though they are not routinely monitored in oncology facilities. Clinical factors such as comorbid conditions, pain co-medications and high cisplatin dose increase the risk of developing treatment-induced toxicities (TITs). High BMI was a predictor of peripheral neuropathy development. Lifestyle factors such as history of alcohol consumption can increase the risk of treatment-induced toxicities. In this study, HIV was not a risk factor for any of the TITs and treatment outcomes such as relapse, disease progression and mortality. Older patients are more prone to poor prognosis compared with younger patients highlighting a need for cancer screening even beyond the prescribed age of 40 years. Comprehensive TIT monitoring should be implemented in Zimbabwe primary care for cancer patients, to include peripheral neuropathy and ototoxicity, toward improving patient management. More studies to describe TITs in low-resource settings such as Zimbabwe are required in order to personalize medicine. [ABSTRACT FROM AUTHOR]

BCL-w is a BCL-2 family protein that promotes cell survival in tissue- and disease-specific contexts. The canonical anti-apoptotic functionality of BCL-w is mediated by a surface groove that traps the BCL-2 homology 3 (BH3) α-helices of pro-apoptotic members, blocking cell death. A distinct N-terminal portion of BCL-w, termed the BCL-2 homology 4 (BH4) domain, selectively protects axons from paclitaxel-induced degeneration by modulating IP3 receptors, a noncanonical BCL-2 family target. Given the potential of BCL-w BH4 mimetics to prevent or mitigate chemotherapy-induced peripheral neuropathy, we sought to characterize the interaction between BCL-w BH4 and the IP3 receptor, combining "staple" and alanine scanning approaches with molecular dynamics simulations. We generated and identified stapled BCL-w BH4 peptides with optimized IP3 receptor binding and neuroprotective activities. Point mutagenesis further revealed the sequence determinants for BCL-w BH4 specificity, providing a blueprint for therapeutic targeting of IP3 receptors to achieve neuroprotection. [Display omitted] • Hydrocarbon staple scanning yielded optimal BCL-w BH4 domain binders of IP3R1 • Molecular dynamics simulations identified a BH4-binding site in ARM2 of IP3R1 • Point mutagenesis revealed the binding determinants for BH4 interaction • A lead stapled BCL-w BH4 peptide protects axons from chemo-induced degeneration Tang et al. report that staple and alanine scanning of the BCL-w BH4 domain revealed binding determinants for targeting IP3R1 by interaction with a surface groove on ARM2, as predicted by molecule dynamics simulations. A lead construct protected axons from paclitaxel-induced degeneration, with point mutagenesis impairing IP3R1 interaction and neuroprotection. [ABSTRACT FROM AUTHOR]

Diabetes-related foot ulcers are a leading cause of morbidity and mortality globally, in which the most significant contributing factor is peripheral neuropathy. The purpose of this research was to evaluate the influence of diabetic peripheral neuropathy and ulceration on lower limb and foot joint kinematics during gait. Are there any significant alterations lower limb and foot joint kinematics during gait in the presence of active and history of diabetic neuropathic ulceration? A prospective, cross-sectional study was conducted, recruiting eighty adult participants who were equally divided into four groups, namely, the diabetes (DM), diabetic peripheral neuropathy (DPN), active diabetic neuropathic ulceration (DNU) and history of diabetic neuropathic ulceration (DHNU) groups. Three-dimensional gait analysis was performed, and participants were instructed to walk barefoot over a 10-m walkway at self-selected speed. The acquired pelvic, hip, knee, ankle and foot joint segmental kinematic data was compared between individuals with and without active neuropathic ulceration. Mean scores between the four independent groups was performed using the Kruskal-Wallis test. Participants within the DNU and DHNU groups demonstrated significantly reduced knee flexion, ankle dorsiflexion and first metatarsal dorsiflexion kinematics with resultant increased anterior pelvic tilt, hip flexion and midtarsal kinematics (all values p<0.01) when compared to participants within the DM and DPN groups. Through the integration of a more individualised, biomechanical approach, the findings in this study may provide improved preventative and management strategies of ulceration amongst the diabetic population. • Joint kinematic related to active and history of neuropathic ulceration. • Proximal lower limb kinematics were significantly altered as foot joint segments. • Including a detailed biomechanical evaluation during diabetic assessment is advised. [ABSTRACT FROM AUTHOR]

Peripheral neuropathy is a common complication of diabetes and increases the risk of falls, possibly through gait (quality) impairments in daily life. Characteristics of gait quality have been associated with peripheral neuropathy in a laboratory setting, but little is known about the more relevant association with gait quality in daily life. What is the association between peripheral neuropathy and gait quality characteristics in daily life in people with diabetes? Data from two cross-sectional studies were combined in an exploratory analysis, including a total of 98 participants with diabetes (mean age: 68 (SD 7) years, 32 females), of which 68 with peripheral neuropathy. Participants wore a tri-axial accelerometer for seven consecutive days. Walking episodes ≥5 seconds were identified and analysed to determine various gait quality characteristics. Associations were assessed using linear regression analyses, adjusted for walking speed and other potential confounders. Peripheral neuropathy was significantly associated with a lower walking speed (people with neuropathy: 0.81 vs without neuropathy: 0.88 m/s; β (95 % confidence interval (CI)): −0.114 (−0.202 to −0.026)), a lower stride frequency (0.81 vs 0.85 strides/s; β (95 % CI): −0.030 (−0.057 to −0.003)), lower gait intensity (i.e. lower root mean square) in vertical direction (1.38 vs 1.63 m/s2; β (95 % CI): −0.074 (−0.143 to −0.006)), and less gait symmetry (i.e. lower harmonic ratio) in vertical direction (1.82 vs 2.27; β (95 % CI): −0.322 (−0.474 to −0.170)). People with peripheral neuropathy had non-significantly poorer gait quality for most of the other 21 gait quality characteristics. Peripheral neuropathy seems to negatively affect several gait quality characteristics measured in daily life. These results need to be replicated in future studies and may help to develop targeted gait training to improve gait quality and potentially reduce fall risk in people with diabetes and peripheral neuropathy. • Sensor based daily-life gait quality was assessed in people with diabetes. • Peripheral neuropathy from diabetes reduces walking speed and stride frequency. • Peripheral neuropathy is associated with lower vertical gait intensity and symmetry. • Peripheral neuropathy negatively affects gait quality in people with diabetes. [ABSTRACT FROM AUTHOR]

The sural nerve provides sensory innervation to the skin on the distal posterolateral third of the lower extremity. The morphological variants are characterized by high variability. However, it most commonly arises from a union of the medial sural cutaneous nerve and the peroneal communicating branch of the common fibular nerve. This article overviews the anatomical and clinical significance of the sural nerve. Despite the remarkable development of genetic diagnostics, sural nerve biopsy is still a very important tool to diagnose peripheral neuropathies such as diabetic, vascular and inflammatory neuropathies. Furthermore, the sural nerve is also commonly transplanted due to its characteristics. Such a procedure is applicable in cases of segmental nerve loss, but it is also used to restore potency in patients after radical prostatectomy. The knowledge of anatomical variants of the sural nerve is also crucial as it allows to minimize its damage during surgical procedures. Furthermore, during an ankle surgery, a nerve block can be used to complement anesthesia. The major aim of this work is to review contributions of the sural nerve to physiological and pathophysiological processes. [ABSTRACT FROM AUTHOR]

Increasing cyclic GMP activates 26S proteasomes via phosphorylation by Protein Kinase G and stimulates the intracellular degradation of misfolded proteins. Therefore, agents that raise cGMP may be useful therapeutics against neurodegenerative diseases and other diseases in which protein degradation is reduced and misfolded proteins accumulate, including Charcot Marie Tooth 1A and 1B peripheral neuropathies, for which there are no treatments. Here we increased cGMP in the S63del mouse model of CMT1B by treating for three weeks with either the phosphodiesterase 5 inhibitor tadalafil, or the brain-penetrant soluble guanylyl cyclase stimulator CYR119. Both molecules activated proteasomes in the affected peripheral nerves, reduced polyubiquitinated proteins, and improved myelin thickness and nerve conduction. CYR119 increased cGMP more than tadalafil in the peripheral nerves of S63del mice and elicited greater biochemical and functional improvements. To determine whether raising cGMP could be beneficial in other neuropathies, we first showed that polyubiquitinated proteins and the disease-causing protein accumulate in the sciatic nerves of the C3 mouse model of CMT1A. Treatment of these mice with CYR119 reduced the levels of polyubiquitinated proteins and the disease-causing protein, presumably by increasing their degradation, and improved myelination, nerve conduction, and motor coordination. Thus, pharmacological agents that increase cGMP are promising treatments for CMT1 neuropathies and may be useful against other proteotoxic and neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Background and Purpose: Mitochondrial dysfunction contributes to the pathogenesis and maintenance of chemotherapy‐induced peripheral neuropathy (CIPN), a significant limitation of cancer chemotherapy. Recently, the stimulation of mitophagy, a pivotal process for mitochondrial homeostasis, has emerged as a promising treatment strategy for neurodegenerative diseases, but its therapeutic effect on CIPN has not been explored. Here, we assessed the mitophagy‐inducing activity of 3,5‐dibromo‐2‐(2′,4′‐dibromophenoxy)‐phenol (PDE701), a diphenyl ether derivative isolated from the marine sponge Dysidea sp., and investigated its therapeutic effect on a CIPN model. Experimental Approach: Mitophagy activity was determined by a previously established mitophagy assay using mitochondrial Keima (mt‐Keima). Mitophagy induction was further verified by western blotting, immunofluorescence, and electron microscopy. Mitochondrial dysfunction was analysed by measuring mitochondrial superoxide levels in SH‐SY5Y cells and Drosophila larvae. A thermal nociception assay was used to evaluate the therapeutic effect of PDE701 on the paclitaxel‐induced thermal hyperalgesia phenotype in Drosophila larvae. Key Results: PDE701 specifically induced mitophagy but was not toxic to mitochondria. PDE701 ameliorated paclitaxel‐induced mitochondrial dysfunction in both SH‐SY5Y cells and Drosophila larvae. Importantly, PDE701 also significantly ameliorated paclitaxel‐induced thermal hyperalgesia in Drosophila larvae. Knockdown of ATG5 or ATG7 abolished the effect of PDE701 on thermal hyperalgesia, suggesting that PDE701 exerts its therapeutic effect through mitophagy induction. Conclusion and Implications: This study identified PDE701 as a novel mitophagy inducer and a potential therapeutic compound for CIPN. Our results suggest that mitophagy stimulation is a promising strategy for the treatment of CIPN and that marine organisms are a potential source of mitophagy‐inducing compounds. [ABSTRACT FROM AUTHOR]

Pain is a common symptom of many clinical diseases; it adversely affects patients' physical and mental health, reduces their quality of life, and heavily burdens patients and society. Pain treatment is one of the most difficult problems today. There is an urgent need to explore the potential factors involved in the pathogenesis of pain to improve its diagnosis and treatment rate. Piezo1/2, a newly identified mechanosensitive ion channel opens in response to mechanical stimuli and plays a critical role in regulating painrelated diseases. Inhibition or downregulation of Piezo1/2 alleviates diseaseinduced pain. Therefore, in this study, we comprehensively discussed the biology of this gene, focusing on its potential relevance in pain-related diseases, and explored the pharmacological effects of drugs using this gene for the treatment of pain. [ABSTRACT FROM AUTHOR]

Background: Paclitaxel-induced peripheral neuropathy (PIPN) is one of the most common and debilitating toxicity. Up till now, no treatment or preventive medication is recommended by guidelines. Pentoxifylline has been found to prevent PIPN in animal models. This study aimed to evaluate the tolerability and efficacy of pentoxifylline in preventing PIPN. To our knowledge, this is the first clinical trial to evaluate the potential effect of pentoxifylline on the prevention of PIPN in breast cancer (BC) patients. Results: A simple-randomized placebo-controlled study was conducted on 60 BC patients receiving weekly paclitaxel and either pentoxifylline 400 mg twice daily (n = 30) or placebo (n = 30) for 12 weeks. Only 55 patients completed the study. The main objective was the evaluation of the effect of pentoxifylline on the incidence of PIPN which revealed no significant difference between the pentoxifylline group (85%) and the placebo group (100%). Secondary objectives included time to develop grade 2 or 3 (TTG 2/3) PIPN, the patient’s quality of life (QOL), serum tumor necrosis factor-α (TNF-α) and malondialdehyde and the tolerability of pentoxifylline. The median TTG 2/3 PIPN was not reached in the pentoxifylline group compared to 77 days (95% confidence interval of 70.91 to 83.07) in the placebo group. However, the difference did not reach significance. The assessment of the impact of PIPN on QOL was performed at baseline and at weeks 4, 8 and 12 using Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX) subscale. The magnitude of the worsening in the QOL was significantly lower in the pentoxifylline group than in the placebo group at weeks 4, 8, and 12 (p values = 0.028, 0.003, and 0.018, respectively). Analysis of the serum TNF-α and malondialdehyde revealed no significant differences between the groups. Pentoxifylline was safe, tolerable and did not affect paclitaxel toxicity. Conclusion: Oral pentoxifylline (400 mg twice daily) did not decrease the incidence of PIPN. However, it improved patients’ QOL significantly. Trial registration Clinical Trials.gov, NCT05189535. Registered 4 October 2021, . [ABSTRACT FROM AUTHOR]

ABSTRACT Background Methods Results Conclusions 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).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).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).Among patients with colon cancer who received oxaliplatin‐based chemotherapy, higher baseline dietary quality was associated with a reduced risk of moderate‐severe CIPN. [ABSTRACT FROM AUTHOR]

Background: Bartonella species are fastidious, intracellular bacteria responsible for an expanding array of human pathologies. Most are considered to be transmitted by direct inoculation with infected bodily fluids from a mammalian reservoir species or vector-transmitted through a variety of arthropod species and their excrement. However, there are mounting reports of infection in the absence of documented animal or vector contact. A variety of Bartonella species have been documented in conditions affecting both the peripheral and central nervous systems. More common conditions, including neuroretinitis, are often associated with Bartonella henselae. However, Bartonella quintana, the agent of trench fever, as well as emerging pathogens related to rodent reservoir species, B. grahamii and B. elizabethae, have also been documented. Encephalitis and encephalopathy, also most often associated with B. henselae, have been reported with B. quintana, B. washoensis (ground squirrels) and B. vinsonii subsp. vinsonii (voles) infections. Bartonella infections have also been associated with peripheral neuropathies, such as cranial nerve paresis and neuropathic pain, including infection with less commonly encountered species such as Bartonella koehlerae. Recently, molecular diagnostic testing revealed that DNA from Bartonella spp. was found to be more prevalent in blood of patients with neuropsychiatric disorders such as schizophrenia and psychoses compared to healthy controls. Methods: A systematic literature search was conducted on PubMed, Google Scholar and Web of Science. Search terms included Bartonella and specific neurological conditions and focused on peer-reviewed case reports published after 2012 pursuant to a prior review, with limited exceptions for conditions not previously covered. Published diagnostic testing, serology, molecular testing or pathology, were necessary for inclusion, except for one case which had clinical and epidemiological evidence consistent with diagnosis along with follow-up. Results: Neurobartonelloses included neuralgic amyotrophy, complex regional pain syndrome, chronic inflammatory demyelinating polyneuropathy, cranial nerve paralysis, Guillain-Barré syndrome, peripheral vasculitic polyneuropathy, acute transverse myelopathy, neuroretinitis, encephalitis/encephalopathy, cerebral vasculitis/aneurysm and neuropsychiatric conditions. Conclusions: The breadth of reported symptoms and clinical syndromes associated with an increasing number of Bartonella species continues to expand. Increased clinical awareness of this important zoonotic pathogen is necessary to advance One Health among the medical and veterinary communities. [ABSTRACT FROM AUTHOR]

Background: This study investigated the prognostic importance of the hemoglobin glycation index (HGI) for macrovascular and microvascular outcomes, mortality, and hypoglycemia occurrence in a type 2 diabetes cohort and compared it to glycated hemoglobin (HbA1c). Methods: Baseline and mean first-year HGI and HbA1c, and the variability thereof, were assessed in 687 individuals with type 2 diabetes (median follow-up, 10.6 years). Multivariable Cox regression was conducted to evaluate the associations of HGI and HbA1c parameters with macrovascular (total and major cardiovascular events) and microvascular outcomes (microalbuminuria, advanced renal failure, retinopathy, and peripheral neuropathy), mortality (all-cause and cardiovascular), and moderate/severe hypoglycemia occurrence. Results: During follow-up, there were 215 total cardiovascular events (176 major) and 269 all-cause deaths (131 cardiovascular). Microalbuminuria developed in 126 patients, renal failure in 104, retinopathy in 161, and neuropathy in 177. There were 90 hypoglycemia episodes. Both HGI and HbA1c predicted all adverse outcomes, except microalbuminuria and hypoglycemia. Their adjusted risks were roughly equivalent for all outcomes. For example, the adjusted hazard ratios (HRs) with 95% confidence intervals (CIs), estimated for 1 standard deviation increments, of mean first-year HGI were 1.23 (1.05 to 1.44), 1.20 (1.03 to 1.38), 1.36 (1.11 to 1.67), 1.28 (1.09 to 1.67), and 1.29 (1.09 to 1.54), respectively, for cardiovascular events, all-cause mortality, renal failure, retinopathy, and neuropathy; whereas the respective HRs (95% CIs) of mean HbA1c were 1.31 (1.12 to 1.53), 1.28 (1.11 to 1.48), 1.36 (1.11 to 1.67), 1.33 (1.14 to 1.55), and 1.29 (1.09 to 1.53). Conclusion: HGI was no better than HbA1c as a predictor of adverse outcomes in individuals with type 2 diabetes, and its clinical use cannot be currently advised. [ABSTRACT FROM AUTHOR]

Introduction: The state of Goa has the highest prevalence of diabetes and prediabetes in India. Pain because of abnormalities in the somatosensory system due to diabetes is referred to as Painful Diabetic Peripheral Neuropathy (PDPN). A common complication associated with PDPN is poor Quality of Life (QoL), which can lead to lifelong disability. Aim: To estimate the prevalence of PDPN and its impact on QoL in patients in Goa, India. Materials and Methods: In this cross-sectional observational study, 320 participants were screened at Goa Medical College, Bambolim, Goa, India, from August 2021 to August 2022, and 288 were diagnosed with Diabetic Peripheral Neuropathy (DPN). Among those 288 individuals, 91 reported experiencing PDPN, as assessed using the Douleur Neuropathique 4 (DN-4) questionnaire. The investigator interviewed participants aged 18 to 75 years, of all genders, who were diagnosed with either Type 1 or Type 2 diabetes. Baseline characteristics, including age, weight, height, Body Mass Index (BMI), duration of diabetes, and results from the lateralisation test using the graded motor imagery app, were recorded. Participants were assessed using the Neuropathy Symptom Score, and only those who scored at least 1 were included, indicating the presence of DPN. These participants then completed the DN-4 questionnaire; those scoring 3 or more were diagnosed with PDPN. Subsequently, QoL was assessed using the RAND QoL questionnaire {RAND Short Form Survey (SF-36)}. Demographic and clinical characteristics were presented as mean±Standard Deviation (SD). Comparisons between patients with PDPN and those without PDPN were made using an Independent t-test. The normality of continuous variables was tested using the Kolmogorov-Smirnov test. All analyses were carried out using IBM Statistical Package for the Social Sciences (SPSS) (version 28.0). Results: The prevalence of PDPN was found to be 31.6%, with significant impairments in the physical functioning, social functioning, and pain domains (p-value <0.001). Conclusion: The prevalence of PDPN was found to be 31.6%. Significant impairments in various QoL domains were noted in participants with PDPN. [ABSTRACT FROM AUTHOR]

Background & Objective: The most common microvascular consequence of diabetes is peripheral neuropathy. A very common ailment that has a significant impact on a patient's quality of life is peripheral neuropathy (PN). The purpose of this study was to look into the possible link between retinol binding protein 4 (RBP4) and peripheral neuropathy in individuals with type 2 diabetes mellitus (T2D), as the relationship between RBP4 and PN is still unclear. Methodology: We enrolled 152 participants who were matched for age and sex in a case control study during August and December 2023. There were 50 healthy controls, 50 diabetic patients without PN, and 52 diabetic patients with PN. ELISA was used to measure serum RBP4. Results: Diabetic individuals with PN had significantly greater serum levels of RBP4 than diabetic patients without PN (P < 0.001). Increased age (r = 0.262, P < 0.01), DM duration (r = 0.565, P < 0.01), and BMI (r = 0.183, P < 0.05) were all substantially linked with RBP4 levels. RBP4 levels exhibited a negative correlation with high-density lipoproteins (HDL) and a positive correlation with total cholesterol, triglycerides, low-density lipoprotein (LDL), and very low-density lipoprotein (VLDL). Conclusion: Elevated RBP4 level is strongly and independently linked with PN in type 2 diabetic patients, and may play an important role in PN progression. [ABSTRACT FROM AUTHOR]

Peripheral nerve lesions of the upper extremity are common and are associated with devastating limitations for the patient. Rapid and accurate diagnosis of the lesion by electroneurography, neurosonography, or even MR neurography is important for treatment planning. There are different therapeutic approaches, which may show individual differences depending on the injured nerve. If a primary nerve repair is not possible, several strategies exist to bridge the gap. These may include autologous nerve grafts, bioartificial nerve conduits, or acellular nerve allografts. Tendon and nerve transfers are also of major importance in the treatment of nerve lesions in particular with long regeneration distances. As a secondary reconstruction, in addition to tendon transfers, there is also the option for free functional muscle transfer. In amputations, the prevention of neuroma is of great importance, for which different strategies exist, such as target muscle reinnervation, regenerative peripheral nerve interface, or neurotized flaps. In this article, we give an overview of the latest methods for the therapy of peripheral nerve lesions. [ABSTRACT FROM AUTHOR]

Background: Tug-of-War (TOW) games involve repetitive hand movements and vigorous force, raising the risk of peripheral neuropathy in the upper extremities. The prevalence of carpal tunnel syndrome (CTS) in TOW athletes remains unclear. We hypothesize that elite female TOW athletes have a higher prevalence of CTS than the general population. Methods: Twenty-nine female TOW athletes were recruited from a national team and participated in the study. CTS was clinically diagnosed by history taking and physical examination. Nerve conduction studies (NCS) were additionally performed to confirm CTS. Results: Twelve athletes were clinically diagnosed with CTS; however, only nine were confirmed by NCS. Ten athletes were diagnosed with subclinical CTS by NCS, while seven were classified as truly-non-CTS by both clinical assessment and NCS. The prevalence of CTS and subclinical CTS among the athletes was found to be 33.3% and 37.0%, respectively, significantly higher than 2.7% in the general population by electrodiagnosis. The body weight (p = 0.025) of the athletes with CTS and subclinical CTS was significantly different from those of the athletes without CTS. Conclusions: Our observations revealed a higher prevalence of CTS among elite female TOW athletes, with body weight being a risk factor. The forceful grasping and pulling of the rope may contribute to the development of CTS. [ABSTRACT FROM AUTHOR]

Paclitaxel (PTX)‐induced peripheral neuropathy (PIPN) is a disabling side effect of PTX, which adversely affects the life quality of cancer patients. Flavonoids such as hesperidin methyl chalcone (HMC) and taxifolin (TAX) can alleviate neuropathic pain via their anti‐inflammatory, antioxidant, neuroprotective, and antinociceptive properties. The current study aimed to assess the efficacy of HMC and TAX in preventing PIPN individually or in combination. Pretreatment with HMC and TAX mitigated PTX‐induced mechanical allodynia and hyperalgesia, cold allodynia, and thermal hyperalgesia as well as restore the normal histological architecture. Remarkably, neuropathic pain was relieved by suppression of nerve growth factor (NGF), p38 mitogen‐activated protein kinase (p38 MAPK), and transient receptor potential vanilloid type‐1 (TRPV1), which ultimately lead to reduced calcitonin gene‐related peptide (CGRP). Furthermore, both HMC or TAX enhanced nuclear factor erythroid 2–related factor 2 (Nrf2), leading to elevated glutathione (GSH) and total antioxidant capacity (TAC) along with lowered malondialdehyde (MDA), which in turn, downregulated nuclear factor kappa B P65 (NF‐κB P65) and its phosphorylated form and eventually reduced tumor necrosis factor alpha (TNF‐α) and interleukin‐1 beta (IL‐1β) then lowered the apoptotic indices. Promisingly, the combination of both agents was superior to each drug alone through targeting more diverse signaling pathways and achieving synergistic and comprehensive therapeutic effects. In conclusion, pretreatment with HMC and TAX separately or in combination alleviated PIPN via modulating NGF/p38 MAPK/NF‐κB P65/TRPV1/CGRP pathway. [ABSTRACT FROM AUTHOR]

Heterozygous pathogenic variants in the histidyl‐tRNA synthetase (HARS) gene are associated with Charcot–Marie–Tooth (CMT) type 2W disease, classified as an axonal peripheral neuropathy. To date, at least 60 variants causing CMT symptoms have been identified in seven different aminoacyl‐tRNA synthetases, with eight being found in the catalytic domain of HARS. The genetic data clearly show a causative role of aminoacyl‐tRNA synthetases in CMT; however, the cellular mechanisms leading to pathology can vary widely and are unknown in the case of most identified variants. Here we describe a novel HARS variant, c.412T>C; p.Y138H, identified through a CMT gene panel in a patient with peripheral neuropathy. To determine the effect of p.Y138H we employed a humanized HARS yeast model and recombinant protein biochemistry, which identified a deficiency in protein dimerization and a growth defect which shows mild but significant improvement with histidine supplementation. This raises the potential for a clinical trial of histidine. [ABSTRACT FROM AUTHOR]

The article discusses research which examined associations of peripheral neuropathy (PN) with lower extremity physical performance, including gait speed, in community-dwelling older adults with and without diabetes. Cited are the demographic and clinical characteristics of the study participants, results confirming the relationship between PN and slow gait persists into advanced age, and findings supporting the usefulness and feasibility of monofilament testing for gait dysfunction.

Consequences of brachial plexus injuries (BPI) would likely impact participation, but outcomes are not well understood. This exploratory study aimed to report the participation in productive, leisure and social roles for individuals following BPI. Fourteen male participants were diagnosed with a traumatic, BPI. Descriptive data reported included demographic, injury, surgical, and participation measures. Two-sample t-tests were conducted for comparative analysis with other studies following life altering conditions. Just over two-thirds reported feeling satisfied to very satisfied with their participation in everyday life. This long-term follow up study found on-going and profound impact on participation in a range of life situations for this diagnostic group. Participation in productive roles, home duties, and physical exercise were particularly impacted and need to be prioritized during rehabilitation. [ABSTRACT FROM AUTHOR]

Objectives To assess self-reported symptoms of neuropathy, disability, pain, health-related quality of life (HR-QOL) and autonomic dysfunction in patients with vasculitis. Methods Patients with vasculitis (with or without neuropathy) were invited by Vasculitis UK to complete an anonymous online survey. Results Three hundred and twelve patients (71% female) responded. Median age was 61–70 years. Median duration of vasculitis was 4 years (<2 months to >15 years). Vasculitic types included granulomatosis with polyangiitis (34%), unspecified ANCA-associated vasculitis (13%), microscopic polyangiitis (11%), eosinophilic granulomatosis with polyangiitis (11%), giant cell arteritis (10%), non-systemic vasculitic neuropathy (2%) and other (19%). Many patients reported foot/hand symptoms suggestive of neuropathy, including numbness (64%), pain (54%) or weakness (40%). Two hundred and forty-two patients (78%) met our definition of probable vasculitic neuropathy: diagnosis of neuropathy by vasculitis team OR numbness OR weakness in feet/hands. Only 52% had been formally diagnosed with neuropathy. Compared with 70 patients without neuropathy, neuropathy patients had greater disability measured by the inflammatory Rasch-built Overall Disability Scale (centile mean 63.1 [ s. d. 17.3] vs 75.2 [16.7]; P  < 0.0001), Inflammatory Neuropathy Cause and Treatment scale (median 2 [interquartile range 1–4] vs 0.5 [0–2]; P  < 0.0001) and modified Rankin scale (median 2 [interquartile range 1–3] vs 2 [1–2)]; P  = 0.0002); greater pain on an 11-point rating scale (mean 4.6 [ s. d. 2.6] vs 3.5 [2.8]; P  = 0.0009); and poorer HR-QOL on the EQ5D-3L (summary index mean 0.58 [ s. d. 0.29] vs 0.69 [0.28]; P  < 0.0001). Two-thirds reported autonomic symptoms (not associated with neuropathy). Conclusion Neuropathy is common and associated with significant disability, pain and impaired HR-QOL in patients with systemic vasculitis. [ABSTRACT FROM AUTHOR]

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and dose-limiting side effect of chemotherapy. CIPN is difficult to grade objectively, and therefore efforts have been aimed at identifying an objective biomarker of CIPN. During the past 4 years, neurofilament light chain (NFL) has emerged as a preclinical and clinical biomarker of CIPN. Several chemotherapeutics cause rapid and dramatic increases in NFL levels in in vitro systems, rodent models, and clinical studies, which indicates that NFL reflects neuronal damage. Thus far, paclitaxel appears to cause the most pronounced increases. Early elevations in serum NFL may predict later occurrence of CIPN in cancer patients. NFL shows promise as an objective biomarker of CIPN especially in in vitro and in rodent models. The prognostic value of NFL to predict CIPN is still not established and requires prospective evaluation. Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of chemotherapy. The frequency of CIPN ranges from one in three to almost all patients depending on type of chemotherapy and dose. It causes symptoms that can range from sensitivity to touch and numbness to neuropathic pain in hands and feet. CIPN is notoriously difficult to grade objectively and has mostly relied on a clinician- or patient-based rating that is subjective and poorly reproducible. Thus, considerable effort has been aimed at identifying objective biomarkers of CIPN. Recent in vitro , animal, and clinical studies suggest that neurofilament light chain (NFL), a structural neuronal protein, may be an objective biomarker of CIPN. NFL released from cells to cell culture media reflects in vitro neurotoxicity, while NFL in serum reflects neuronal damage caused by chemotherapy in rodent models. Finally, NFL in serum may be a diagnostic biomarker of CIPN, but its prognostic ability to predict CIPN requires prospective evaluation. We discuss current limitations and future perspectives on the use of NFL as a preclinical and clinical biomarker of CIPN. [ABSTRACT FROM AUTHOR]

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a significant side effect of some chemotherapeutic agents. Effective treatment is limited. OBJECTIVES: This single patient case details gua sha as an intervention to reduce CIPN. METHODS: A 38-year-old female patient received weekly treatment of gua sha in one-hour sessions for 10 weeks. The patient completed the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX) subscale to describe her CIPN throughout and postintervention. A research assistant measured the extent of numbness or tingling along the limb from baseline to 18 months after gua sha. Descriptive data were used to summarize this case. FINDINGS: After gua sha, the total FACT/GOG-NTX subscale score increased from 13 to 36, indicating a sevenfold greater change than the minimum clinically important difference. The range of limb numbness and tingling decreased, and the symptoms remained stable during follow-up. Gua sha showed a positive clinical effect. [ABSTRACT FROM AUTHOR]

• Increased intraneural microvascular could be detected in patients with peripheral neuropathies using sonography. • Intraneural hypervascularization was frequently observed in patients with inflammatory neuropathies. • Superb microvascular imaging is the most sensitive technique for evaluating microvessel flow within peripheral nerves. We assessed microvessel flow within peripheral nerves using nerve sonography in patients with peripheral neuropathy. This study included consecutive patients with peripheral neuropathy who were admitted to our hospital. The patients were divided into two groups: inflammatory neuropathies for immune-mediated neuropathies, such as Guillain − Barré syndrome and chronic inflammatory demyelinating polyneuropathy, and the rest were defined as non-inflammatory neuropathies. We assessed nerve size and intraneural blood flow at four sites on each median and ulnar nerve. Blood flow was evaluated using color Doppler imaging, advanced dynamic flow (ADF), and superb microvascular imaging (SMI) techniques. Thirty-nine patients (median age, 60.0 years; 20 male) were enrolled in this study. An increase in intraneural blood flow was observed in five patients when evaluated by color Doppler, five patients by ADF, and 13 patients by SMI. An overall analysis of the three methods showed that intraneural blood flow was significantly higher in patients with inflammatory neuropathy than in those with non-inflammatory neuropathy (54.2% vs. 0%, p = 0.0005). Intraneural hypervascularization is more frequent in patients with inflammatory neuropathy than in those with non-inflammatory neuropathy. Evaluation of microvessel flow within peripheral nerves may contribute to the diagnosis of peripheral neuropathy. [ABSTRACT FROM AUTHOR]

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune disease of the peripheral nervous system that can lead to severe disability from muscle weakness and sensory disturbances. Around a third of patients do not respond to currently available treatments, and many patients with a partial response have residual neurological impairment, highlighting the need for effective alternatives. Efgartigimod alfa, a human IgG1 antibody Fc fragment, has demonstrated efficacy and safety in patients with generalised myasthenia gravis. We evaluated the safety, tolerability, and efficacy of subcutaneous efgartigimod PH20 in adults with CIDP. ADHERE, a multistage, double-blind, placebo-controlled trial, enrolled participants with CIDP from 146 clinical sites from Asia–Pacific, Europe, and North America. Participants with evidence of clinically meaningful deterioration entered an open-label phase of weekly 1000 mg subcutaneous efgartigimod PH20 for no longer than 12 weeks (stage A). Those with confirmed evidence of clinical improvement (ECI; treatment responders) entered a randomised-withdrawal phase of 1000 mg subcutaneous efgartigimod PH20 weekly treatment versus placebo for a maximum of 48 weeks (stage B). Participants were randomised (1:1) through interactive response technology and stratified by their adjusted Inflammatory Neuropathy Cause and Treatment (aINCAT) score change during stage A and their most recent CIDP medication within 6 months before screening. Investigators, the clinical research organisation, and participants were masked to the treatment. The primary endpoint in stage A, evaluated in the stage A safety population, was confirmed ECI (≥1 points aINCAT decrease, ≥4 points [centile metric] Inflammatory Rasch-built Overall Disability Scale increase, or ≥8 kPa grip strength increase after four injections and two consecutive visits). The primary endpoint in stage B, evaluated in the modified intention-to-treat population, was the risk of relapse (time to first aINCAT increase of ≥1 points). ADHERE is registered with ClinicalTrials.gov (NCT04281472) and EudraCT (2019-003076-39) and is completed. Between April 15, 2020, and May 11, 2023, 629 participants were screened; 322 (114 female, 208 male) entered stage A, of whom 214 (66%, 95% CI 61·0−71·6) had confirmed ECI. In stage B, 221 participants were randomised (79 female, 142 male; 111 to subcutaneous efgartigimod PH20, 110 to placebo). Subcutaneous efgartigimod PH20 significantly reduced the risk of relapse versus placebo (hazard ratio 0·39 [95% CI 0·25−0·61]; p<0·0001). 31 (27·9% [19·6–36·3]) participants given subcutaneous efgartigimod PH20 had a relapse versus 59 (53·6% [44·3–63·0]) given placebo. In stage A, treatment-emergent adverse events (TEAEs) occurred in 204 (63%) participants and serious TEAEs in 21 (7%). In stage B, TEAEs occurred in 71 (64%) participants on subcutaneous efgartigimod PH20 and 62 (56%) participants on placebo, and serious TEAEs in six (5%) on subcutaneous efgartigimod PH20 and six (5%) on placebo. Three deaths occurred: two in stage A (one non-related and one unlikely related to treatment) and one in stage B (placebo group). ADHERE showed the efficacy of subcutaneous efgartigimod PH20 in reducing the risk of relapse versus placebo in people with CIDP who responded to treatment. Further studies are needed to provide data on the longer-term effects of efgartigimod alfa and how it compares with currently available treatment options. argenx. [ABSTRACT FROM AUTHOR]