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Background and Purpose Methods Results Conclusions Small‐fiber neuropathy (SFN) affects only unmyelinated and thin myelinated fibers. It may be caused by amyloidogenic mutations of the transthyretin (TTR) gene, but not all TTR gene variants are pathogenic. The nonamyloidogenic c.76G>A (rs1800458) and c.337‐18G>C (rs36204272) variants of TTR were recently reported to be associated with SFN. We investigated this putative association by analyzing TTR gene sequencing data retrospectively for two cohorts of patients, one with SFN and a control group.In this retrospective single‐center study, we analyzed the frequency of the c.76G>A and c.337‐18G>C TTR gene variants in a cohort of patients meeting a strict definition of SFN, with or without dysautonomia, a control cohort of patients investigated for nonneurological conditions, and the gnomAD international database.We included 55 SFN patients in this study, 17 of whom had dysautonomia. The allelic frequencies of the two variants in our cohort of 55 SFN patients were 7.27% for c.76G>A TTR and 5.25% for c.337‐18G>C. The frequencies of both variants were statistically similar in the 337 control patients and the gnomAD database.The c.76G>A and c.337‐18G>C TTR gene variants are not associated with SFN. [ABSTRACT FROM AUTHOR]

Biallelic SORD mutations cause one of the most frequent forms of recessive hereditary neuropathy, estimated to affect ∼10 000 patients in North America and Europe alone. Pathogenic SORD loss-of-function changes in the encoded enzyme sorbitol dehydrogenase result in abnormally high sorbitol levels in cells and serum. How sorbitol accumulation leads to peripheral neuropathy remains to be elucidated. A reproducible animal model for SORD neuropathy is essential to illuminate the pathogenesis of SORD deficiency and for preclinical studies of potential therapies. Therefore, we have generated a Sord knockout (KO), Sord −/−, Sprague Dawley rat, to model the human disease and to investigate the pathophysiology underlying SORD deficiency. We have characterized the phenotype in these rats with a battery of behavioural tests as well as biochemical, physiological and comprehensive histological examinations. Sord −/− rats had remarkably increased levels of sorbitol in serum, CSF and peripheral nerve. Moreover, serum from Sord −/− rats contained significantly increased levels of neurofilament light chain, an established biomarker for axonal degeneration. Motor performance significantly declined in Sord −/− animals starting at ∼7 months of age. Gait analysis evaluated with video motion-tracking confirmed abnormal gait patterns in the hindlimbs. Motor nerve conduction velocities of the tibial nerves were slowed. Light and electron microscopy of the peripheral nervous system revealed degenerating myelinated axons, de- and remyelinated axons, and a likely pathognomonic finding—enlarged 'ballooned' myelin sheaths. These findings mainly affected myelinated motor axons; myelinated sensory axons were largely spared. In summary, Sord −/− rats develop a motor-predominant neuropathy that closely resembles the human phenotype. Our studies revealed novel significant aspects of SORD deficiency, and this model will lead to an improved understanding of the pathophysiology and the therapeutic options for SORD neuropathy. [ABSTRACT FROM AUTHOR]

Vincristine-induced peripheral neuropathy is a common side effect of vincristine treatment, which is accompanied by pain and can be dose-limiting. The molecular mechanisms that underlie vincristine-induced pain are not well understood. We have established an animal model to investigate pathophysiological mechanisms of vincristine-induced pain. Our previous studies have shown that the tetrodotoxin-sensitive voltage-gated sodium channel Nav1.6 in medium-diameter dorsal root ganglion (DRG) neurons contributes to the maintenance of vincristine-induced allodynia. In this study, we investigated the effects of vincristine administration on excitability in small-diameter DRG neurons and whether the tetrodotoxin-resistant (TTX-R) Nav1.8 channels contribute to mechanical allodynia. Current-clamp recordings demonstrated that small DRG neurons become hyper-excitable following vincristine treatment, with both reduced current threshold and increased firing frequency. Using voltage-clamp recordings in small DRG neurons, we now show an increase in TTX-R current density and a −7.3 mV hyperpolarizing shift in the half-maximal potential (V1/2) of activation of Nav1.8 channels in vincristine-treated animals, which likely contributes to the hyperexcitability that we observed in these neurons. Notably, vincristine treatment did not enhance excitability of small DRG neurons from Nav1.8 knockout mice, and the development of mechanical allodynia was delayed but not abrogated in these mice. Together, our data suggest that sodium channel Nav1.8 in small DRG neurons contributes to the development of vincristine-induced mechanical allodynia. [ABSTRACT FROM AUTHOR]

Charcot-Marie-Tooth disease (CMT) is one of the most common and genetically heterogeneous inherited neurological diseases, with more than 130 disease-causing genes. Whole genome sequencing (WGS) has improved diagnosis across genetic diseases, but the diagnostic impact in CMT is yet to be fully reported. We present the diagnostic results from a single specialist inherited neuropathy centre, including the impact of WGS diagnostic testing. Patients were assessed at our specialist inherited neuropathy centre from 2009 to 2023. Genetic testing was performed using single gene testing, next-generation sequencing targeted panels, research whole exome sequencing and WGS and, latterly, WGS through the UK National Health Service. Variants were assessed using the American College of Medical Genetics and Genomics and Association for Clinical Genomic Science criteria. Excluding patients with hereditary ATTR amyloidosis, 1515 patients with a clinical diagnosis of CMT and related disorders were recruited. In summary, 621 patients had CMT1 (41.0%), 294 CMT2 (19.4%), 205 intermediate CMT (CMTi, 13.5%), 139 hereditary motor neuropathy (HMN, 9.2%), 93 hereditary sensory neuropathy (HSN, 6.1%), 38 sensory ataxic neuropathy (2.5%), 72 hereditary neuropathy with liability to pressure palsies (HNPP, 4.8%) and 53 'complex' neuropathy (3.5%). Overall, a genetic diagnosis was reached in 76.9% (1165/1515). A diagnosis was most likely in CMT1 (96.8%, 601/621), followed by CMTi (81.0%, 166/205) and then HSN (69.9%, 65/93). Diagnostic rates remained less than 50% in CMT2, HMN and complex neuropathies. The most common genetic diagnosis was PMP22 duplication (CMT1A; 505/1165, 43.3%), then GJB1 (CMTX1; 151/1165, 13.0%), PMP22 deletion (HNPP; 72/1165, 6.2%) and MFN2 (CMT2A; 46/1165, 3.9%). We recruited 233 cases to the UK 100 000 Genomes Project (100KGP), of which 74 (31.8%) achieved a diagnosis; 28 had been otherwise diagnosed since recruitment, leaving a true diagnostic rate of WGS through the 100KGP of 19.7% (46/233). However, almost half of the solved cases (35/74) received a negative report from the study, and the diagnosis was made through our research access to the WGS data. The overall diagnostic uplift of WGS for the entire cohort was 3.5%. Our diagnostic rate is the highest reported from a single centre and has benefitted from the use of WGS, particularly access to the raw data. However, almost one-quarter of all cases remain unsolved, and a new reference genome and novel technologies will be important to narrow the 'diagnostic gap'. [ABSTRACT FROM AUTHOR]

Background and Aims: Prior to next‐generation sequencing (NGS), the evaluation of a patient with neuropathy typically consisted of screening for acquired causes, followed by clinical genetic testing of PMP22, MFN2, GJB1, and MPZ in patients with a positive family history and symptom onset prior to age 50. In this study, we examined the clinical utility of NGS in a large cohort of patients analyzed in a commercial laboratory. Methods: A cohort of 6849 adult patients underwent clinician‐ordered peripheral neuropathy multigene panel testing ranging from 66 to 111 genes that included NGS and intragenic deletion/duplication analysis. Results: A molecular diagnosis was identified for 8.4% of the cohort (n = 573/6849). Variants in PMP22, MFN2, GJB1, MPZ, and TTR accounted for 73.8% of molecular diagnoses. Results had potential clinical actionability for 398 (69.5%) patients. Our results suggest that 225/573 (39.3%) of molecular diagnoses and 113/398 (28.4%) of clinical interventions would have been missed if the testing approach had been restricted to older guidelines. Interpretation: Our results highlight the need for expanded genetic testing guidelines that account for the increased number of genes associated with hereditary neuropathy, address the overlap of acquired and hereditary neuropathy, and provide broader access to genetic diagnosis for patients. [ABSTRACT FROM AUTHOR]

Aims: To develop a standardised, automated protocol for detecting protein gene product 9.5 (PGP9.5) positive intra‐epidermal nerve fibres (IENFs) in skin biopsies, transitioning from the established manual technique to an automated platform. This automated method, although currently intended for research applications, may improve the accessibility of this diagnostic test for small fibre neuropathy in clinical settings. Methods: Skin biopsies (n = 274) from 100 participants (fibromyalgia syndrome n = 62; idiopathic small fibre neuropathy: n = 16; healthy volunteers: n = 22) were processed using an automated immunohistochemistry platform. IENF quantification was performed by blinded examiners, with reliability assessed via a two‐way mixed‐effects model to evaluate inter‐ and intra‐observer variability. Results: The automated staining system reproduced intra‐epidermal nerve fibre density (IENFD) counts consistent with free‐floating sections (mean ± standard deviation: free‐floating: 5.6 ± 3.4 fibres/mm; automated: 5.9 ± 3.2 fibres/mm). A median difference of 0.3 with a lower bound 95% Confidence Interval (CI) at −0.00005 established non‐inferiority against a margin of −0.4 (p =.08). Specifically, the inter‐class correlation coefficient (class denotes consistency in measured observations) was 99% (95% CI: 0.9–1), indicating excellent agreement between free‐floating and automated methods. The inter‐ and intra‐class coefficient between examiners were both 99% (95% CI: 0.9–0.1) for IENFD, demonstrating high reliability using sections stained using the automated method. Interpretation: Automated immunohistochemistry provides high‐throughput reliable and reproducible intra‐epidermal nerve fibre quantification. This method, although currently proof‐of‐concept, for research use only, may be more widely deployed in histopathology laboratories to increase the adoption of IENFD assessment for the diagnosis of peripheral neuropathies. [ABSTRACT FROM AUTHOR]

Background and Objectives: Systemic Lupus Erythematosus (SLE) often causes damage to small nerve fibers, leading to distressing painful and autonomic symptoms. Despite this, Small Fiber Neuropathy (SFN) remains an underrecognized complication for SLE patients. In this cross‐sectional study, we aimed to assess SFN in patients with SLE and to explore its correlations with immunologic disease features and clinical manifestations. Methods: We recruited 50 SLE patients (1 male to 12.5 females, aged 20–80 years) reporting painful disturbances. We conducted a comprehensive clinical and neurophysiological evaluation, using Nerve Conduction Studies and Quantitative Sensory Testing. Additionally, we carried out an extensive laboratory assessment of disease‐related serological parameters. We also performed a thorough skin biopsy analysis, investigating somatic and autonomic innervation while detecting complement and inflammatory cell infiltrates within the skin. Results: Out of 50 patients, 19 were diagnosed with SFN, primarily characterized by a non‐length‐dependent distribution; 7 had a mixed neuropathy, with both large and small fiber involvement. Patients with SFN were younger than patients with a mixed neuropathy (p =.0143); furthermore, they were more likely to have a history of hypocomplementemia (p =.0058) and to be treated with cyclosporine A (p =.0053) compared to patients without neuropathy. However, there were no significant differences in painful and autonomic symptoms between patients with and without SFN. Discussion: This study highlights the relevant frequency of SFN with a non‐length‐dependent distribution among SLE patients experiencing painful symptoms. Indeed, SFN emerges as an early manifestation of SLE‐related neuropathy and is closely associated with hypocomplementemia, suggesting a potential pathogenic role of the complement system. Moreover, SFN may be influenced by disease‐modifying therapies. However, the precise role of SFN in shaping painful and autonomic symptoms in patients with SLE remains to be fully elucidated. [ABSTRACT FROM AUTHOR]

Background: Trigeminal nerve injury following endodontic treatment, leading to unpleasant sensations or partial sensory loss in the face or oral mucosa, is uncommon but significant when it occurs. Objective: This study analysed the pharmacological management of trigeminal nerve injuries (TNI) in a university‐based hospital. Methods: We conducted a retrospective analysis of 47 patients who visited the Department of Orofacial Pain and Oral Medicine at Yonsei University Dental Hospital, Seoul, Korea, after TNI following endodontic procedures in primary clinics. Both objective tests and subjective evaluations, assessed the extent and duration of sensory injury during the initial visit. The patient's initial symptoms, presumed cause of TNI, referral delay (time interval between TNI and the first visit to our clinic), and medications were analysed to determine whether these factors affected the outcomes. Results: Most patients with TNI experienced dysesthesia with hypoesthesia (70.2%). The mandibular molars were predominantly affected (72.3%), with the inferior alveolar nerve (IAN), lingual nerve (LN), both IAN and LN, and maxillary nerve compromised in 83.0, 12.8, 2.1, and 2.1% of cases, respectively. Causes of TNI included local anaesthesia (29.8%), overfilling/over‐instrumentation (25.5%), endodontic surgery (17.0%), and unknown factors (27.7%). A shorter referral delay was associated with better outcomes, with an average delay of 8.6 weeks for symptom improvement compared with 44.1 weeks for no change. The medication regimens included steroids, NSAIDs, topical lidocaine, vitamin B complex, Adenosine Triphosphate (ATP), antiepileptics, antidepressants, and opioids administered alone or in combination, with a mean duration of 20.7 weeks. 53.2% of the patients reported improvement in their symptoms, 27.7% experienced no significant change, and 19.1% had unknown outcomes. Conclusions: Swift referral to an orofacial pain specialist is recommended for effective recovery in cases of TNI arising from endodontic treatment. [ABSTRACT FROM AUTHOR]

Background and Aims Methods Results Conclusions The COVID‐19 pandemic significantly disrupted lower limb diabetes care. We aimed to map trends in diabetes‐related lower limb amputation and hospitalisation rates through the COVID‐19 pandemic.We performed a retrospective cohort study of all individuals who underwent a lower limb amputation for a diabetes‐related foot complication from 2018 to 2021 at the Royal Melbourne Hospital, a quaternary hospital in Australia. Hospitalisation rates with a diabetes‐related foot complication were collected for comparison. The start of the COVID‐19 epoch was defined as 16 March 2020, when a state of emergency was declared in Melbourne.During the study period, 360 lower limb amputations for diabetes‐related foot complications were performed in 247 individuals. The median monthly number of amputations remained stable prior to and during the COVID‐19 epoch; there was a median of 8.0 amputations per month (interquartile range (IQR) = 6.5–11) before COVID‐19, compared to 6.5 amputations (IQR = 5.0–8.3) during the COVID‐19 epoch (P = 0.23). Hospitalisation with a diabetes‐related foot complication significantly increased from a median monthly rate of 11 individuals (IQR = 9.0–14) before COVID‐19 to 19 individuals (IQR = 14–22) during the COVID‐19 epoch (p < 0.001).Despite increased hospitalisations for diabetes‐related foot complications during COVID‐19, there was not a corresponding increase in amputation rates. Face‐to‐face care of diabetes‐related foot complications was prioritised at this centre and may have contributed to stable amputation rates during the pandemic. [ABSTRACT FROM AUTHOR]

Introduction Methods Results Conclusions Radiation‐induced peripheral neuropathy is a rare, but serious complication often resulting in profound morbidity, life‐long disability, and chronic debilitating pain. Unfortunately, this type of peripheral neuropathy is usually progressive, and almost always irreversible. To date, a standardized rat model of radiation‐induced peripheral neuropathy has not been established. The purpose of the present study was to examine neuropathic pain, sensorimotor impairment, and muscle force parameters following the administration of a clinically relevant radiation dose in a rat model.Ten rats were randomly assigned to one of two experimental groups: (1) radiation and (2) sham‐radiated controls. Radiated animals were given a clinically relevant dose of 35 Gray (Gy) divided into five daily doses of 7 Gy/day. This regimen represents a human equivalent dose of 70 Gy, approximating the same dosage utilized for radiotherapy in oncologic patients. Sham‐radiated controls were anesthetized and placed in the radiation apparatus but were not given radiation. All animals were tested for baseline values in both sensorimotor and pain behavioral tests. Sensorimotor testing consisted of the evaluation of walking tracks with the calculation of the Sciatic Functional Index (SFI). Pain‐related behavioral measures consisted of mechanical allodynia (von Frey test), cold allodynia (Acetone test), and thermal allodynia (Hargreaves test). Animals were tested serially over an 8‐week period. At the study endpoint, electrophysiological and muscle force assessments were completed, and histomorphometric analysis was performed on all sciatic nerves.Animals that underwent radiation treatment displayed significantly greater pain hypersensitivity to mechanical stimulation as compared to sham radiated controls from weeks 4 to 8 of testing. SFI values indicated sensorimotor impairments in the overground gait of radiated animals as compared to non‐radiated animals. Furthermore, radiated animals displayed reduced twitch and tetanic muscle force when compared to sham radiated controls.A clinically relevant human equivalent dose of fractionated 35 Gy in rats established significant pain hypersensitivity, impairments in sensorimotor locomotion, and decreased muscle force capacity. This novel rodent model of radiation‐induced peripheral neuropathy can be utilized to assess the potential efficacy of therapeutic treatments to either prevent or remediate this clinically debilitating condition. [ABSTRACT FROM AUTHOR]

Diabetic peripheral neuropathy (DPN) is a primary complication observed in diabetes that severely affects quality of life. Recent evidence suggests that photobiomodulation (PBM) is a promising therapy against painful conditions and nerve damage. However, the effects of PBM on DPN remains mostly unknown. In the present study, we investigated the efficacy of PBM therapy in modulating proinflammatory cytokine expression in both central and peripheral nervous systems of rats with Streptozotocin (STZ)-induced type 1 diabetes. Male Wistar rats were allocated into control (naïve), diabetic (STZ), and treatment (STZ + PBM) groups. A single intraperitoneal (i.p.) injection of STZ (85 mg/kg) was administered for the induction of diabetes. Animals were subjected to 10 treatment sessions, every other day. The results herein presented indicate that PBM treatment diminishes Receptor for Advanced Glycation End-products (RAGE) and Nuclear Factor Kappa B (NF-ϰB) expression in peripheral nervous system and suppresses TNF-α expression in central nervous system tissues. Furthermore, PBM-therapy in diabetic rats also induces increased levels of the anti-inflammatory protein IL-10 in both peripheral and central nervous system. Collectively, our findings demonstrate compelling evidence that PBM-therapy modulates cytokine dynamics and influences RAGE/NF-ϰB axis in a STZ-induced model of type 1 diabetes. [ABSTRACT FROM AUTHOR]

Simple Summary: Chronic cancer-related pain, caused by surgery, radiotherapy, or systemic treatments, affects almost half of all breast cancer patients, and current therapeutic options are insufficient. Pain neuroscience education (PNE) has provided relief in many chronic pain syndromes but has been rarely applied in the cancer field. PNE is also without side effects and could therefore be implemented at different moments of the patient's journey. We analyzed trials investigating PNE efficacy for managing breast cancer-related pain, identifying methodological issues that should be addressed in future studies to obtain high-quality data. Chronic pain is a common consequence of breast cancer (BC) and its treatments. Pain neuroscience education (PNE) is a non-pharmacological intervention that adopts a biopsychosocial approach and has already been proven to be effective for different chronic pain syndromes. The present review aims to critically assess clinical trials comparing the efficacy of PNE to traditional biomedical education (BME) in reducing BC-related pain and improving quality of life. We conducted a literature search in scientific databases, including all studies regarding PNE use specifically for BC-related pain. Ongoing randomized controlled and observational studies were identified from ClinicalTrials.gov and congress proceedings. A total of eight clinical trials met the review criteria. The participants were all administered physical therapy and assigned to receive either BME or PNE interventions. Among the completed clinical studies, one reported no statistically relevant differences between the two groups, whereas the other showed lower levels of pain-related indexes in the PNE population compared to the BME one. While the current literature is inconclusive regarding the effectiveness of PNE for managing BC pain, we strongly support the need for further trials, as PNE could empower BC patients in both prevention of and coping with pain, offering the advantage of having no side effects. [ABSTRACT FROM AUTHOR]

Erythropoietin (EPO) has demonstrated neuroprotective properties and has been used in small case series to treat methanol optic neuropathy. This study aims to evaluate the effectiveness of EPO. This retrospective case series included data from patients diagnosed with methanol optic neuropathy between November 2022 and December 2023 from two centers in Jeddah, Saudi Arabia. Demographic information, time of consumption of methanol to EPO treatment, and other treatments administered were collected. Vision assessment was performed before and after EPO treatment. A total of 8 male patients were included, with an average age of 38.25 ± 7.15 years. The median duration of the follow-up was 66 days, ranging from 13 to 660 days. The means of vision in the logMAR of both eyes before EPO treatment was 1.98 ± 1.08, which changed to 1.87 ± 0.89 after EPO treatment. Patient’s presenting vision before EPO treatment is a significant positive predictor for the vision after treatment with coefficient = 0.782 and 95% CI = 0.349, 0.936. Time to EPO treatment was not statistically significant in defining end vision. Treating methanol optic neuropathy is challenging and time sensitive. In this case series, EPO and adjuvant steroids showed variable effects on visual improvement. Although the vision improved after the treatment, these differences were not statistically significant. Repeat EPO did not give better outcomes. Long-term follow-up is needed to determine the overall impact of EPO treatment. [ABSTRACT FROM AUTHOR]

The development of combination antiretroviral therapy (cART) has transformed human immunodeficiency virus (HIV) infection from a lethal diagnosis into a chronic disease, and people living with HIV on cART can experience an almost normal life expectancy. However, these individuals often develop various complications that lead to a decreased quality of life, some of the most significant of which are neuropathic pain and the development of painful peripheral sensory neuropathy (PSN). Critically, although cART is thought to induce pain pathogenesis, the relative contribution of different classes of antiretrovirals has not been systematically investigated. In this study, we measured the development of pathological pain and peripheral neuropathy in mice orally treated with distinct antiretrovirals at their translational dosages. Our results show that only nucleoside reverse transcriptase inhibitors (NRTIs), not other types of antiretrovirals such as proteinase inhibitors, non-nucleoside reverse transcriptase inhibitors, integrase strand transfer inhibitors, and CCR5 antagonists, induce pathological pain and PSN. Thus, these findings suggest that NRTIs are the major class of antiretrovirals in cART that promote the development of neuropathic pain. As NRTIs form the essential backbone of multiple different current cART regimens, it is of paramount clinical importance to better understand the underlying mechanism to facilitate the design of less toxic forms of these drugs and/or potential mitigation strategies. [ABSTRACT FROM AUTHOR]

In order to understand abnormal gait, this article will first review normal gait, discuss how neuromuscular diseases disturb gait patterns and review orthotic interventions. In normal gait, concentric contractions accelerate and eccentric contractions decelerate the limb. Neuromuscular gait disorders can be grouped into (1) proximal weakness, (2) distal weakness, (3) nonlength‐dependent or generalized weakness, (4) asymmetric weakness, and (5) sensory disorders. Identification of gait disturbance type in neuromuscular diseases leads to the appropriate orthotic prescription since orthotic strategies are grouped into (1) proximal weakness, (2) distal weakness, and (3) sensory disturbances. Orthotics is not indicated in all types of gait disturbance. Weakness in proximal hip musculature can be managed with gait aids such as walkers. In contrast, distal muscle weakness can be managed with orthotics. Preservation of gait assists in maintenance of daily function and integration in society. [ABSTRACT FROM AUTHOR]

Diabetic peripheral neuropathy (DPN) is highly prevalent among Jordanian patients, mostly are asymptomatic. Early recognition and appropriate management of neuropathy is important to improve symptoms, reduce sequelae, and improve quality of life. This study aims at exploring the role of pharmacists in the early recognition of DPN and providing quick screening for the presence of it among diabetic patients. A cross-sectional study was conducted at multi-pharmacy settings, in Irbid, Jordan. Twenty trained pharmacists who had bachelor's degrees in pharmacy participated in data collection. A total of 400 patients with confirmed diagnosis of type 2 diabetes mellitus (DM) according to the World Health Organization diagnostic criteria were recruited. DPN was assessed using the translated Arabic version of Michigan Neuropathy Screening Instrument (MNSI) history version. The mean MNSI questionnaire score for all participants was 4.40 ± 3.00. Mean age of the patients was 62.6 ± 10.7 years old and duration of diabetes was 8.25 ± 6.9. DN was present in 23.7% of the population. Diabetic patients with neuropathy were older than patients without neuropathy (p < 0.05) and had had diabetes longer (p < 0.05). Poor glycemic control, hypertension and gender, were significantly risk factors for DN (p < 0.05). In addition to delivering medications, this study suggests that pharmacists can have a role in screening and counseling about diabetic peripheral neuropathy using a simple objective, and non-invasive tool and also can determine level of damage and risk. [ABSTRACT FROM AUTHOR]

Purpose: Chemotherapy-induced peripheral neuropathy (CIPN) is one of the major side effects and main reasons for affecting quality of life and dose reduction or even discontinuation of treatment in breast cancer patients. One of the most widely prescribed chemotherapies is the "taxanes." Considering that duloxetine has been used in treating neuropathies in recent years, this study aimed to investigate its effectiveness in preventing taxane-related neuropathy. Material and methods: This is a randomized controlled trial on 47 patients: 24 received a placebo and 23 received duloxetine at 30 mg daily in the first week following the injection of paclitaxel and 60 mg during the second week in each chemotherapy cycle. Patients objective (nerve conduction velocity (NCV) values) and subjective symptoms (visual analog scale including; neuropathy, paresthesia, pain, cold sensitivity, and numbness), the grades of the patients' neuropathy (calculated according to Common Terminology Criteria for Adverse Events (CTCAE) v.5), and the presence of complications, before and after each chemotherapy cycle, were recorded. Results: The placebo group experienced significantly higher occurrences of new neuropathy (8/23 in duloxetine vs 16/24 in placebo, P = 0.029) in NCV by tibial nerve latency (− 0.28% vs 19.87%, P = 0.006), tibial amplitude (4.40% vs − 10.88%, P = 0.049), and median nerve latency (8.72% vs 31.16%, P = 0.039); administration of duloxetine significantly reduced the scores of neuropathies (P < 0.001), pain (P = 0.027), during chemotherapy, and 6 weeks later; however, no significant effect was observed on paresthesia, numbness, cold sensitivity, and other NCV measurements. Conclusions: Paclitaxel can cause neuropathy, lasting for a long time. Our study showed duloxetine is potentially an effective medication that can prevent subjective and objective neuropathy. [ABSTRACT FROM AUTHOR]

Context: Sweat glands (SGs) play a vital role in thermal regulation. The function and structure are altered during the different pathological conditions. Objective: These alterations are studied through three techniques: biopsy, sweat analytes and electrical activity of SG. Methods: The morphological study of SG through biopsy and various techniques involved in quantifying sweat analytes is focussed on here. Electrical activities of SG in diabetes, neuropathy and nephropathy cases are also discussed, highlighting their limitations and future scope. Results and Conclusion: The result of this review identified three areas of the knowledge gap. The first is wearable sensors to correlate pathological conditions. Secondly, there is no device to look for its structure and quantify its associated function. Finally, therapeutic applications of SG are explored, especially for renal failure. With these aspects, this paper provides information collection and correlates SG with pathologies related to diabetes. Hence this could help researchers develop suitable technologies for the gaps identified. [ABSTRACT FROM AUTHOR]

The diagnostic evaluation of a peripheral neuropathy includes testing for the presence of monoclonal gammopathy, which can be found in about 10% of patients with peripheral neuropathy. Our role, as physicians, is to determine whether the neuropathy is directly related to the gammopathy or whether the co‐occurrence of these two disorders is purely coincidental. The evaluating physician needs to be familiar with the different types of neuropathies associated with monoclonal gammopathies, their clinical and electrodiagnostic characteristics, and their appropriate diagnostic evaluation and management. Testing for monoclonal protein disorders includes serum protein electrophoresis (SPEP) and immunofixation of blood, and in some cases of urine, as well as measurement of free light chains and quantitative immunoglobulins. Specific antibody testing is directed by paraprotein type and neuropathy phenotype. Patients with abnormal free light chains in association with sensory and autonomic neuropathy should be evaluated for AL amyloidosis. When a lambda monoclonal protein is identified together with a clinical phenotype of chronic inflammatory demyelinating neuropathy (CIDP), a diagnosis of polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes (POEMS) syndrome should be considered. Patients with IgM paraprotein associated neuropathy should be assessed for distal acquired demyelinating sensorimotor (DADS) neuropathy, with or without anti myelin associated glycoprotein (MAG) antibody or CANOMAD syndrome. In many cases, a monoclonal gammopathy of uncertain significance (MGUS) is incidental and unrelated to the neuropathy. Collaboration with oncology is critical in evaluating patients with monoclonal proteins to assess for underlying plasma cell neoplasms or B cell lymphomas. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the combined performance of orbital MRI and intracranial visual pathway diffusion kurtosis imaging (DKI) in diagnosing dysthyroid optic neuropathy (DON). Methods: We retrospectively enrolled 61 thyroid-associated ophthalmopathy (TAO) patients, including 25 with DON (40 eyes) and 36 without DON (72 eyes). Orbital MRI–based apical muscle index (MI), diameter index (DI) of the optic nerve (ON), area index (AI) of the ON, apparent diffusion coefficient (ADC) and signal intensity ratio (SIR) of the ON, DKI-based kurtosis fractional anisotropy (KFA) and mean kurtosis (MK) of the optic tract (OT), optic radiation (OR), and Brodmann areas (BAs) 17, 18, and 19 were measured and compared between groups. The diagnostic performances of models were evaluated using receiver operating characteristic curve analyses and compared using the DeLong test. Results: TAO patients with DON had significantly higher apical MI, apical AI, and SIR of the ON, but significantly lower ADC of the ON than those without DON (p < 0.05). Meanwhile, the DON group exhibited significantly lower KFA across the OT, OR, BA17, BA18, and BA19 and lower MK at the OT and OR than the non-DON group (p < 0.05). The model integrating orbital MRI and intracranial visual pathway DKI parameters performed the best in diagnosing DON (AUC = 0.926), with optimal diagnostic sensitivity (80%) and specificity (94.4%), followed by orbital MRI combination (AUC = 0.890), and then intracranial visual pathway DKI combination (AUC = 0.832). Conclusion: Orbital MRI and intracranial visual pathway DKI can both assist in diagnosing DON. Combining orbital and intracranial imaging parameters could further optimize diagnostic efficiency. Clinical relevance statement: The novel finding could bring novel insights into the precise diagnosis and treatment of dysthyroid optic neuropathy, accordingly, contributing to the improvement of the patients' prognosis and quality of life in the future. Key Points: • Orbital MRI and intracranial visual pathway diffusion kurtosis imaging can both assist in diagnosing dysthyroid optic neuropathy. • Combining orbital MRI and intracranial visual pathway diffusion kurtosis imaging optimized the diagnostic efficiency of dysthyroid optic neuropathy. [ABSTRACT FROM AUTHOR]

Objective: To determine the inter-reader reliability and diagnostic performance of classification and severity scales of Neuropathy Score Reporting And Data System (NS-RADS) among readers of differing experience levels after limited teaching of the scoring system. Methods: This is a multi-institutional, cross-sectional, retrospective study of MRI cases of proven peripheral neuropathy (PN) conditions. Thirty-two radiology readers with varying experience levels were recruited from different institutions. Each reader attended and received a structured presentation that described the NS-RADS classification system containing examples and reviewed published articles on this subject. The readers were then asked to perform NS-RADS scoring with recording of category, subcategory, and most likely diagnosis. Inter-reader agreements were evaluated by Conger's kappa and diagnostic accuracy was calculated for each reader as percent correct diagnosis. A linear mixed model was used to estimate and compare accuracy between trainees and attendings. Results: Across all readers, agreement was good for NS-RADS category and moderate for subcategory. Inter-reader agreement of trainees was comparable to attendings (0.65 vs 0.65). Reader accuracy for attendings was 75% (95% CI 73%, 77%), slightly higher than for trainees (71% (69%, 72%), p = 0.0006) for nerves and comparable for muscles (attendings, 87.5% (95% CI 86.1–88.8%) and trainees, 86.6% (95% CI 85.2–87.9%), p = 0.4). NS-RADS accuracy was also higher than average accuracy for the most plausible diagnosis for attending radiologists at 67% (95% CI 63%, 71%) and for trainees at 65% (95% CI 60%, 69%) (p = 0.036). Conclusion: Non-expert radiologists interpreted PN conditions with good accuracy and moderate-to-good inter-reader reliability using the NS-RADS scoring system. Clinical relevance statement: The Neuropathy Score Reporting And Data System (NS-RADS) is an accurate and reliable MRI-based image scoring system for practical use for the diagnosis and grading of severity of peripheral neuromuscular disorders by both experienced and general radiologists. Key Points: • The Neuropathy Score Reporting And Data System (NS-RADS) can be used effectively by non-expert radiologists to categorize peripheral neuropathy. • Across 32 different experience-level readers, the agreement was good for NS-RADS category and moderate for NS-RADS subcategory. • NS-RADS accuracy was higher than the average accuracy for the most plausible diagnosis for both attending radiologists and trainees (at 75%, 71% and 65%, 65%, respectively). [ABSTRACT FROM AUTHOR]

Immunoglobulin Mu‐binding protein 2 (IGHMBP2) pathogenic variants result in the fatal, neurodegenerative disease spinal muscular atrophy with respiratory distress type 1 (SMARD1) and the milder, Charcot–Marie‐Tooth (CMT) type 2S (CMT2S) neuropathy. More than 20 years after the link between IGHMBP2 and SMARD1 was revealed, and 10 years after the discovery of the association between IGHMBP2 and CMT2S, the pathogenic mechanism of these diseases is still not well defined. The discovery that IGHMBP2 functions as an RNA/DNA helicase was an important step, but it did not reveal the pathogenic mechanism. Helicases are enzymes that use ATP hydrolysis to catalyse the separation of nucleic acid strands. They are involved in numerous cellular processes, including DNA repair and transcription; RNA splicing, transport, editing and degradation; ribosome biogenesis; translation; telomere maintenance; and homologous recombination. IGHMBP2 appears to be a multifunctional factor involved in several cellular processes that regulate gene expression. It is difficult to determine which processes, when dysregulated, lead to pathology. Here, we summarise our current knowledge of the clinical presentation of IGHMBP2‐related diseases. We also overview the available models, including yeast, mice and cells, which are used to study the function of IGHMBP2 and the pathogenesis of the related diseases. Further, we discuss the structure of the IGHMBP2 protein and its postulated roles in cellular functioning. Finally, we present potential anomalies that may result in the neurodegeneration observed in IGHMBP2‐related disease and highlight the most prominent ones. [ABSTRACT FROM AUTHOR]

Introduction: Acquired amyloid neuropathy is an iatrogenic disease that appears years after a domino liver transplant. The objectives of our study are to analyze the efficacy and tolerability of tafamidis for the treatment of acquired amyloid neuropathy in domino liver transplant recipients. This post-authorization, prospective, longitudinal study included seven domino liver transplant recipients with acquired amyloid neuropathy who received treatment with tafamidis for 18 months. Methods: The primary endpoints were the response rate, defined as those patients with an increase of < 2 points on the Neurological Impairment Score (NIS) from baseline, and the change in the NIS score from baseline. Secondary endpoints included the Quantitative Sensory Test, 10-m walk test, quality of life (Norfolk), and disability (Rasch-built Overall Disability Scale). As safety parameters, the evidence of graft rejection, changes in immunosuppressive trough levels and changes in antiviral and allogeneic cellular immunity before and 12 months after tafamidis treatment were also assessed. Results: Six patients (85.7%) had responded at 18-months. Compared to baseline, we observed non-statistically significant improvement in mean NIS score at 6 months (− 2.54 points, CI − 5.92 to 0.84), 12 months (− 3.25 points; CI − 6.63 to 0.13), and 18 months (− 2.35 points; CI − 5.74 to 1.02). Changes in the Quantitative Sensory Test, 10-m walk tests and the quality of life and disability questionnaires were not statistically significant. The use of tafamidis did not induce relevant side effects or drug interactions. Also, no acute rejections events nor changes in functional adaptive immunity were observed. Conclusion: Our study supports the safety and tolerability of tafamidis for the treatment of acquired amyloid neuropathy in domino liver transplant recipients. Tafamidis shows promise as a useful treatment in the clinical management of these patients. Future randomized placebo-controlled clinical trials with longer follow-up durations are needed. [ABSTRACT FROM AUTHOR]

Charcot–Marie–Tooth disease type 1E (CMT1E) is an inherited autosomal dominant peripheral neuropathy caused by mutations in the peripheral myelin protein 22 (PMP22) gene. The identical leucine‐to‐proline (L16P) amino acid substitution in PMP22 is carried by the Trembler J (TrJ) mouse and is found in CMT1E patients presenting with early‐onset disease. Peripheral nerves of patients diagnosed with CMT1E display a complex and varied histopathology, including Schwann cell hyperproliferation, abnormally thin myelin, axonal degeneration, and subaxonal morphological changes. Here, we have taken an unbiased data‐independent analysis (DIA) mass spectrometry (MS) approach to quantify proteins from nerves of 3‐week‐old, age and genetic strain‐matched wild‐type (Wt) and heterozygous TrJ mice. Nerve proteins were dissolved in lysis buffer and digested into peptide fragments, and protein groups were quantified by liquid chromatography‐mass spectrometry (LC–MS). A linear model determined statistically significant differences between the study groups, and proteins with an adjusted p‐value of less than 0.05 were deemed significant. This untargeted proteomics approach identified 3759 quality‐controlled protein groups, of which 884 demonstrated differential expression between the two genotypes. Gene ontology (GO) terms related to myelin and myelin maintenance confirm published data while revealing a previously undetected prominent decrease in peripheral myelin protein 2. The dataset corroborates the described pathophysiology of TrJ nerves, including elevated activity in the proteasome‐lysosomal pathways, alterations in protein trafficking, and an increase in three macrophage‐associated proteins. Previously unrecognized perturbations in RNA processing pathways and GO terms were also discovered. Proteomic abnormalities that overlap with other human neurological disorders besides CMT include Lafora Disease and Amyotrophic Lateral Sclerosis. Overall, this study confirms and extends current knowledge on the cellular pathophysiology in TrJ neuropathic nerves and provides novel insights for future examinations. Recognition of shared pathomechanisms across discrete neurological disorders offers opportunities for innovative disease‐modifying therapeutics that could be effective for distinct neuropathies. [ABSTRACT FROM AUTHOR]

The enteric nervous system (ENS) commands moment‐to‐moment gut functions through integrative neurocircuitry housed in the gut wall. The functional continuity of ENS networks is disrupted in enteric neuropathies and contributes to major disturbances in normal gut activities including abnormal gut motility, secretions, pain, immune dysregulation, and disrupted signaling along the gut–brain axis. The conditions under which enteric neuropathy occurs are diverse and the mechanistic underpinnings are incompletely understood. The purpose of this brief review is to summarize the current understanding of the cell types involved, the conditions in which neuropathy occurs, and the mechanisms implicated in enteric neuropathy such as oxidative stress, toll like receptor signaling, purines, and pre‐programmed cell death. [ABSTRACT FROM AUTHOR]

Purpose: Oxaliplatin-containing adjuvant chemotherapy yields a significant survival benefit in stage III colon cancer and is the standard of care. Simultaneously, it causes dose-dependent peripheral neuropathy that may increase the risk of fall-related injury (FRI) such as fracture and laceration. Because these events carry significant morbidity and the global burden of colon cancer is on the rise, we examined the association between treatment with a full versus shortened course of adjuvant chemotherapy and post-treatment FRI and fracture. Methods: In this overlap propensity score weighted, retrospective cohort study, we included patients aged ≥ 18 years with resected stage III colon cancer diagnosed 2007–2019 and treated with oxaliplatin-containing adjuvant chemotherapy (oxaliplatin plus a fluoropyrimidine; capecitabine [CAPOX] or 5-fluorouracil and leucovorin [FOLFOX]). Propensity score methods facilitate the separation of design from analysis and comparison of baseline characteristics across the weighted groups. Treatment groups were defined as 50% (4 cycles CAPOX/6 cycles FOLFOX) and > 85% (7–8 cycles CAPOX/11–12 cycles FOLFOX) of a maximal course of adjuvant chemotherapy to approximate the treatment durations received in the IDEA collaboration. The main outcomes were time to any FRI and time to fracture. We determined the subdistribution hazard ratios (sHR) estimating the association between FRI/fracture and treatment group, accounting for the competing risk of death. Results: We included 3,461 patients; 473 (13.7%) received 50% and 2,988 (86.3%) received > 85% of a maximal course of adjuvant therapy. For post-treatment FRI, median follow-up was 4.6 years and total follow-up was 17,968 person-years. There were 508 FRI, 301 fractures, and 692 deaths. Treatment with > 85% of a maximal course of therapy conferred a sHR of 0.84 (95% CI 0.62–1.13) for post-treatment FRI and a sHR of 0.72 (95% CI 0.49–1.06) for post-treatment fracture. Conclusion: For patients with stage III colon cancer undergoing treatment with oxaliplatin-containing adjuvant chemotherapy, any potential neuropathy associated with longer durations of treatment was not found to result in greater rates of FRI and fracture. Within the limits of this retrospective study, our findings suggest concern about FRI, while mechanistically plausible, ought not to determine treatment duration. [ABSTRACT FROM AUTHOR]

Simple Summary: Taste and smell alterations (TSAs) are a distressing yet underdiagnosed side effect in cancer patients undergoing chemotherapy. However, long-term investigations using both questionnaires and chemosensory tests are scarce. We examined the prevalence of quantitative and qualitative TSAs, as well as their connection with clinical characteristics such as age, sex, anorexia, and neuropathy. We also compared patients receiving perpetual or temporary chemotherapy. All patients were examined up to five times within 12 to 24 months, commencing before the beginning of chemotherapy. We found TSAs in approximately 4 out of 5 patients during chemotherapy. The highest prevalence was documented among patients above 60 years of age as well as among those reporting anorexia or presenting signs of neuropathy. Post-therapy, taste and smell function recovered; however, scores did not reach baseline levels within 6 to 12 months. Future investigations will assess potential interventions to prevent or reduce TSAs. Previous data regarding chemotherapy-induced olfactory and gustatory dysfunction (CIOGD) are heterogeneous due to inconsistent study designs and small numbers of patients. To provide consistent, reliable data, we conducted a cohort study using standardized testing. Patients diagnosed with lymphoma, leukemia, or gastrointestinal malignancies were examined up to five times (T1 to T5), beginning prior to chemotherapy. We examined patients receiving temporary treatment up to 12 months post-therapy. Clinical assessment included extensive questionnaires, psychophysical tests of olfactory and gustatory function, and measurement of peripheral neuropathy. Statistical analysis included non-parametric tests to evaluate the longitudinal development of CIOGD. Our data (n = 108) showed a significant decline in olfactory and gustatory testing during chemotherapy (p-values < 0.001). CIOGD appeared stronger among patients above 60 years, while sex did not matter significantly. However, we identified distinct associations between CIOGD and reported anorexia as well as with higher neuropathy scores. Self-assessment appeared less sensitive to chemosensory dysfunction than psychophysical testing. Post-therapy, olfactory and gustatory function regenerated, though baseline levels were not attained within 6 to 12 months. In conclusion, our data highlight the wide prevalence and slow recovery of CIOGD. Understanding CIOGD as a potential neurotoxic effect may disclose new therapeutic prospects. [ABSTRACT FROM AUTHOR]

Many studies have examined the role of inflammation in the development of diabetic neuropathy (DPN). Evaluate the relation of the serum level of Transforming Growth Factor-β and Tumor Necrosis Factor-α and development of diabetic peripheral neuropathy DPN. In a case-control study, randomly selected 140 diabetic patients were included, the randomly selected patients were divided equally and matched into a case group who have diabetic peripheral neuropathy and diabetic neuropathy-free patients as a control group. For both groups whole blood sample was examined to compare for (TGF-β), and (TNF-α) levels determination by ELISA technique. The age of the study samples ranged from 25 to 80 years with a male ratio of 1.45:1 although the sex differences between both groups were not significant. The mean levels of (TNF-α) and (TGF-β) was significantly higher among cases group than that of controls group (254.86 ± 75.9 vs158.01 ± 50.600) for TNF-α and for TGF- β (312.85 ± 62.27 vs. 217.82 ± 52.95) respectively. Both TNF-α and TGF-β have high sensitivity and specificity in detection of DPN. The sensitivity of TNF-α was 95.7% and specificity of 61.4% area under the ROC curve (AUC) of 0.870 ± 0.029, while the sensitivity of TGF-β was 91.4%, and specificity of 67.1 with good area under the ROC curve (AUC) of 0.891 ± 0.026 (P=0.000). TNF-α and TGF -β are significantly elevated levels in patients with DPN, these cytokines could be used as indicators for the development of DPN. [ABSTRACT FROM AUTHOR]

This study investigated the effects of cilostazol on motor dysfunction, spinal motor neuron abnormalities, and schwannopathy in rats with diabetes. Diabetes mellitus (DM) was induced in rats via femoral intravenous streptozotocin (STZ) injection (60 mg/kg). After successful DM induction, cilostazol was administered on day 15 via oral gavage (100 mg/kg/day) for 6 weeks until sacrifice. Behavioral assays, including motor function, were performed weekly. The sciatic nerve, L5 spinal cord, and spinal ventral root were collected to evaluate the expression of the glial fibrillary acidic protein (GFAP), myelin protein zero (P0), and choline acetyltransferase (ChAT) by immunofluorescence and Western blotting. DM rats displayed decreased running speeds, running distances, and toe spread but increased foot pressure. In addition, loss of non-myelinating Schwann cells and myelin sheaths was observed in the sciatic nerve and L5 spinal ventral root. Reduced numbers of motor neurons were also found in the L5 spinal ventral horn. Cilostazol administration significantly potentiated running speed and distance; increased hind paw toe spread; and decreased foot pressure. In the sciatic nerve and L5 spinal ventral root, cilostazol treatment significantly improved non-myelinated Schwann cells and increased myelin mass. ChAT expression in motor neurons in the spinal ventral horn was improved, but not significantly. Cilostazol administration may protect sensorimotor function in diabetic rats. [ABSTRACT FROM AUTHOR]

To investigate the effectiveness of optic nerve decompression (OND) in the treatment of severe traumatic optic neuropathy (TON) through pterional and supraorbital approaches, and to identify the prognostic factor for postoperative visual acuity (VA) following OND. Patients with severe TON treated with OND through either pterional or supraorbital approach in our institute from September 2019 to June 2022 were retrospectively reviewed in this study. Demographic information, trauma factors, the interval between trauma and complete blindness, the interval between trauma and surgery, and the associated craniofacial traumas were recorded. Hospitalization days and the postoperative VA of patients in two groups were compared. There were 54 severe TON patients with NLP included in this study; 21 patients underwent OND through the pterional approach, and the other 33 underwent the supraorbital approach. Respectively, in groups of pterional and supraorbital approaches, the average hospitalization days were 9.8 ± 3.2 and 10.7 ± 2.9 days (p = 0.58), the mean durations of follow-up were 18.9 ± 4.3 and 20.8 ± 3.7 months (p = 0.09), and the average circumference of OND were 53.14 ± 15.89 ◦ (range 220 ◦ -278◦) and 181.70 ± 6.56◦ (range 173 ◦ -193◦) (p<0.001). The overall improvement rates of pterional and supraorbital approaches are 57.1% and 45.5% (p = 0.40), respectively. Optic canal fracture (OCF) was revealed to be significantly associated with postoperative VA in the supraorbital approach (Binary: p = 0.014, CI: 1.573–57.087; Ordinal: p = 0.003, CI: 1.517–5.503), but not in the pterional approach. In the group of supraorbital approach, patients with OFC had a higher rate of a better outcome (78.6%) than those without (21.4%). Patients with severe traumatic TON may benefit from OND through either the pterional or supraorbital approach. OCF is a potential prognostic factor for postoperative VA following OND through the supraorbital approach. [ABSTRACT FROM AUTHOR]

AbstractPurposeMethodsResultsConclusionWe designed a dual-modal fusion network to detect glaucomatous optic neuropathy, which utilized both retinal nerve fiber layer thickness from optical coherence tomography reports and fundus images.A total of 327 healthy subjects (410 eyes) and 87 glaucomatous optic neuropathy patients (113 eyes) were included. The retinal nerve fiber layer thickness from optical coherence tomography reports and fundus images were used as predictors in the dual-modal fusion network to diagnose glaucoma. The area under the receiver operation characteristic curve, accuracy, sensitivity, and specificity were measured to compare our method and other approaches.The accuracy of our dual-modal fusion network using both retinal nerve fiber layer thickness from optical coherence tomography reports and fundus images was 0.935 and we achieved a significant larger area under the receiver operation characteristic curve of our method with 0.968 (95% confidence interval, 0.937–0.999). For only using retinal nerve fiber layer thickness, we compared the area under the receiver operation characteristic curves between our network and other three approaches: 0.916 (95% confidence interval, 0.855, 0.977) with our optical coherence tomography Net; 0.841 (95% confidence interval, 0.749, 0.933) with Clock sectors division; 0.862 (95% confidence interval, 0.757, 0.968) with inferior, superior, nasal temporal sectors division and 0.886 (95% confidence interval, 0.815, 0.957) with optic disc sectors division. For only using fundus images, we compared the area under the receiver operation characteristic curves between our network and other two approaches: 0.867 (95% confidence interval: 0.781–0.952) with our Image Net; 0.774 (95% confidence interval: 0.670, 0.878) with ResNet50; 0.747 (95% confidence interval: 0.628, 0.866) with VGG16.Our dual-modal fusion network utilizing both retinal nerve fiber layer thickness from optical coherence tomography reports and fundus images can diagnose glaucoma with a much better performance than the current approaches based on optical coherence tomography only or fundus images only. [ABSTRACT FROM AUTHOR]

Background: Diabetic peripheral neuropathy (DPN) occurs in >50% of diabetic patients and is a high risk‐factor of balance problems and risk of falls. Impaired balance can lead to reduced function, which has a detrimental effect on patients' quality of life. Structured strength and balance training can result in sustained improvements in muscle strength, coordination, balance, functional status and quality of life. Objective: To determine the combined effects of strength and balance training versus aerobic training on balance, severity of symptoms of DPN, and quality of life in patients with DPN. Methods: This double blinded, two arm parallel design Randomized Clinical Trial. The study was conducted from March to December 2020 in the AIMS diabetic center Peshawar, Pakistan. Participants were selected through convenience sampling technique and randomly allocated into strength plus balance and aerobic training groups. Type 2 diabetic patients of both sexes, aged 40 to 80 years, with a Toronto neuropathy score ≥6 recruited, while patients with ulceration/infection of feet, medical/Surgical conditions, and non‐ambulatory patients were excluded from this study. Intervention was applied 3 days a week for 8 weeks. The Toronto clinical neuropathy system was used to assess neuropathy severity, SF‐36 to assess quality of life and the Berg balance scale was used for assessment of balance. Assessment was done at the baseline and after 8 weeks of intervention using SPSS. Version 22 was used for analysis. Results: The mean age of the participants was 60.80 ± 9.73. Between group analysis, which showed were statistically insignificant for neuropathy severity, balance and all domains of quality of life (p‐value >0.05) except SF‐36 General Health Perception Score, with Mean ± SD of 62.50 ± 7.54 in group A versus Mean ± SD of in group B 60.00 ± 15.98 (p‐value = 0.05). Within group analysis showed statistically significant results for neuropathy severity, balance and all domains of quality of life (p‐value<0.05). Conclusion: This study concluded that there is a statistically significant effect of structured balance and strength training and aerobic training on severity of DPN, balance and quality of life. But there was no statistically significant difference in improvement between the two intervention groups. [ABSTRACT FROM AUTHOR]

Aim: To develop and employ machine learning (ML) algorithms to analyse electrocardiograms (ECGs) for the diagnosis of cardiac autonomic neuropathy (CAN). Materials and Methods: We used motif and discord extraction techniques, alongside long short‐term memory networks, to analyse 12‐lead, 10‐s ECG tracings to detect CAN in patients with diabetes. The performance of these methods with the support vector machine classification model was evaluated using 10‐fold cross validation with the following metrics: accuracy, precision, recall, F1 score, and area under the receiver‐operating characteristic curve (AUC). Results: Among 205 patients (mean age 54 ± 17 years, 54% female), 100 were diagnosed with CAN, including 38 with definite or severe CAN (dsCAN) and 62 with early CAN (eCAN). The best model performance for dsCAN classification was achieved using both motifs and discords, with an accuracy of 0.92, an F1 score of 0.92, a recall at 0.94, a precision of 0.91, and an excellent AUC of 0.93 (95% confidence interval [CI] 0.91–0.94). For the detection of any stage of CAN, the approach combining motifs and discords yielded the best results, with an accuracy of 0.65, F1 score of 0.68, a recall of 0.75, a precision of 0.68, and an AUC of 0.68 (95% CI 0.54–0.81). Conclusion: Our study highlights the potential of using ML techniques, particularly motifs and discords, to effectively detect dsCAN in patients with diabetes. This approach could be applied in large‐scale screening of CAN, particularly to identify definite/severe CAN where cardiovascular risk factor modification may be initiated. [ABSTRACT FROM AUTHOR]

Persons with diabetic peripheral neuropathy (DPN) may face challenges such as balance issues due to reduced somatosensory feedback and an increased risk of developing diabetic foot ulcers (DFUs) due to increased plantar pressure. Pressure reducing footwear is thought to further impair balance. We introduced 3D-printed rocker midsoles and self-adjusting insoles that are able to reduce elevated plantar pressure values and aimed to prevent balance deterioration. However, their effect on the balance during walking (dynamic stability) is not analyzed yet. Is dynamic stability of persons with DPN impaired compared to healthy individuals and what is the effect of the 3D-printed rocker midsoles and self-adjusting insoles on the dynamic stability in this population? Dynamic stability, specifically the margins of stability (MOS) in the anterior-posterior (AP) and medio-lateral (ML) direction, was measured in ten healthy and nineteen persons with DPN. Independent-samples t-test was applied to analyze the difference in the MOS between groups. One-way repeated measures analyses of variance (ANOVA) was conducted to test the difference between the therapeutic footwear combinations within the DPN group. There is no significant difference between the healthy and DPN group in MOS-AP. MOS-ML is significantly larger in DPN compared to the healthy participants. Using the self-adjusting insole shows a significantly lower (negative) MOS-AP compared to when using a rocker shoe within the DPN group. This study provides valuable information on whether DPN and our therapeutic footwear have a negative effect on the dynamic stability. DPN does not have a negative effect on dynamic stability in the AP direction. For the ML direction, DPN seems to cause larger MOS-ML by likely using a compensation strategy (e.g., wider steps) while our experimental footwear does not further impair the MOS-ML. • DPN causes no change in anterior-posterior margins of stability (MOS-AP). • No negative effect of therapeutic footwear on MOS-AP. • No negative effect of therapeutic footwear on MOS in medio-lateral (ML) direction. • DPN causes larger MOS-ML as possible compensation strategy. [ABSTRACT FROM AUTHOR]

The treatment of early triple-negative breast cancer (eTNBC) has improved patients' prognosis but often leads to adverse events and sequelae affecting quality of life (QoL). Pain Neuroscience Education (PNE) is a promising non-pharmacological intervention in this field. Preliminary data have shown the beneficial effect of PNE in BC survivors. However, there are still gaps in knowledge regarding its optimal use in eTNBC. To address this issue, a prospective pilot study will enroll 30 consecutive patients diagnosed with eTNBC at IRCCS Humanitas Research Hospital. The PNE program will consist of 10 weekly sessions to be started within 4 weeks of the onset or worsening of a pain syndrome (PS). QoL, pain, and disability will be assessed before, during, at the end of, and 6 months after PNE using validated questionnaires. Peripheral venous blood samples will be taken before and at the end of PNE to evaluate inflammatory serum biomarker levels. The primary objective is to evaluate whether PNE leads to clinical improvement in QoL and pain. If successful, it will be validated in a larger multi-centric cohort, potentially leading to its widespread implementation as a standard pain management tool for eTNBC patients. [ABSTRACT FROM AUTHOR]

Background: Although diabetic gastroenteropathy (DGE) is associated with small intestinal bacterial overgrowth (SIBO), most studies have evaluated SIBO with a hydrogen breath test, which may be affected by altered transit in DGE. The risk factors for the consequences of SIBO in DGE are poorly understood. We aimed to evaluate the prevalence of, risk factors for, and gastrointestinal symptoms associated with SIBO in patients with DGE. Methods: In 75 patients with DGE and dyspepsia, we tested for SIBO (≥105 colony forming units /mL of aerobic and/or anaerobic bacteria in a duodenal aspirate) and assessed gastric emptying (GE) of solids, symptoms during a GE study and during an enteral lipid challenge (300 kcal/2 h), and daily symptoms with a Gastroparesis Cardinal Symptom Index diary for 2 weeks. Symptoms and GE were compared in patients with versus without SIBO. Key Results: Of 75 patients, 34 (45%) had SIBO, which was not associated with the use of proton pump inhibitors, daily symptoms, GE, or symptoms during a GE study. During enteral lipid challenge, severe nausea (p = 0.006), fullness (p = 0.02) and bloating (p = 0.009) were each associated with SIBO. Twenty patients (59%) with versus 13 (32%) without SIBO had at least one severe symptom during the lipid challenge (p = 0.006). Conclusions & Inferences: Among patients with DGE 45% had SIBO, which was associated with symptoms during enteral lipid challenge but not with delayed GE, symptoms during a GE study, or daily symptoms. Perhaps bacterial products and even fatty acids are recognized by and activate mast cells that drive the increased lipid sensitivity in SIBO. [ABSTRACT FROM AUTHOR]

Background: The factors underlying the topography of nitrous oxide (N2O)‐induced neurological complications are unknown. Methods: We included all consecutive patients admitted to the university hospital of Marseille for N2O‐induced neurological complications in a prospective observational study. Patients underwent neurological examination, spinal cord magnetic resonance imaging, and nerve conduction studies within the first 4 weeks after admission. Results: In total, 61 patients were included: 45% with myeloneuropathy, 34% with isolated myelopathy, and 21% with isolated neuropathy. On multivariable analysis, the odds of myelopathy were associated with the amount of weekly N2O consumption (~600 g cylinder per week, odds ratio [OR] = 1.11, 95% confidence interval [CI] = 1.001–1.24). The extent of the myelopathy (number of vertebral segments) was correlated with the number of ~600‐g cylinders consumed weekly (ρ = 0.40, p < 0.005). The odds of neuropathy were associated with the duration of consumption (per month; OR = 1.29, 95% CI = 1.05–1.58). Mean lower‐limb motor nerve amplitude was correlated with the duration of consumption (in months; ρ = −0.34, p < 0.05). Conclusions: The odds of myelopathy increased with the amount of N2O consumption, and the odds of neuropathy increased with the duration of N2O exposure, which suggests distinct pathophysiological mechanisms underlying these two neurological complications. [ABSTRACT FROM AUTHOR]

This document is a letter to the editor published in the journal Neurological Sciences. It discusses a unique case study of a teenager with congenital myasthenic syndrome and demyelinating sensorimotor neuropathy. The patient had a specific genetic mutation and experienced significant improvement in symptoms with salbutamol monotherapy. The letter emphasizes the importance of identifying the genetic basis of each syndrome for genetic counseling and appropriate therapy. The study highlights the variability of clinical manifestations in congenital myasthenic syndromes and the potential efficacy of salbutamol as a treatment option. Further research is needed to understand the effects of salbutamol on demyelinating neuropathy and its overall therapeutic efficacy in AChR deficiency-related congenital myasthenic syndromes. [Extracted from the article]

We describe the baseline ophthalmic and cardiovascular risk factors across countries, race, and sex for the Quark207 treatment trial for acute nonarteritic anterior ischemic optic neuropathy (NAION). Prospective, randomized controlled clinical trial. Adults 50 to 80 years of age with acute NAION recruited from 80 sites across 8 countries. Ophthalmic features of NAION and cardiovascular risk factors. We evaluated demographics and clinical and ophthalmologic data, including best-corrected visual acuity (BCVA) and average visual field total deviation (TD), in affected eyes and cup-to-disc ratio in fellow eyes at enrollment. We report the prevalence (mean and standard devition, and median and interquartile range [IQR]) of ophthalmic features and cardiovascular risk factors, stratified by country, race, and sex. We corrected for multiple comparisons using Dunn's test with Bonferroni correction for continuous variables and chi-square testing with Holm-Bonferroni correction for categorical variables. The study enrolled 500 men and 229 women with a median age of 60 and 61 years (P = 0.027), respectively. Participants were predominantly White (n = 570) and Asian (n = 149). The study eye BCVA was 71 characters (IQR, 53–84 characters; approximately 0.4 logarithm of the minimum angle of resolution), and the TD was –16.5 dB (IQR, –22.2 to –12.6 dB) for stimulus III and –15.7 dB (IQR, –20.8 to –10.9 dB) for stimulus V. The vertical and horizontal cup-to-disc ratio was 0.1 (IQR, 0.1–0.3) for unaffected fellow eyes. The prevalence of cardiovascular risk factors varied among countries. The most notable differences were in the baseline comorbidities and ophthalmologic features, which differed between Asian and White races. Men and women differed with respect to a few clinically meaningful features. The cardiovascular risk factors in the NAION cohort varied among the 7 countries, race, and sex, but were not typically more prevalent than in the general population. Ophthalmic features, typical of NAION, generally were consistent across countries, race, and sex, except for worse BCVA and TD in China. Men have a frequency of NAION twice that of women. Having a small cup-to-disc ratio in the fellow eye was the most prevalent risk factor across all demographics. This study suggests that factors, not yet identified, may contribute to the development of NAION. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. [ABSTRACT FROM AUTHOR]

Small-Fiber Neuropathy (SFN) is a disorder of the peripheral nervous system, characterised by neuropathic pain; approximately 11% of cases are linked to variants in Voltage-Gated Sodium Channels (VGSCs). This study aims to broaden the genetic knowledge on painful SFN by applying Whole-Exome Sequencing (WES) in Early-Onset (EO) cases. A total of 88 patients from Italy (n = 52) and the Netherlands (n = 36), with a disease onset at age ≤ 45 years old and a Pain Numerical Rating Score ≥ 4, were recruited. After variant filtering and classification, WES analysis identified 142 potentially causative variants in 93 genes; 8 are Pathogenic, 15 are Likely Pathogenic, and 119 are Variants of Uncertain Significance. Notably, an enrichment of variants in transient receptor potential genes was observed, suggesting their role in pain modulation alongside VGSCs. A pathway analysis performed by comparing EO cases with 40 Italian healthy controls found enriched mutated genes in the "Nicotinic acetylcholine receptor signaling pathway". Targeting this pathway with non-opioid drugs could offer novel therapeutic avenues for painful SFN. Additionally, with this study we demonstrated that employing a gene panel of reported mutated genes could serve as an initial screening tool for SFN in genetic studies, enhancing clinical diagnostics. [ABSTRACT FROM AUTHOR]

Objectives: This case series reports clinical features and outcome of four patients with non-systemic vasculitic neuropathy (NSVN) treated with the anti-CD20 agent rituximab. Methods: Clinical, electrophysiological and biopsy data were retrospectively obtained and evaluated. Only patients with pathological definite or probable NSVN were included. Extensive clinical and laboratory work-up excluded systemic vasculitis. Follow-up data for at least 12 months and up to five years is provided. Outcome of the patients was assessed using the MRC-Sum Score, Prineas Score and Neurological Symptom Score. Results: Two of four patients treated with rituximab achieved disease remission and one patient remained stable under anti-CD20 therapy after a required treatment switch due to toxic side effects of cyclophosphamide. One patient deteriorated under rituximab induction. Rituximab was well tolerated in all patients. Discussion: Anti-CD20 therapy might be an alternative in NSVN patients requiring further treatment escalation or treatment switch due to side effects of corticosteroids or cyclophosphamide. [ABSTRACT FROM AUTHOR]

Introduction: Recent diagnostic criteria for optic neuritis include T2-hyperintensity of the optic nerve (ON), even without associated contrast enhancement. However, isolated ON-T2-hyperintensity is a nonspecific finding found in any optic neuropathy or severe retinopathy. We applied the 2022 optic neuritis diagnostic criteria to a cohort of patients with noninflammatory optic neuropathy and ON-T2-hyperintensity in at least one eye, to assess the rate of optic neuritis misdiagnosis using these criteria. Methods: Retrospective study of consecutive patients who underwent brain/orbit MRI with/without contrast between 07/01/2019 and 06/30/2022. Patients with ON-T2-hyperintensity in at least one eye were included. The 2022 optic neuritis diagnostic criteria were applied to patients with noninflammatory optic neuropathies who had an ophthalmologic examination available for review. Results: Of 150 patients included, 85/150 had compressive optic neuropathy; 32/150 had glaucoma; 12/150 had papilledema; 8/150 had hereditary (3), radiation-induced (3), nutritional (1), traumatic (1) optic neuropathies (none fulfilled the criteria); 13/150 had ischemic optic neuropathy and 4 fulfilled the criteria as definite optic neuritis due to contrast enhancement of the ON head. Seven additional patients would have satisfied the diagnostic criteria if red flags for alternative diagnoses had been overlooked. Discussion: The application of the 2022 optic neuritis diagnostic criteria in patients with noninflammatory optic neuropathy and ON-T2-hyperintensity in at least one ON resulted in misdiagnosis of optic neuritis in only 4 patients because of ON head enhancement, all with nonarteritic anterior ischemic optic neuropathy. Neuro-ophthalmologic evaluation and exclusion of the ON head as a location in the MRI criteria would have prevented optic neuritis misdiagnosis in our study. [ABSTRACT FROM AUTHOR]

Purpose: To determine and report the underlying cause of local inflammation causing recurrent neuropathy and multiple operations in a patient with a Barricaid® device. Methods: After removal of this patient's Barricaid® device, we sent local inflammatory tissue to pathology for histochemical analysis. Upon discovery of giant cells formation with polarizable foreign bodies, we performed a literature review regarding the Barricaid® device and its elements. Results: After two previous operations and three trials of conservative management, the presented patient underwent an L5/S1 TLIF with removal of her previously installed Barricaid® device. There were no signs of device instability/failure nor were there obvious signs of infection. Inflamed tissue proximal to the Barricaid® device was discovered, debrided, and sample sent to pathology. Removal of the Barricaid® device led to subsequent and durable relief of her symptoms. During review of this case, we discovered the polyethylene terephthalate (PET) weave used in the Barricaid® device is known to induce foreign body reactions, and this precise finding was seen in the majority of animal data submitted to the FDA for the device's acceptance. Conclusion: Given the constellation of this patient's symptoms, imaging, intraoperative, and pathology findings, previously published reports, and pre-approval data submitted to the FDA, we conclude that the inflammatory response to the PET weave in this patient's Barricaid® device was the ultimate cause of her continued neuropathy despite multiple prior surgical interventions. [ABSTRACT FROM AUTHOR]

A 54‐year‐old man with diabetes mellitus presented with fever, pain, muscle weakness, and sensory disturbances in the lower limbs. His serum C‐reactive protein level was markedly increased; However, no autoantibodies, other than anti‐glutamic acid decarboxylase antibody, were detected. Nerve conduction studies revealed axonal polyneuropathy. 18F‐fluorodeoxyglucose positron emission tomography/computed tomography revealed patchy uptake patterns specific to restricted lower‐limb vasculitis. The muscle and nerve biopsy specimens suggested vasculitic neuropathy. Treatment with oral prednisolone and cyclophosphamide pulse therapy markedly improved his lower‐limb weakness and paresthesia. Clinicians should consider the involvement of vasculitic neuropathy, as well as myopathy, in patients with restricted lower‐limb vasculitis. [ABSTRACT FROM AUTHOR]

Key Clinical Message: We report on the successful use of chemotherapy for treatment of stage 2B testicular seminoma in a carrier of the Leber's hereditary optic neuropathy 11778 mitochondrial mutation. Neurotoxic chemotherapy may not prompt disease conversion. [ABSTRACT FROM AUTHOR]

Objectives: MR neurography has the ability to detect and depict peripheral nerve injuries. This study evaluated the potential of MR neurography in the diagnosis of post-traumatic trigeminal neuropathy. Methods: Forty-one participants prospectively underwent MR neurography of the lingual and inferior alveolar nerves using a 3D TSE STIR black-blood sequence. Two blinded and independent observers recorded the following information for each nerve of interest: presence of injury, nerve thickness, nerve signal intensity, MR neurography Sunderland class, and signal gap. Afterwards, the apparent nerve-muscle contrast-to-noise ratio and apparent signal-to-noise ratio were calculated. Clinical data (neurosensory testing score and clinical Sunderland class) was extracted retrospectively from the medical records of patients diagnosed with post-traumatic trigeminal neuropathy. Results: Compared to neurosensory testing, MR neurography had a sensitivity of 38.2% and specificity of 93.5% detecting nerve injuries. When differentiated according to clinical Sunderland class, sensitivity was 19.1% in the presence of a low class injury (I to III) and improved to 83.3% in the presence of a high class (IV to V). Specificity remained unchanged. The area under the curve using the apparent nerve-muscle contrast-to-noise ratio, apparent signal-to-noise ratio, and nerve thickness to predict the presence of an injury was 0.78 (p <.05). Signal intensities and nerve diameter increased in injured nerves (p <.05). Clinical and MR neurography Sunderland scores positively correlated (correlation coefficient = 0.53; p =.005). Conclusions: This study shows that MR neurography can accurately differentiate between injured and healthy nerves, especially in the presence of a more severe nerve injury. Clinical relevance statement: MR neurography is not only able to detect trigeminal nerve injuries, but it can also provide information about the anatomical specifications of the injury, which is not possible with clinical neurosensory testing. This makes MR neurography an added value in the management of post-traumatic trigeminal neuropathy. Key Points: • The current diagnosis of post-traumatic trigeminal neuropathy is mainly based on clinical examination. • MR neurography is able to visualize and stratify peripheral trigeminal nerve injuries. • MR neurography contributes to the diagnostic process as well as to further decision-making. [ABSTRACT FROM AUTHOR]

To report a rare case of bilateral optic neuropathy in a patient with diffuse cutaneous systemic sclerosis with interstitial lung disease. Retrospective case report. A middle-aged female, who was a known case of systemic sclerosis with interstitial lung disease, was presented with sudden painless bilateral loss of vision for a month. The fundoscopy findings were suggestive of bilateral optic atrophy. Anti-topoisomerase I was found in the serum. Serum B12 and folate levels were reduced. HRCT Chest was suggestive of interstitial lung disease. MRI brain was normal and MRI orbit showed kinking of the left optic nerve. The findings were suggestive of diffuse cutaneous systemic sclerosis with interstitial lung disease and bilateral optic neuropathy. This is a rare case of bilateral optic neuropathy in a patient with diffuse cutaneous systemic sclerosis and interstitial lung disease with profound vision loss, in the absence of renal or cardiac involvement. [ABSTRACT FROM AUTHOR]

Background: The understanding of neuropathic pain remains incomplete, highlighting the need for research on biomarkers for improved diagnosis and treatment. This review focuses on identifying potential biomarkers in blood and cerebrospinal fluid for neuropathic pain in different neuropathies. Methods: Searches were performed in six databases: PubMed, Web of Science, Scopus, Cochrane Library, EMBASE, and CINAHL. Included were observational studies, namely cross-sectional, cohort, and case-control, that evaluated quantitative biomarkers in blood or cerebrospinal fluid. Data were qualitatively synthesized, and meta-analyses were conducted using R. The study is registered with PROSPERO under the ID CRD42022323769. Results: The literature search resulted in 16 studies for qualitative and 12 for quantitative analysis, covering patients over 18 years of age with painful neuropathies. A total of 1403 subjects were analyzed, identifying no significant differences in levels of C-Reactive Protein (CRP), Interleukin-6 (IL-6), and Tumor Necrosis Factor-alpha (TNF-alpha) between patients with and without pain. Despite the high inter-rater reliability and adequate bias assessment, the results suggest negligible differences in inflammatory biomarkers, with noted publication bias and heterogeneity among studies, indicating the need for further research. Conclusions: Our review underscores the complex nature of neuropathic pain and the challenges in identifying biomarkers, with no significant differences found in CRP, IL-6, and TNF-alpha levels between patients with and without pain. Despite methodological robustness, the results are limited by publication bias and heterogeneity. This emphasizes the need for further research to discover definitive biomarkers for improved diagnosis and personalized treatment of neuropathic pain. [ABSTRACT FROM AUTHOR]

Introduction: As inhibitors of advanced glycation end products (AGEs), such as pyridoxamine, significantly inhibit the development of retinopathy and neuropathy in rats with streptozotocin-induced diabetes, treatment with AGE inhibitors is believed to be a potential strategy for the prevention of aging, age- related diseases, and lifestyle-related diseases, including diabetic complications. In the present study, the MeOH extract of Epimedii Herba (EH; aerial parts of Epimedium spp.) was found to inhibit the formation of NE-(carboxymethyl)lysine (CML) and N"-(carboxymethyl) arginine (CMA) during the incubation of collagen- derived gelatin with ribose. Materials and methods: EH was purchased from Uchida Wakan-yaku Co., and a MeOH extract was prepared. Several steps of column chromatography purified the extract. Each fraction was tested for inhibitory activity by ELISA using monoclonal antibodies for CML and CMA. Results: After activity-guided fractionation and purification by column chromatography, three new prenylflavonoids [named Koreanoside L (1), Koreanoside E1 (2), and Koreanoside E2 (3)] and 40 known compounds (4-43) were isolated from EH, and their inhibitory effects against CML and CMA formation were tested. Among these, epimedokoreanin B (8), epimedonin E (21), epicornunin B (22), and epicornunin F (24) inhibited the formation of both CML and CMA, with epimedokoreanin B (8) having the most potent inhibitory effect among the isolated compounds. To obtain the structure-activity relationships of 8, the phenolic hydroxy groups of 8 were methylated by trimethylsilyl-diazomethane to afford the partially and completely methylated compounds of 8. Prenyl derivatives of propolis (artepillin C, baccharin, and drupanin) were used in the assay. Discussion: As only 8 showed significant activity among these compounds, the catechol group of the B ring and the two prenyl groups attached to the flavanone skeleton were essential for activity. These data suggest that 8 could prevent the clinical complications of diabetes and age-related diseases by inhibiting AGEs. [ABSTRACT FROM AUTHOR]

The peripheral nervous system can encounter alterations due to exposure to some of the most commonly used anticancer drugs (platinum drugs, taxanes, vinca alkaloids, proteasome inhibitors, thalidomide), the so-called chemotherapy-induced peripheral neurotoxicity (CIPN). CIPN can be long-lasting or even permanent, and it is detrimental for the quality of life of cancer survivors, being associated with persistent disturbances such as sensory loss and neuropathic pain at limb extremities due to a mostly sensory axonal polyneuropathy/neuronopathy. In the state of the art, there is no efficacious preventive/curative treatment for this condition. Among the reasons for this unmet clinical and scientific need, there is an uncomplete knowledge of the pathogenetic mechanisms. Ion channels and transporters are pivotal elements in both the central and peripheral nervous system, and there is a growing body of literature suggesting that they might play a role in CIPN development. In this review, we first describe the biophysical properties of these targets and then report existing data for the involvement of ion channels and transporters in CIPN, thus paving the way for new approaches/druggable targets to cure and/or prevent CIPN. [ABSTRACT FROM AUTHOR]