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Gait analysis could be used in animal models as an indicator of sensory ataxia due to chemotherapy-induced peripheral neurotoxicity (CIPN). Over the years, gait analysis in in vivo studies has evolved from simple observations carried out by a trained operator to computerised systems with machine learning that allow the quantification of any variable of interest and the establishment of algorithms for behavioural classification. However, there is not a consensus on gait analysis use in CIPN animal models; therefore, we carried out a systematic review. Of 987 potentially relevant studies, 14 were included, in which different methods were analysed (observation, footprint and CatWalk™). We presented the state-of-the-art of possible approaches to analyse sensory ataxia in rodent models, addressing advantages and disadvantages of different methods available. Semi-automated methods may be of interest when preventive or therapeutic strategies are evaluated, also considering their methodological simplicity and automaticity; up to now, only CatWalk™ analysis has been tested. Future studies should expect that CIPN-affected animals tend to reduce hind paw support due to pain, allodynia or loss of sensation, and an increase in swing phase could or should be observed. Few available studies documented these impairments at the last time point, and only appeared later on respect to other earlier signs of CIPN (such as altered neurophysiological findings). For that reason, gait impairment could be interpreted as late repercussions of loss of sensory.

This study aims to examine the association between baseline level and change of autonomic nervous function with subsequent development of arterial stiffness. Autonomic nervous function was assessed in 4901 participants of the Whitehall II occupational cohort by heart rate variability (HRV) indices and resting heart rate (rHR) three times between 1997 and 2009, while arterial stiffness was assessed by carotid-femoral pulse wave velocity (PWV) measured twice between 2007 and 2013. First, individual HRV/rHR levels and annual changes were estimated. Then, we modelled the development of PWV by HRV/rHR using linear mixed effect models. First, we adjusted for sex and ethnicity (model 1), and then for socioeconomic and lifestyle factors, various clinical measurements, and medications (model 2). A decrease in HRV and unchanged rHR was associated with subsequent higher levels of PWV, but the effect of a change in HRV was less pronounced at higher ages. A typical individual aged 65 years with a SDNN level of 30 ms and a 2% annual decrease in SDNN had 1.32 (0.95; 1.69) higher PWV compared to one with the same age and SDNN level but with a 1% annual decrease in SDNN. Further adjustment had no major effect on the results. People who experience a steeper decline in autonomic nervous function have higher levels of arterial stiffness. The association was stronger in younger people., This study aims to examine the association between baseline level and change of autonomic nervous function with subsequent development of arterial stiffness. Autonomic nervous function was assessed in 4901 participants of the Whitehall II occupational cohort by heart rate variability (HRV) indices and resting heart rate (rHR) three times between 1997 and 2009, while arterial stiffness was assessed by carotid-femoral pulse wave velocity (PWV) measured twice between 2007 and 2013. First, individual HRV/rHR levels and annual changes were estimated. Then, we modelled the development of PWV by HRV/rHR using linear mixed effect models. First, we adjusted for sex and ethnicity (model 1), and then for socioeconomic and lifestyle factors, various clinical measurements, and medications (model 2). A decrease in HRV and unchanged rHR was associated with subsequent higher levels of PWV, but the effect of a change in HRV was less pronounced at higher ages. A typical individual aged 65 years with a SDNN level of 30 ms and a 2% annual decrease in SDNN had 1.32 (0.95; 1.69) higher PWV compared to one with the same age and SDNN level but with a 1% annual decrease in SDNN. Further adjustment had no major effect on the results. People who experience a steeper decline in autonomic nervous function have higher levels of arterial stiffness. The association was stronger in younger people.

The dominant sensory phenotype in patients with diabetic polyneuropathy and neuropathic pain is a loss of function. This raises questions as to which mechanisms underlie pain generation in the face of potentially reduced afferent input. One potential mechanism is spinal disinhibition, whereby a loss of spinal inhibition leads to increased ascending nociceptive drive due to amplification of, or a failure to suppress, incoming signals from the periphery. We aimed to explore whether a putative biomarker of spinal disinhibition, impaired rate-dependent depression of the Hoffmann reflex, is associated with a mechanistically appropriate and distinct pain phenotype in patients with painful diabetic neuropathy. In this cross-sectional study, 93 patients with diabetic neuropathy underwent testing of Hoffmann reflex rate-dependent depression and detailed clinical and sensory phenotyping, including quantitative sensory testing. Compared to neuropathic patients without pain, patients with painful diabetic neuropathy had impaired Hoffmann reflex rate-dependent depression at 1, 2 and 3 Hz (P ≤ 0.001). Patients with painful diabetic neuropathy exhibited an overall loss of function profile on quantitative sensory testing. However, within the painful diabetic neuropathy group, cluster analysis showed evidence of greater spinal disinhibition associated with greater mechanical pain sensitivity, relative heat hyperalgesia and higher ratings of spontaneous burning pain. These findings support spinal disinhibition as an important centrally mediated pain amplification mechanism in painful diabetic neuropathy. Furthermore, our analysis indicates an association between spinal disinhibition and a distinct phenotype, arguably akin to hyperpathia, with combined loss and relative gain of function leading to increasing nociceptive drive.

Objective Since there is a lack of effective pharmacological therapies for chemotherapy-induced neuropathy and many patients ask for integrative cancer therapies such as acupuncture, the objective of this pilot study was to describe patients’ experiences, and to study the feasibility and short-term effects of genuine acupuncture for chemotherapy-induced neuropathic pain and unpleasant sensations compared to sham acupuncture. Methods: The pilot study used mixed methods, collecting quantitative and qualitative data. Patients (n = 12) with chemotherapy-induced neuropathy after colorectal cancer were blindly randomized to genuine acupuncture or telescopic sham acupuncture. Individual interviews were conducted, and were analyzed using qualitative content analysis. The patients registered pain and unpleasant sensations (100 mm Visual Analog Scales) before and after n = 120 sessions, n = 60 genuine and n = 60 sham acupuncture sessions. Results: Five categories of patient experiences were described. The neuropathy negatively affected life. Physical activity was perceived to be important for health, but neuropathy was a barrier. The neuropathy required symptom-managing strategies. Acupuncture was pleasant and valuable, but some patients presented doubts regarding its effect mechanisms. After the genuine acupuncture sessions, pain (mean −2.0 steps relief during each session) and unpleasant sensations (−2.4) in the face was reduced more than after sham acupuncture (+0.1 steps worse pain, P = .018, +0.1 steps worse unpleasant sensations, P = .036). After genuine acupuncture, unpleasant sensations in the hands were reduced less (−0.23) compared to after sham acupuncture (−5.5, P = .002). Pain or unpleasant sensations in the feet did not change. Conclusions: Patients experienced that the neuropathy negatively changed their life and that acupuncture was pleasant and valuable. Patients receiving genuine acupuncture had short-term effects regarding pain and unpleasant sensations in

Objective Since there is a lack of effective pharmacological therapies for chemotherapy-induced neuropathy and many patients ask for integrative cancer therapies such as acupuncture, the objective of this pilot study was to describe patients’ experiences, and to study the feasibility and short-term effects of genuine acupuncture for chemotherapy-induced neuropathic pain and unpleasant sensations compared to sham acupuncture. Methods: The pilot study used mixed methods, collecting quantitative and qualitative data. Patients (n = 12) with chemotherapy-induced neuropathy after colorectal cancer were blindly randomized to genuine acupuncture or telescopic sham acupuncture. Individual interviews were conducted, and were analyzed using qualitative content analysis. The patients registered pain and unpleasant sensations (100 mm Visual Analog Scales) before and after n = 120 sessions, n = 60 genuine and n = 60 sham acupuncture sessions. Results: Five categories of patient experiences were described. The neuropathy negatively affected life. Physical activity was perceived to be important for health, but neuropathy was a barrier. The neuropathy required symptom-managing strategies. Acupuncture was pleasant and valuable, but some patients presented doubts regarding its effect mechanisms. After the genuine acupuncture sessions, pain (mean −2.0 steps relief during each session) and unpleasant sensations (−2.4) in the face was reduced more than after sham acupuncture (+0.1 steps worse pain, P = .018, +0.1 steps worse unpleasant sensations, P = .036). After genuine acupuncture, unpleasant sensations in the hands were reduced less (−0.23) compared to after sham acupuncture (−5.5, P = .002). Pain or unpleasant sensations in the feet did not change. Conclusions: Patients experienced that the neuropathy negatively changed their life and that acupuncture was pleasant and valuable. Patients receiving genuine acupuncture had short-term effects regarding pain and unpleasant sensations in

Gastroenteropathy is a common complication in diabetes associated with damages to the enteric nervous system. Systemic low-grade inflammation facilitates neurotoxicity, and associations with peripheral and autonomic neuropathy have been reported. However, less is known of associations with gastroenteropathy. To explore the area cross-sectionally, we included individuals with diabetes (type 1: 56, type 2: 100) and 21 healthy controls. Serum levels of interleukin (IL)-6, IL-8, IL-10, tumour necrosis factor (TNF)-alpha, and interferon (IFN)-gamma were measured by multiplex technology. Segmental gastrointestinal transit times were assessed by wireless motility capsule investigations. Symptoms of gastroparesis were rated on Gastroparesis Cardinal Symptom Index questionnaires. Compared to healthy, levels of TNF-alpha were decreased in type 1 diabetes and increased in type 2 diabetes, while colonic transit time was increased (all p < 0.05). In diabetes, associations between IL-8 and prolonged gastric emptying (odds ratio (OR) 1.07, p = 0.027) and between IL-10 and prolonged colonic transit (OR 29.99, p = 0.013) were seen. Inverse correlations between IL-6 and nausea/vomiting (rho = -0.19, p = 0.026) and bloating (rho = -0.29; p < 0.001) were found. These findings indicate a plausible interaction between inflammation and the enteric nervous system in diabetes, which raises the question of whether anti-inflammatory strategies could be applied in management of diabetic gastroenteropathy.

Objective Since there is a lack of effective pharmacological therapies for chemotherapy-induced neuropathy and many patients ask for integrative cancer therapies such as acupuncture, the objective of this pilot study was to describe patients’ experiences, and to study the feasibility and short-term effects of genuine acupuncture for chemotherapy-induced neuropathic pain and unpleasant sensations compared to sham acupuncture. Methods: The pilot study used mixed methods, collecting quantitative and qualitative data. Patients (n = 12) with chemotherapy-induced neuropathy after colorectal cancer were blindly randomized to genuine acupuncture or telescopic sham acupuncture. Individual interviews were conducted, and were analyzed using qualitative content analysis. The patients registered pain and unpleasant sensations (100 mm Visual Analog Scales) before and after n = 120 sessions, n = 60 genuine and n = 60 sham acupuncture sessions. Results: Five categories of patient experiences were described. The neuropathy negatively affected life. Physical activity was perceived to be important for health, but neuropathy was a barrier. The neuropathy required symptom-managing strategies. Acupuncture was pleasant and valuable, but some patients presented doubts regarding its effect mechanisms. After the genuine acupuncture sessions, pain (mean −2.0 steps relief during each session) and unpleasant sensations (−2.4) in the face was reduced more than after sham acupuncture (+0.1 steps worse pain, P = .018, +0.1 steps worse unpleasant sensations, P = .036). After genuine acupuncture, unpleasant sensations in the hands were reduced less (−0.23) compared to after sham acupuncture (−5.5, P = .002). Pain or unpleasant sensations in the feet did not change. Conclusions: Patients experienced that the neuropathy negatively changed their life and that acupuncture was pleasant and valuable. Patients receiving genuine acupuncture had short-term effects regarding pain and unpleasant sensations in

Gastroenteropathy is a common complication in diabetes associated with damages to the enteric nervous system. Systemic low-grade inflammation facilitates neurotoxicity, and associations with peripheral and autonomic neuropathy have been reported. However, less is known of associations with gastroenteropathy. To explore the area cross-sectionally, we included individuals with diabetes (type 1: 56, type 2: 100) and 21 healthy controls. Serum levels of interleukin (IL)-6, IL-8, IL-10, tumour necrosis factor (TNF)-alpha, and interferon (IFN)-gamma were measured by multiplex technology. Segmental gastrointestinal transit times were assessed by wireless motility capsule investigations. Symptoms of gastroparesis were rated on Gastroparesis Cardinal Symptom Index questionnaires. Compared to healthy, levels of TNF-alpha were decreased in type 1 diabetes and increased in type 2 diabetes, while colonic transit time was increased (all p < 0.05). In diabetes, associations between IL-8 and prolonged gastric emptying (odds ratio (OR) 1.07, p = 0.027) and between IL-10 and prolonged colonic transit (OR 29.99, p = 0.013) were seen. Inverse correlations between IL-6 and nausea/vomiting (rho = -0.19, p = 0.026) and bloating (rho = -0.29; p < 0.001) were found. These findings indicate a plausible interaction between inflammation and the enteric nervous system in diabetes, which raises the question of whether anti-inflammatory strategies could be applied in management of diabetic gastroenteropathy.

CONTEXT: Blood oxygen saturation (SpO2) is lower in type 1 diabetes (T1D) compared with nondiabetic controls. Hypoxia (low tissue oxygenation) is thought to be a risk factor for progression of diabetic complications, but it is unknown whether hypoxemia (low SpO2) is associated with diabetic complications. OBJECTIVE: To test if hypoxemia is associated with presence of diabetic complications in T1D. DESIGN, SETTING, AND METHODS: Cross-sectional study in persons with T1D divided by a previously suggested threshold in low (<96%) and high (≥96%) SpO2, measured in the supine position with pulse oximetry. Complications included albuminuria (2 of 3 consecutive measurements ≥30 mg/g), any diabetic retinopathy, neuropathy, and history of cardiovascular disease (CVD). Odds ratios were adjusted for age, diabetes duration, sex, smoking, physical activity, body mass index, systolic blood pressure, and blood hemoglobin. RESULTS: We included 659 persons, 23 (3.5%) with low and 636 (96.5%) with high SpO2. In total, 151 (23%) had albuminuria, 233 (36%) had retinopathy, 231 (35%) had neuropathy, and 72 (11%) had CVD. The adjusted odds ratio (95% CI, P value) for low vs high SpO2 was 3.4 (1.3-8.7, P = 0.01) for albuminuria, 2.8 (1.0-7.5, P = 0.04) for retinopathy, 5.8 (1.8-18.6, P < 0.01) for neuropathy, and nonsignificant for CVD (0.6 [0.2-2.4, P = 0.51]). CONCLUSIONS: SpO2 below 96% was associated with increased presence of albuminuria, retinopathy, and neuropathy in T1D, but not with CVD. Whether hypoxemia could be a target of intervention to prevent progression in microvascular disease in type 1 diabetes should be investigated.

Objective Since there is a lack of effective pharmacological therapies for chemotherapy-induced neuropathy and many patients ask for integrative cancer therapies such as acupuncture, the objective of this pilot study was to describe patients’ experiences, and to study the feasibility and short-term effects of genuine acupuncture for chemotherapy-induced neuropathic pain and unpleasant sensations compared to sham acupuncture. Methods: The pilot study used mixed methods, collecting quantitative and qualitative data. Patients (n = 12) with chemotherapy-induced neuropathy after colorectal cancer were blindly randomized to genuine acupuncture or telescopic sham acupuncture. Individual interviews were conducted, and were analyzed using qualitative content analysis. The patients registered pain and unpleasant sensations (100 mm Visual Analog Scales) before and after n = 120 sessions, n = 60 genuine and n = 60 sham acupuncture sessions. Results: Five categories of patient experiences were described. The neuropathy negatively affected life. Physical activity was perceived to be important for health, but neuropathy was a barrier. The neuropathy required symptom-managing strategies. Acupuncture was pleasant and valuable, but some patients presented doubts regarding its effect mechanisms. After the genuine acupuncture sessions, pain (mean −2.0 steps relief during each session) and unpleasant sensations (−2.4) in the face was reduced more than after sham acupuncture (+0.1 steps worse pain, P = .018, +0.1 steps worse unpleasant sensations, P = .036). After genuine acupuncture, unpleasant sensations in the hands were reduced less (−0.23) compared to after sham acupuncture (−5.5, P = .002). Pain or unpleasant sensations in the feet did not change. Conclusions: Patients experienced that the neuropathy negatively changed their life and that acupuncture was pleasant and valuable. Patients receiving genuine acupuncture had short-term effects regarding pain and unpleasant sensations in

Background: Diabetes and Peripheral Arterial Disease (PAD) are leading causes of non-traumatic amputations and certain populations including Hispanics/LatinX and Native Americans (LXNA) have higher rates of amputations compared to matched White people. Many have attributed this to differential access to health care and the prevalence of DM and PAD in these populations. In addition to these important topics, microvascular disease likely contributes to limb loss and a racial disparity in the prevalence of MVD could exist. Microvascular disease (MVD) describes systemic changes in small vessels (~100 mm diameter) that impair tissue oxygenation and perfusion. Although prevalent but not exclusive to Diabetics, MVD is clinically relevant in limb salvage as it synergistically acts with large vessel peripheral arterial disease to increase the risk of limb loss by 22.7-fold. Clinically, retinopathy and neuropathy are considered markers of MVD, however, these markers act as surrogate endpoints and do not directly provide information on the state of the microvasculature of the feet. In a bid to understand the effect of MVD on the feet of those with PAD, we utilize a non-invasive technology called Spatial Frequency Domain Imaging (SFDI) that has been proven to stratify the severity of clinical microvascular disease by quantifying the amount of hemoglobin (HbT1) in the capillaries of the superficial dermis (1-2mm deep) and tissue oxygenation (StO2) in the dermal microvasculature of the feet. This study aims to evaluate the role of MVD in foot ulcers/limb loss in at-risk populations with PAD. We also seek to determine if the LXNA populations have a higher risk of MVD independent of Diabetes. Lastly, using a non-invasive technology proven to quantify microvascular changes directly in the feet, we aim to assess if a difference exists in the limbs of patients with lower extremity vascular disease (those with a combination of clinical MVD and PAD as compared to those with only PAD). M

Numerous patients who have uncontrolled diabetes have developed complications associated with diabetic neuropathy. The apparent knowledge deficit and noncompliance have led to the development of clinical concerns related to improving patient outcomes. This scholarly project assesses the effects of dietary, weight, and exercise management on improving diabetic neuropathy symptoms. The debilitating effects of diabetes continue to affect numerous people each day. Uncontrolled diabetes can create innumerable complications, including diabetic neuropathy. Appropriate nutrition associated with accountability, monitoring, and proper education can alleviate the progression of uncontrolled diabetes. Assessment of the improvement of diabetic neuropathy with dietary and exercise management is examined among a group of twelve participants selected randomly.

Objective Since there is a lack of effective pharmacological therapies for chemotherapy-induced neuropathy and many patients ask for integrative cancer therapies such as acupuncture, the objective of this pilot study was to describe patients’ experiences, and to study the feasibility and short-term effects of genuine acupuncture for chemotherapy-induced neuropathic pain and unpleasant sensations compared to sham acupuncture. Methods: The pilot study used mixed methods, collecting quantitative and qualitative data. Patients (n = 12) with chemotherapy-induced neuropathy after colorectal cancer were blindly randomized to genuine acupuncture or telescopic sham acupuncture. Individual interviews were conducted, and were analyzed using qualitative content analysis. The patients registered pain and unpleasant sensations (100 mm Visual Analog Scales) before and after n = 120 sessions, n = 60 genuine and n = 60 sham acupuncture sessions. Results: Five categories of patient experiences were described. The neuropathy negatively affected life. Physical activity was perceived to be important for health, but neuropathy was a barrier. The neuropathy required symptom-managing strategies. Acupuncture was pleasant and valuable, but some patients presented doubts regarding its effect mechanisms. After the genuine acupuncture sessions, pain (mean −2.0 steps relief during each session) and unpleasant sensations (−2.4) in the face was reduced more than after sham acupuncture (+0.1 steps worse pain, P = .018, +0.1 steps worse unpleasant sensations, P = .036). After genuine acupuncture, unpleasant sensations in the hands were reduced less (−0.23) compared to after sham acupuncture (−5.5, P = .002). Pain or unpleasant sensations in the feet did not change. Conclusions: Patients experienced that the neuropathy negatively changed their life and that acupuncture was pleasant and valuable. Patients receiving genuine acupuncture had short-term effects regarding pain and unpleasant sensations in

Multiple pathological mechanisms are involved in the development of chemotherapy-induced peripheral neurotoxicity (CIPN). Recent work has provided insights into the molecular mechanisms underlying chemotherapy-induced axonal degeneration. This review integrates evidence from preclinical and clinical work on the onset, progression and outcome of axonal degeneration in CIPN. We review likely triggers of axonal degeneration in CIPN and highlight evidence of molecular pathways involved in axonal degeneration and their relevance to CIPN, including SARM1-mediated axon degeneration pathway. We identify potential clinical markers of axonal dysfunction to provide early identification of toxicity as well as present potential treatment strategies to intervene in axonal degeneration pathways. A greater understanding of axonal degeneration processes in CIPN will provide important information regarding the development and progression of axonal dysfunction more broadly and will hopefully assist in the development of successful interventions for CIPN and other neurodegenerative disorders.

Peripheral Neuropathies (PN) are common conditions whose treatment is still lacking in most cases. Animal models are crucial, but experimental procedures should be refined in some cases. We performed a detailed characterization of the ventral caudal nerve to contribute to a more effective assessment of axonal damage in future PN studies. PN was induced via weekly systemic injection of a neurotoxic drug (paclitaxel); we compared the control and PN-affected rats, performing serial neurophysiological evaluations of the caudal nerve for its entire length. On the same nerve portions, we performed light microscopy and ultrastructural pathological observations to assess the severity of damage and verify the integrity of the surrounding structures. Neurophysiological and morphological analyses confirmed that a severe axonopathy had ensued in the PN group, with a length-dependent modality, matching morphological observations. The site of neurophysiological recording (e.g., distance from the base of the tail) was critical for achieving useful data. A flexible experimental paradigm should be considered in animal studies investigating axonal PN, particularly if the expected severity is relevant; the mid-portion of the tail might be the most appropriate site: there damage might be remarkable but neither as extreme as at the tip of the tail nor as mild as at the base of the tail.

Background: Management for chemotherapy-induced peripheral neuropathy (CIPN) includes prompt recognition and dose reduction or discontinuation of the neurotoxic agents. CIPN remains under-detected in routine clinical practice and better methods for its early detection are warranted. Aims: To evaluate the feasibility of a point-of-care device in the early detection of CIPN. Methods and Results: Cancer patients (n = 12) scheduled to receive neurotoxic chemotherapy docetaxel, oxaliplatin (OX), or vincristine were recruited for the pilot study (NCT04778878). The patients were assessed with a point-of-care nerve conduction study device (Mediracer® NCS), EORTC QLQ-CIPN20 and NPSI questionnaires, and healthcare professional-assessed CTCAE-based grading at baseline and thereafter every 6-weeks up to 18 weeks or until chemotherapy discontinuation. The set-up of point-of-care device was easy but it only provide successful NCS measurement results in 55% of the patients. The factors related to failed measurement were older age, more frequent comorbidities, and a history of smoking. With the follow-up measurements, decreasing median nerve mean conduction velocity and amplitude, and increasing median nerve mean distal latency were detected on OX-patients. Of the used questionnaires, NPSI was found to be non-feasible with majority of the patients failing to complete the questionnaire while CIPN20 was feasible on all the subjects. CIPN20 score did not show any changes in the follow-up. Conclusions: Point-of-care assessment for NCS was feasible but measurements frequently failed especially on patients with pre-existing high-risk for neuropathy. OX-treated showed decreasing NCS results while other measures were unable to access the change. The system should be further validated with a larger patient cohort preferably treated with OX and low-risk for pre-existing neuropathy.

La neuropatia periferica indotta da chemioterapia (CIPN) rappresenta da tempo uno degli effetti collaterali neurologici più rilevanti delle terapie oncologiche. Tuttavia, nonostante i progressi dei regimi terapeutici oncologici, la comparsa di importanti eventi avversi influisce ancora sull’efficacia della terapia antineoplastica, portando alla riduzione o all’interruzione del trattamento. Il paclitaxel è un efficace agente antitumorale utilizzato nel trattamento di diversi tumori, sebbene il suo uso clinico sia spesso limitato dall’insorgenza della neuropatia periferica indotta da paclitaxel (PIPN). Si è ipotizzato che numerose alterazioni legate all’invecchiamento siano alla base della suscettibilità al danno nervoso in età avanzata. Tuttavia, i risultati di questi studi non sono conclusivi e altri potenziali biomarcatori di danno nervoso meritano di essere considerati. Su queste basi, lo scopo del nostro studio è stato quello di indagare gli effetti legati all'età del trattamento con paclitaxel sul sistema nervoso periferico e i cambiamenti metabolici che potrebbero essere indotti dalla somministrazione di paclitaxel a diverse età. Il nostro progetto comprendeva esperimenti di neurotossicità basati su valutazioni neurofisiologiche, comportamentali e istopatologiche per valutare le alterazioni fenotipiche indotte dalla chemioterapia in relazione all’età in un modello neuropatico di PIPN. Abbiamo inoltre analizzato, attraverso un approccio metabolomico mirato basato sulla cromatografia liquida ad alta prestazione e sulla spettrometria di massa (UPLC-MS), le differenze nei profili dei metaboliti plasmatici ed epatici, al fine di identificare potenziali biomarcatori di sviluppo e progressione della PIPN, in base all'età. Le nostre analisi hanno rivelato che l’età potrebbe essere un potenziale fattore di rischio per una CIPN più severa e dovrebbe essere presa in considerazione in studi futuri per adattare il regime terapeutico e il dosaggio del chemioterapico alla sus, Chemotherapy-induced peripheral neuropathy (CIPN) has long represented one of the most relevant neurological side effects of oncological therapies. Nevertheless, despite the progress in drug regimens, the occurrence of troublesome adverse events still affects the efficacy of antineoplastic therapy, leading to the reduction or discontinuation of the treatment. Paclitaxel is an anti-tubulin drug which has emerged as an efficacious antitumor agent in the treatment of different cancers. However, its clinical use is often limited by the onset of paclitaxel-induced peripheral neuropathy (PIPN). Numerous alterations related to aging have been hypothesized to underlie age-related susceptibility to nerve damage. Nevertheless, the results of these studies are inconclusive and other targets, which might be used as potential biomarkers of nerve impairment, deserve to be considered. On these bases, the aim of our study was to investigate the age-related effects of paclitaxel treatment on the peripheral nervous system, and the metabolic changes that might be induced by paclitaxel administration at different ages. Our project included neurotoxicity experiments based on neurophysiological, behavioral and histopathological evaluations to assess age-related chemotherapy-induced phenotypic alterations in a neuropathic model of PIPN. We additionally investigated through a targeted Ultra-Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS) based metabolomics approach differences in the plasma and liver metabolite profiles in order to identify potential biomarkers of PIPN development and progression, according to age. Our results suggest that age might be a potential risk factor for more severe CIPN, and should be considered in future studies in order to tailor the chemotherapy regimen and dosage on individual susceptibility of older cancer patients. Our study also identifies for the first time multiple related metabolic axes involved in paclitaxel-induced neurotoxicity, as prom

PURPOSE: Resting heart rate variability (HRV) is an important biomarker linking mental health to cardiovascular outcomes. However, resting HRV is also impaired in autonomic neuropathy, a common and underdiagnosed complication of common medical conditions which is detected by testing autonomic reflexes. We sought to describe the relationship between autonomic reflex abnormalities and resting HRV, taking into consideration medical comorbidities and demographic variables. METHODS: Participants (n = 209) underwent a standardized autonomic reflex screen which was summarized as the Composite Autonomic Severity Score (CASS) and included measures of reflexive HRV, e.g., heart rate with deep breathing (HRDB). Resting HRV measures were: pNN50 (percentage of NN intervals that differ by > 50 ms) and cvRMSSD (adjusted root mean square of successive differences). RESULTS: In univariate analyses, lower resting HRV was associated with: older age, higher CASS, neuropathy on examination, hypertension, diabetes, chronic obstructive pulmonary disease, chronic kidney disease, and psychiatric disease. Adaptive regression spline analysis revealed that HRDB explained 27% of the variability in resting HRV for participants with values of HRDB in the normal range. Outside this range, there was no linear relationship because: (1) when HRDB was low (indicating autonomic neuropathy), resting HRV was also low with low variance; and (2) when HRDB was high, the variance in resting HRV was high. In multivariate models, only HRDB was significantly independently associated with cvRMSSD and pNN50. CONCLUSION: Subclinical autonomic neuropathy, as evidenced by low HRDB and other autonomic reflexes, should be considered as a potential confounder of resting HRV in research involving medically and demographically diverse populations.

The impact of preoperative electrophysiology on outcome of surgical treatment in ulnar nerve entrapment at the elbow (UNE) is not clarified. Our aim was to evaluate influence of preoperative electrophysiologic grading on outcome and analyse how age, sex, and in particular diabetes affect such grading. Electrophysiologic protocols for 406 UNE cases, surgically treated at two hand surgery units reporting to the Swedish National Quality Register for Hand Surgery (HAKIR; 2010-2016), were retrospectively assessed, and graded as normal, reduced conduction velocity, conduction block or axonal degeneration. Outcome of surgery after primary and revision surgery was evaluated using QuickDASH and a doctor reported outcome measure (DROM) grading. No differences in QuickDASH or DROM were found between the four groups with different electrophysiologic grading preoperatively, or at three and 12 months or at follow up, respectively. When dichotomizing the electrophysiologic grading into normal and pathologic electrophysiology, cases with normal electrophysiology had worse QuickDASH than cases with pathologic electrophysiology preoperatively (p=0.046). Presence of a conduction block or axonal degeneration indicated a worse outcome by DROM grading (p=0.011). Primary surgeries had electrophysiologic more pronounced nerve pathology compared to revision surgeries (p=0.017). Cases of older age, men, and those with diabetes had more severe electrophysiologic nerve affection (p<0.0001). In the linear regression analysis, increasing age (unstandardized B=0.03, 95% CI 0.02-0.04; p<0.0001) and presence of diabetes (unstandardized B=0.60, 95% CI 0.25-0.95; p=0.001) were associated with a higher risk of a worse electrophysiologic classification. Female sex was associated with a better electrophysiologic grading (unstandardized B=-0.51, 95% CI -0.75- -0.27; p<0.0001). We conclude that older age, male sex, and concomitant diabetes are associated with more severe preoperative electrophysi, Funding agencies: Lund University, ALF[grant number 2018-Project 0104], Region Skåne (Funds from Skåne University Hospital Malmö-Lund), the Swedish Diabetes Foundation [grant number DIA2016-117 and DIA2020-492], the Swedish Research Council [grant number 2021-01942], Sydvästra Skånes Diabetesförening, Sweden, and ALF Grants [grant numberLIO-823361], Region Östergötland, Sweden

The impact of preoperative electrophysiology on outcome of surgical treatment in ulnar nerve entrapment at the elbow (UNE) is not clarified. Our aim was to evaluate influence of preoperative electrophysiologic grading on outcome and analyse how age, sex, and in particular diabetes affect such grading. Electrophysiologic protocols for 406 UNE cases, surgically treated at two hand surgery units reporting to the Swedish National Quality Register for Hand Surgery (HAKIR; 2010-2016), were retrospectively assessed, and graded as normal, reduced conduction velocity, conduction block or axonal degeneration. Outcome of surgery after primary and revision surgery was evaluated using QuickDASH and a doctor reported outcome measure (DROM) grading. No differences in QuickDASH or DROM were found between the four groups with different electrophysiologic grading preoperatively, or at three and 12 months or at follow up, respectively. When dichotomizing the electrophysiologic grading into normal and pathologic electrophysiology, cases with normal electrophysiology had worse QuickDASH than cases with pathologic electrophysiology preoperatively (p=0.046). Presence of a conduction block or axonal degeneration indicated a worse outcome by DROM grading (p=0.011). Primary surgeries had electrophysiologic more pronounced nerve pathology compared to revision surgeries (p=0.017). Cases of older age, men, and those with diabetes had more severe electrophysiologic nerve affection (p<0.0001). In the linear regression analysis, increasing age (unstandardized B=0.03, 95% CI 0.02-0.04; p<0.0001) and presence of diabetes (unstandardized B=0.60, 95% CI 0.25-0.95; p=0.001) were associated with a higher risk of a worse electrophysiologic classification. Female sex was associated with a better electrophysiologic grading (unstandardized B=-0.51, 95% CI -0.75- -0.27; p<0.0001). We conclude that older age, male sex, and concomitant diabetes are associated with more severe preoperative electrophysi, Funding agencies: Lund University, ALF[grant number 2018-Project 0104], Region Skåne (Funds from Skåne University Hospital Malmö-Lund), the Swedish Diabetes Foundation [grant number DIA2016-117 and DIA2020-492], the Swedish Research Council [grant number 2021-01942], Sydvästra Skånes Diabetesförening, Sweden, and ALF Grants [grant numberLIO-823361], Region Östergötland, Sweden

The impact of preoperative electrophysiology on outcome of surgical treatment in ulnar nerve entrapment at the elbow (UNE) is not clarified. Our aim was to evaluate influence of preoperative electrophysiologic grading on outcome and analyse how age, sex, and in particular diabetes affect such grading. Electrophysiologic protocols for 406 UNE cases, surgically treated at two hand surgery units reporting to the Swedish National Quality Register for Hand Surgery (HAKIR; 2010-2016), were retrospectively assessed, and graded as normal, reduced conduction velocity, conduction block or axonal degeneration. Outcome of surgery after primary and revision surgery was evaluated using QuickDASH and a doctor reported outcome measure (DROM) grading. No differences in QuickDASH or DROM were found between the four groups with different electrophysiologic grading preoperatively, or at three and 12 months or at follow up, respectively. When dichotomizing the electrophysiologic grading into normal and pathologic electrophysiology, cases with normal electrophysiology had worse QuickDASH than cases with pathologic electrophysiology preoperatively (p=0.046). Presence of a conduction block or axonal degeneration indicated a worse outcome by DROM grading (p=0.011). Primary surgeries had electrophysiologic more pronounced nerve pathology compared to revision surgeries (p=0.017). Cases of older age, men, and those with diabetes had more severe electrophysiologic nerve affection (p<0.0001). In the linear regression analysis, increasing age (unstandardized B=0.03, 95% CI 0.02-0.04; p<0.0001) and presence of diabetes (unstandardized B=0.60, 95% CI 0.25-0.95; p=0.001) were associated with a higher risk of a worse electrophysiologic classification. Female sex was associated with a better electrophysiologic grading (unstandardized B=-0.51, 95% CI -0.75- -0.27; p<0.0001). We conclude that older age, male sex, and concomitant diabetes are associated with more severe preoperative electrophysi, Funding agencies: Lund University, ALF[grant number 2018-Project 0104], Region Skåne (Funds from Skåne University Hospital Malmö-Lund), the Swedish Diabetes Foundation [grant number DIA2016-117 and DIA2020-492], the Swedish Research Council [grant number 2021-01942], Sydvästra Skånes Diabetesförening, Sweden, and ALF Grants [grant numberLIO-823361], Region Östergötland, Sweden

The impact of preoperative electrophysiology on outcome of surgical treatment in ulnar nerve entrapment at the elbow (UNE) is not clarified. Our aim was to evaluate influence of preoperative electrophysiologic grading on outcome and analyse how age, sex, and in particular diabetes affect such grading. Electrophysiologic protocols for 406 UNE cases, surgically treated at two hand surgery units reporting to the Swedish National Quality Register for Hand Surgery (HAKIR; 2010-2016), were retrospectively assessed, and graded as normal, reduced conduction velocity, conduction block or axonal degeneration. Outcome of surgery after primary and revision surgery was evaluated using QuickDASH and a doctor reported outcome measure (DROM) grading. No differences in QuickDASH or DROM were found between the four groups with different electrophysiologic grading preoperatively, or at three and 12 months or at follow up, respectively. When dichotomizing the electrophysiologic grading into normal and pathologic electrophysiology, cases with normal electrophysiology had worse QuickDASH than cases with pathologic electrophysiology preoperatively (p=0.046). Presence of a conduction block or axonal degeneration indicated a worse outcome by DROM grading (p=0.011). Primary surgeries had electrophysiologic more pronounced nerve pathology compared to revision surgeries (p=0.017). Cases of older age, men, and those with diabetes had more severe electrophysiologic nerve affection (p<0.0001). In the linear regression analysis, increasing age (unstandardized B=0.03, 95% CI 0.02-0.04; p<0.0001) and presence of diabetes (unstandardized B=0.60, 95% CI 0.25-0.95; p=0.001) were associated with a higher risk of a worse electrophysiologic classification. Female sex was associated with a better electrophysiologic grading (unstandardized B=-0.51, 95% CI -0.75- -0.27; p<0.0001). We conclude that older age, male sex, and concomitant diabetes are associated with more severe preoperative electrophysi, Funding agencies: Lund University, ALF[grant number 2018-Project 0104], Region Skåne (Funds from Skåne University Hospital Malmö-Lund), the Swedish Diabetes Foundation [grant number DIA2016-117 and DIA2020-492], the Swedish Research Council [grant number 2021-01942], Sydvästra Skånes Diabetesförening, Sweden, and ALF Grants [grant numberLIO-823361], Region Östergötland, Sweden

Parathyroid carcinoma (PC) is an extremely rare disease. Although it may occasionally occur in genetic syndromes, it is more often sporadic. It is usually associated with a consistent secretion of PTH, causing severe hypercalcemia and potentially all clinical conditions due to primary hyperparathyroidism. Management of PC can be challenging: some clinical, biochemical, and radiological features may be useful, but the final diagnosis of malignancy strictly relies on histological criteria. To date, radical surgery is the first-choice treatment and is the only effective therapy to control hypercalcemia and other clinical manifestations. On the other hand, chemo- or radiotherapy, local treatments, or novel drugs should be reserved for selected cases. We report an exceptionally unusual case of life-threatening PC, associated with several systemic manifestations: moderate pancreatitis, portal thrombosis, kidney stones, brown tumors, osteoporosis, hungry bone syndrome (HBS), chondrocalcinosis, neuropathy, and depression. The clinical case also represents an opportunity to provide a review of the recent literature, associated with a complete evaluation of the main diagnostic and therapeutic approaches.

The impact of preoperative electrophysiology on outcome of surgical treatment in ulnar nerve entrapment at the elbow (UNE) is not clarified. Our aim was to evaluate influence of preoperative electrophysiologic grading on outcome and analyse how age, sex, and in particular diabetes affect such grading. Electrophysiologic protocols for 406 UNE cases, surgically treated at two hand surgery units reporting to the Swedish National Quality Register for Hand Surgery (HAKIR; 2010-2016), were retrospectively assessed, and graded as normal, reduced conduction velocity, conduction block or axonal degeneration. Outcome of surgery after primary and revision surgery was evaluated using QuickDASH and a doctor reported outcome measure (DROM) grading. No differences in QuickDASH or DROM were found between the four groups with different electrophysiologic grading preoperatively, or at three and 12 months or at follow up, respectively. When dichotomizing the electrophysiologic grading into normal and pathologic electrophysiology, cases with normal electrophysiology had worse QuickDASH than cases with pathologic electrophysiology preoperatively (p=0.046). Presence of a conduction block or axonal degeneration indicated a worse outcome by DROM grading (p=0.011). Primary surgeries had electrophysiologic more pronounced nerve pathology compared to revision surgeries (p=0.017). Cases of older age, men, and those with diabetes had more severe electrophysiologic nerve affection (p<0.0001). In the linear regression analysis, increasing age (unstandardized B=0.03, 95% CI 0.02-0.04; p<0.0001) and presence of diabetes (unstandardized B=0.60, 95% CI 0.25-0.95; p=0.001) were associated with a higher risk of a worse electrophysiologic classification. Female sex was associated with a better electrophysiologic grading (unstandardized B=-0.51, 95% CI -0.75- -0.27; p<0.0001). We conclude that older age, male sex, and concomitant diabetes are associated with more severe preoperative electrophysi, Funding agencies: Lund University, ALF[grant number 2018-Project 0104], Region Skåne (Funds from Skåne University Hospital Malmö-Lund), the Swedish Diabetes Foundation [grant number DIA2016-117 and DIA2020-492], the Swedish Research Council [grant number 2021-01942], Sydvästra Skånes Diabetesförening, Sweden, and ALF Grants [grant numberLIO-823361], Region Östergötland, Sweden

Among the features of cisplatin chemotherapy-induced peripheral neuropathy are chronic pain and innocuous mechanical hypersensitivity. The complete etiology of the latter remains unknown. Here, we show that cisplatin targets a heterogeneous population of tyrosine hydroxylase-positive (TH+) primary afferent dorsal root ganglion neurons (DRGNs) in mice, determined using single-cell transcriptome and electrophysiological analyses. TH+ DRGNs regulate innocuous mechanical sensation through C-low threshold mechanoreceptors. A differential assessment of wild-type and vitamin E deficient TH+ DRGNs revealed heterogeneity and specific functional phenotypes. The TH+ DRGNs comprise; fast-adapting eliciting one action potential (AP; 1-AP), moderately-adapting (≥2-APs), in responses to square-pulse current injection, and spontaneously active (SA). Cisplatin increased the input resistance and AP frequency but reduced the temporal coding feature of 1-AP and ≥2-APs neurons. By contrast, cisplatin has no measurable effect on the SA neurons. Vitamin E reduced the cisplatin-mediated increased excitability but did not improve the TH+ neuron temporal coding properties. Cisplatin mediates its effect by targeting outward K+ current, likely carried through K2P18.1 (Kcnk18), discovered through the differential transcriptome studies and heterologous expression. Studies show a potential new cellular target for chemotherapy-induced peripheral neuropathy and implicate the possible neuroprotective effects of vitamin E in cisplatin chemotherapy.

Background: Autonomic dysfunction is common in transthyretin amyloidosis (ATTR amyloidosis), but its frequency, characteristics, and quality-of-life (QoL) impact are not well understood. Methods: The Transthyretin Amyloidosis Outcomes Survey (THAOS) is an ongoing, global, longitudinal survey of patients with ATTR amyloidosis, including patients with inherited (ATTRv) and wild-type (ATTRwt) disease and asymptomatic patients with TTR mutations (ClinicalTrials.gov: NCT00628745). In a descriptive analysis, characteristics and Norfolk QoL-DN total (TQoL) scores at enrolment were compared in patients with vs without autonomic dysfunction (analysis cut-off: 1 August 2020). Results: Autonomic dysfunction occurred in 1181/2922 (40.4%) symptomatic patients, and more commonly in ATTRv (1107/1181 [93.7%]) than ATTRwt (74/1181 [6.3%]) amyloidosis. Time (mean [SD]) from ATTR amyloidosis symptom onset to first autonomic dysfunction symptom was shorter in ATTRv (3.4 [5.7] years) than ATTRwt disease (9.7 [10.4]). In ATTRv disease, patients with vs without autonomic dysfunction had worse QoL (TQoL, 47.3 [33.2] vs 16.1 [18.1]); in ATTRwt disease, those with vs without autonomic dysfunction had similar QoL (23.0 [18.2] vs 19.9 [20.5]). Conclusions: Autonomic dysfunction was more common and presented earlier in symptomatic ATTRv than ATTRwt amyloidosis and adversely affected QoL in ATTRv disease. These THAOS findings may aid clinicians in diagnosing and treating patients with ATTR amyloidosis. Trial registration: ClinicalTrials.gov: NCT00628745.

Background: Autonomic dysfunction is common in transthyretin amyloidosis (ATTR amyloidosis), but its frequency, characteristics, and quality-of-life (QoL) impact are not well understood. Methods: The Transthyretin Amyloidosis Outcomes Survey (THAOS) is an ongoing, global, longitudinal survey of patients with ATTR amyloidosis, including patients with inherited (ATTRv) and wild-type (ATTRwt) disease and asymptomatic patients with TTR mutations (ClinicalTrials.gov: NCT00628745). In a descriptive analysis, characteristics and Norfolk QoL-DN total (TQoL) scores at enrolment were compared in patients with vs without autonomic dysfunction (analysis cut-off: 1 August 2020). Results: Autonomic dysfunction occurred in 1181/2922 (40.4%) symptomatic patients, and more commonly in ATTRv (1107/1181 [93.7%]) than ATTRwt (74/1181 [6.3%]) amyloidosis. Time (mean [SD]) from ATTR amyloidosis symptom onset to first autonomic dysfunction symptom was shorter in ATTRv (3.4 [5.7] years) than ATTRwt disease (9.7 [10.4]). In ATTRv disease, patients with vs without autonomic dysfunction had worse QoL (TQoL, 47.3 [33.2] vs 16.1 [18.1]); in ATTRwt disease, those with vs without autonomic dysfunction had similar QoL (23.0 [18.2] vs 19.9 [20.5]). Conclusions: Autonomic dysfunction was more common and presented earlier in symptomatic ATTRv than ATTRwt amyloidosis and adversely affected QoL in ATTRv disease. These THAOS findings may aid clinicians in diagnosing and treating patients with ATTR amyloidosis. Trial registration: ClinicalTrials.gov: NCT00628745.

Background: Autonomic dysfunction is common in transthyretin amyloidosis (ATTR amyloidosis), but its frequency, characteristics, and quality-of-life (QoL) impact are not well understood. Methods: The Transthyretin Amyloidosis Outcomes Survey (THAOS) is an ongoing, global, longitudinal survey of patients with ATTR amyloidosis, including patients with inherited (ATTRv) and wild-type (ATTRwt) disease and asymptomatic patients with TTR mutations (ClinicalTrials.gov: NCT00628745). In a descriptive analysis, characteristics and Norfolk QoL-DN total (TQoL) scores at enrolment were compared in patients with vs without autonomic dysfunction (analysis cut-off: 1 August 2020). Results: Autonomic dysfunction occurred in 1181/2922 (40.4%) symptomatic patients, and more commonly in ATTRv (1107/1181 [93.7%]) than ATTRwt (74/1181 [6.3%]) amyloidosis. Time (mean [SD]) from ATTR amyloidosis symptom onset to first autonomic dysfunction symptom was shorter in ATTRv (3.4 [5.7] years) than ATTRwt disease (9.7 [10.4]). In ATTRv disease, patients with vs without autonomic dysfunction had worse QoL (TQoL, 47.3 [33.2] vs 16.1 [18.1]); in ATTRwt disease, those with vs without autonomic dysfunction had similar QoL (23.0 [18.2] vs 19.9 [20.5]). Conclusions: Autonomic dysfunction was more common and presented earlier in symptomatic ATTRv than ATTRwt amyloidosis and adversely affected QoL in ATTRv disease. These THAOS findings may aid clinicians in diagnosing and treating patients with ATTR amyloidosis. Trial registration: ClinicalTrials.gov: NCT00628745.

Introduction/Aims: A prevailing concept of motor unit (MU) recruitment used for calculating recruitment ratio (RR) suggests a progressive linear increase in firing rate (FR). The objective of this study is to assess its validity. Methods: Concentric needle electromyography (EMG) recordings were made in normal muscle and abnormal muscle of patients with neurogenic findings. Signals recorded at low force were visually decomposed to study MU FR at onset, recruitment of a second MU, and recruitment of more MUs with further increases in force. Results: We observed one to six MUs discharging at a rate < 15 Hz in normal muscles at low force. The MU FR was 5-8 Hz at onset. With increasing force, FR increased by 3-5 Hz and then idled at <15 Hz while other MUs were recruited. The recruitment frequency (RF) and RR had low sensitivity and were abnormal mainly in moderately to severely weak muscles. Discussion: Our data are consistent with FR analysis results described by other investigators. It does not support a progressive linear increase in MU FR with recruitment. A revised model for MU recruitment at low effort during gradual increase in force is presented. On subjective assessment, the FR of the fastest firing MU can help detect MU loss in neurogenic processes.

Prevalence of type 2 diabetes increased from 2.5% of the US population in 1990 to 10.5% in 2018. This creates a major public health problem, due to increases in long-term complications of diabetes, including neuropathy, retinopathy, nephropathy, skin ulcers, amputations, and atherosclerotic cardiovascular disease. In this review, we evaluated the scientific basis that supports the use of physiologic insulin resensitization. Insulin resistance is the primary cause of type 2 diabetes. Insulin resistance leads to increasing insulin secretion, leading to beta-cell exhaustion or burnout. This triggers a cascade leading to islet cell destruction and the long-term complications of type 2 diabetes. Concurrent with insulin resistance, the regular bursts of insulin from the pancreas become irregular. This has been treated by the precise administration of insulin more physiologically. There is consistent evidence that this treatment modality can reverse the diabetes-associated complications of neuropathy, diabetic ulcers, nephropathy, and retinopathy, and that it lowers HbA1c. In conclusion, physiologic insulin resensitization has a persuasive scientific basis, significant treatment potential, and likely cost benefits.

This review highlights ten important advances in the neuromuscular disease field that either were first reported in 2019, or have reached a broad consensus during that year. The overarching topics include (i) new / emerging diseases; (ii) advances in understanding of disease etiology and pathogenesis; (iii) diagnostic advances; and (iv) therapeutic advances. Within this broad framework, the individual disease entities that are discussed in more detail include myoglobinopathy, POPDC3-mutated limb-girdle muscular dystrophy, neuromuscular adverse events associated with the immune checkpoint inhibition therapy, neuroglial stem cell-derived inflammatory pseudotumor of the spinal cord and spinal cord roots, acute flaccid myelitis, congenital myopathies, idiopathic inflammatory myopathies (with particular emphasis on immune-mediated necrotizing myopathies and sporadic inclusion body myositis), spinal muscular atrophy, and Duchenne muscular dystrophy. In addition, the review highlights several diagnostic advances (such as diagnostic RNA sequencing and development of digital diagnostic tools) that will likely have a significant impact on the overall neuromuscular disease field going forward.

Non-pharmacological self-management interventions for chemotherapy-induced peripheral neurotherapy (CIPN) are of clinical interest; however, no systematic review has synthesized the evidence for their use in people with advanced cancer. Five databases were searched from inception to February 2022 for randomized controlled trials assessing the effect of non-pharmacological self-management interventions in people with advanced cancer on the incidence and severity of CIPN symptoms and related outcomes compared to any control condition. Data were pooled with metaanalysis. Quality of evidence was appraised using the Revised Cochrane Risk of Bias Tool for Randomized Trials (RoB2), with data synthesized narratively. Grading of Recommendations, Assessment, Development and Evaluations (GRADE) was applied to assess the certainty of the evidence. Thirteen studies were included, which had a high (69 %) or unclear (31 %) risk of bias. Greatest confidence was found for physical exercise decreasing CIPN severity (SMD: −0.89, 95 % CI: −1.37 to −0.41; p = 0.0003; I2 = 0 %; n = 2 studies, n = 76 participants; GRADE level: moderate) and increasing physical function (SMD: 0.51, 95 % CI: 0.02 to 1.00; p = 0.04; I2 = 42 %; n = 3 studies, n = 120; GRADE level: moderate). One study per intervention provided preliminary evidence for the positive effects of glutamine supplementation, an Omega-3 PUFA-enriched drink, and education for symptom self-management via a mobile phone game on CIPN symptoms and related outcomes (GRADE: very low). No serious adverse events were reported. The strongest evidence with the most certainty was found for physical exercise as a safe and viable adjuvant to chemotherapy treatment for the prevention and management of CIPN and related physical function in people with advanced cancer. However, the confidence in the evidence to inform conclusions was mostly very low to moderate. Future well-powered and appropriately designed interventions for clinical trials using va

Distal symmetrical polyneuropathy (DSPN) is the most common complication in diabetes but little is known about how diabetes affects the nerves that supply the hands or why some people with DSPN develop neuropathic pain. This thesis assessed the structure, function, and mechanical properties of peripheral nerves using non-invasive methods in healthy individuals (n=31), people with diabetes without DSPN (n=35), with DSPN in feet only (n=31), and with DSPN in hands and feet (n=28). Quantitative sensory tests showed that people with DSPN presented with severe loss of nerve function in their hands, even if DSPN symptoms were only present in the feet. Diffusion MRI analyses showed microstructural changes in the nerves supplying the hands in people with DSPN in hands, in people with DSPN in feet, and in people with diabetes without DSPN. Shear-wave elastography revealed increased nerve stiffness. Regarding neuropathic pain in DSPN, our systematic review and meta-analysis showed a reduction in painful detection thresholds in people with non-painful and painful DSPN. Corneal confocal microscopy showed progressive nerve fibre loss across groups. The proportion of people with abnormal corneal epithelial microneuromas and their prevalence increased in people with painful DSPN compared to all other groups, including non-painful DSPN. Our findings suggest a potential progression of structural, functional, and mechanical changes in peripheral nerves supplying the hands as diabetes and DSPN progress.

Hand-arm vibration (HAV) is a common occupational exposure in Sweden and worldwide that causes both acute transient effects and persistent hand-arm symptoms. The health effects include vibration-induced Raynaud’s phenomenon, neuropathic symptoms, carpal tunnel syndrome (CTS), and musculoskeletal disorders. The overall aim of this thesis was to investigate vascular and neurological effects in the hands of workers exposed to hand-arm vibrations. Methods: In study 1, the aim was to investigate the risk of CTS from hand-arm vibration. This study was conducted as a register study using the National Outpatient Register and a job exposure matrix to estimate HAV exposure. Study 2 aimed to investigate the acute effects of HAV on the nerve functions of the hands and the impact of grip force. Nerve function was evaluated before and after vibration exposure. In study 3, the aim was to identify low molecular organic biomarkers in blood samples from vibration-exposed workers using a novel metabolomics approach. HAV-exposed workers underwent medical examination and blood samples were collected and analysed before and after a work shift. In study 4, the aim was to investigate if arterial abnormalities in the hands could be identified in patients with VWF which also had a positive Allen’s test. In this case series, Doppler ultrasound and magnetic resonance angiography (MRA) investigations were performed to investigate the arterial status in the hands. Results: Study 1 showed that the risk of CTS for HAV exposed individuals increased with an OR of 1.61 (95% CI 1.46-1.77) for the whole population. The risk was highest in HAV exposed younger males. Study 2 showed that HAV exposure with high grip force affect nerve function different than with low grip force. In study 3, workers with VWF had metabolic profiles different from participants without VWF, both before and after vibration exposure. In study 4, ultrasound and MRA identified vascular abnormalities in all participants; these abn

Non-pharmacological self-management interventions for chemotherapy-induced peripheral neurotherapy (CIPN) are of clinical interest; however, no systematic review has synthesized the evidence for their use in people with advanced cancer. Five databases were searched from inception to February 2022 for randomized controlled trials assessing the effect of non-pharmacological self-management interventions in people with advanced cancer on the incidence and severity of CIPN symptoms and related outcomes compared to any control condition. Data were pooled with metaanalysis. Quality of evidence was appraised using the Revised Cochrane Risk of Bias Tool for Randomized Trials (RoB2), with data synthesized narratively. Grading of Recommendations, Assessment, Development and Evaluations (GRADE) was applied to assess the certainty of the evidence. Thirteen studies were included, which had a high (69 %) or unclear (31 %) risk of bias. Greatest confidence was found for physical exercise decreasing CIPN severity (SMD: −0.89, 95 % CI: −1.37 to −0.41; p = 0.0003; I2 = 0 %; n = 2 studies, n = 76 participants; GRADE level: moderate) and increasing physical function (SMD: 0.51, 95 % CI: 0.02 to 1.00; p = 0.04; I2 = 42 %; n = 3 studies, n = 120; GRADE level: moderate). One study per intervention provided preliminary evidence for the positive effects of glutamine supplementation, an Omega-3 PUFA-enriched drink, and education for symptom self-management via a mobile phone game on CIPN symptoms and related outcomes (GRADE: very low). No serious adverse events were reported. The strongest evidence with the most certainty was found for physical exercise as a safe and viable adjuvant to chemotherapy treatment for the prevention and management of CIPN and related physical function in people with advanced cancer. However, the confidence in the evidence to inform conclusions was mostly very low to moderate. Future well-powered and appropriately designed interventions for clinical trials using va

Distal symmetrical polyneuropathy (DSPN) is the most common complication in diabetes but little is known about how diabetes affects the nerves that supply the hands or why some people with DSPN develop neuropathic pain. This thesis assessed the structure, function, and mechanical properties of peripheral nerves using non-invasive methods in healthy individuals (n=31), people with diabetes without DSPN (n=35), with DSPN in feet only (n=31), and with DSPN in hands and feet (n=28). Quantitative sensory tests showed that people with DSPN presented with severe loss of nerve function in their hands, even if DSPN symptoms were only present in the feet. Diffusion MRI analyses showed microstructural changes in the nerves supplying the hands in people with DSPN in hands, in people with DSPN in feet, and in people with diabetes without DSPN. Shear-wave elastography revealed increased nerve stiffness. Regarding neuropathic pain in DSPN, our systematic review and meta-analysis showed a reduction in painful detection thresholds in people with non-painful and painful DSPN. Corneal confocal microscopy showed progressive nerve fibre loss across groups. The proportion of people with abnormal corneal epithelial microneuromas and their prevalence increased in people with painful DSPN compared to all other groups, including non-painful DSPN. Our findings suggest a potential progression of structural, functional, and mechanical changes in peripheral nerves supplying the hands as diabetes and DSPN progress.

Background: Autonomic dysfunction is common in transthyretin amyloidosis (ATTR amyloidosis), but its frequency, characteristics, and quality-of-life (QoL) impact are not well understood. Methods: The Transthyretin Amyloidosis Outcomes Survey (THAOS) is an ongoing, global, longitudinal survey of patients with ATTR amyloidosis, including patients with inherited (ATTRv) and wild-type (ATTRwt) disease and asymptomatic patients with TTR mutations (ClinicalTrials.gov: NCT00628745). In a descriptive analysis, characteristics and Norfolk QoL-DN total (TQoL) scores at enrolment were compared in patients with vs without autonomic dysfunction (analysis cut-off: 1 August 2020). Results: Autonomic dysfunction occurred in 1181/2922 (40.4%) symptomatic patients, and more commonly in ATTRv (1107/1181 [93.7%]) than ATTRwt (74/1181 [6.3%]) amyloidosis. Time (mean [SD]) from ATTR amyloidosis symptom onset to first autonomic dysfunction symptom was shorter in ATTRv (3.4 [5.7] years) than ATTRwt disease (9.7 [10.4]). In ATTRv disease, patients with vs without autonomic dysfunction had worse QoL (TQoL, 47.3 [33.2] vs 16.1 [18.1]); in ATTRwt disease, those with vs without autonomic dysfunction had similar QoL (23.0 [18.2] vs 19.9 [20.5]). Conclusions: Autonomic dysfunction was more common and presented earlier in symptomatic ATTRv than ATTRwt amyloidosis and adversely affected QoL in ATTRv disease. These THAOS findings may aid clinicians in diagnosing and treating patients with ATTR amyloidosis. Trial registration: ClinicalTrials.gov: NCT00628745.

For magnetic resonance imaging (MRI) of non-traumatic brachial plexus (BP) lesions, sequences with contrast injection should be considered in the differentiation between tumors, infection, postoperative conditions, and post-radiation changes. The most common non-traumatic inflammatory BP neuropathy is radiation neuropathy. T2-weighted images may help to distinguish neoplastic infiltration showing a high signal from radiation-induced neuropathy with fibrosis presenting a low signal. MRI findings in inflammatory BP neuropathy are usually absent or discrete. Diffuse edema of the BP localized mainly in the supraclavicular part of BP, with side-to-side differences, and shoulder muscle denervation may be found on MRI. BP infection is caused by direct infiltration from septic arthritis of the shoulder joint, spondylodiscitis, or lung empyema. MRI may help to narrow down the list of differential diagnoses of tumors. The most common tumor of BP is metastasis. The most common primary tumor of BP is neurofibroma, which is visible as fusiform thickening of a nerve. In its solitary state, it may be challenging to differentiate from a schwannoma. The most common MRI finding is a neurogenic variant of thoracic outlet syndrome with an asymmetry of signal and thickness of the BP with edema. In abduction, a loss of fat directly related to the BP may be seen. Diffusion tensor imaging is a promising novel MRI sequences; however, the small diameter of the nerves contributing to the BP and susceptibility to artifacts may be challenging in obtaining sufficiently high-quality images.

For magnetic resonance imaging (MRI) of non-traumatic brachial plexus (BP) lesions, sequences with contrast injection should be considered in the differentiation between tumors, infection, postoperative conditions, and post-radiation changes. The most common non-traumatic inflammatory BP neuropathy is radiation neuropathy. T2-weighted images may help to distinguish neoplastic infiltration showing a high signal from radiation-induced neuropathy with fibrosis presenting a low signal. MRI findings in inflammatory BP neuropathy are usually absent or discrete. Diffuse edema of the BP localized mainly in the supraclavicular part of BP, with side-to-side differences, and shoulder muscle denervation may be found on MRI. BP infection is caused by direct infiltration from septic arthritis of the shoulder joint, spondylodiscitis, or lung empyema. MRI may help to narrow down the list of differential diagnoses of tumors. The most common tumor of BP is metastasis. The most common primary tumor of BP is neurofibroma, which is visible as fusiform thickening of a nerve. In its solitary state, it may be challenging to differentiate from a schwannoma. The most common MRI finding is a neurogenic variant of thoracic outlet syndrome with an asymmetry of signal and thickness of the BP with edema. In abduction, a loss of fat directly related to the BP may be seen. Diffusion tensor imaging is a promising novel MRI sequences; however, the small diameter of the nerves contributing to the BP and susceptibility to artifacts may be challenging in obtaining sufficiently high-quality images.

For magnetic resonance imaging (MRI) of non-traumatic brachial plexus (BP) lesions, sequences with contrast injection should be considered in the differentiation between tumors, infection, postoperative conditions, and post-radiation changes. The most common non-traumatic inflammatory BP neuropathy is radiation neuropathy. T2-weighted images may help to distinguish neoplastic infiltration showing a high signal from radiation-induced neuropathy with fibrosis presenting a low signal. MRI findings in inflammatory BP neuropathy are usually absent or discrete. Diffuse edema of the BP localized mainly in the supraclavicular part of BP, with side-to-side differences, and shoulder muscle denervation may be found on MRI. BP infection is caused by direct infiltration from septic arthritis of the shoulder joint, spondylodiscitis, or lung empyema. MRI may help to narrow down the list of differential diagnoses of tumors. The most common tumor of BP is metastasis. The most common primary tumor of BP is neurofibroma, which is visible as fusiform thickening of a nerve. In its solitary state, it may be challenging to differentiate from a schwannoma. The most common MRI finding is a neurogenic variant of thoracic outlet syndrome with an asymmetry of signal and thickness of the BP with edema. In abduction, a loss of fat directly related to the BP may be seen. Diffusion tensor imaging is a promising novel MRI sequences; however, the small diameter of the nerves contributing to the BP and susceptibility to artifacts may be challenging in obtaining sufficiently high-quality images.

Hand-arm vibration (HAV) is a common occupational exposure in Sweden and worldwide that causes both acute transient effects and persistent hand-arm symptoms. The health effects include vibration-induced Raynaud’s phenomenon, neuropathic symptoms, carpal tunnel syndrome (CTS), and musculoskeletal disorders. The overall aim of this thesis was to investigate vascular and neurological effects in the hands of workers exposed to hand-arm vibrations. Methods: In study 1, the aim was to investigate the risk of CTS from hand-arm vibration. This study was conducted as a register study using the National Outpatient Register and a job exposure matrix to estimate HAV exposure. Study 2 aimed to investigate the acute effects of HAV on the nerve functions of the hands and the impact of grip force. Nerve function was evaluated before and after vibration exposure. In study 3, the aim was to identify low molecular organic biomarkers in blood samples from vibration-exposed workers using a novel metabolomics approach. HAV-exposed workers underwent medical examination and blood samples were collected and analysed before and after a work shift. In study 4, the aim was to investigate if arterial abnormalities in the hands could be identified in patients with VWF which also had a positive Allen’s test. In this case series, Doppler ultrasound and magnetic resonance angiography (MRA) investigations were performed to investigate the arterial status in the hands. Results: Study 1 showed that the risk of CTS for HAV exposed individuals increased with an OR of 1.61 (95% CI 1.46-1.77) for the whole population. The risk was highest in HAV exposed younger males. Study 2 showed that HAV exposure with high grip force affect nerve function different than with low grip force. In study 3, workers with VWF had metabolic profiles different from participants without VWF, both before and after vibration exposure. In study 4, ultrasound and MRA identified vascular abnormalities in all participants; these abn

Background: Autonomic dysfunction is common in transthyretin amyloidosis (ATTR amyloidosis), but its frequency, characteristics, and quality-of-life (QoL) impact are not well understood. Methods: The Transthyretin Amyloidosis Outcomes Survey (THAOS) is an ongoing, global, longitudinal survey of patients with ATTR amyloidosis, including patients with inherited (ATTRv) and wild-type (ATTRwt) disease and asymptomatic patients with TTR mutations (ClinicalTrials.gov: NCT00628745). In a descriptive analysis, characteristics and Norfolk QoL-DN total (TQoL) scores at enrolment were compared in patients with vs without autonomic dysfunction (analysis cut-off: 1 August 2020). Results: Autonomic dysfunction occurred in 1181/2922 (40.4%) symptomatic patients, and more commonly in ATTRv (1107/1181 [93.7%]) than ATTRwt (74/1181 [6.3%]) amyloidosis. Time (mean [SD]) from ATTR amyloidosis symptom onset to first autonomic dysfunction symptom was shorter in ATTRv (3.4 [5.7] years) than ATTRwt disease (9.7 [10.4]). In ATTRv disease, patients with vs without autonomic dysfunction had worse QoL (TQoL, 47.3 [33.2] vs 16.1 [18.1]); in ATTRwt disease, those with vs without autonomic dysfunction had similar QoL (23.0 [18.2] vs 19.9 [20.5]). Conclusions: Autonomic dysfunction was more common and presented earlier in symptomatic ATTRv than ATTRwt amyloidosis and adversely affected QoL in ATTRv disease. These THAOS findings may aid clinicians in diagnosing and treating patients with ATTR amyloidosis. Trial registration: ClinicalTrials.gov: NCT00628745.

Prevalence of type 2 diabetes increased from 2.5% of the US population in 1990 to 10.5% in 2018. This creates a major public health problem, due to increases in long-term complications of diabetes, including neuropathy, retinopathy, nephropathy, skin ulcers, amputations, and atherosclerotic cardiovascular disease. In this review, we evaluated the scientific basis that supports the use of physiologic insulin resensitization. Insulin resistance is the primary cause of type 2 diabetes. Insulin resistance leads to increasing insulin secretion, leading to beta-cell exhaustion or burnout. This triggers a cascade leading to islet cell destruction and the long-term complications of type 2 diabetes. Concurrent with insulin resistance, the regular bursts of insulin from the pancreas become irregular. This has been treated by the precise administration of insulin more physiologically. There is consistent evidence that this treatment modality can reverse the diabetes-associated complications of neuropathy, diabetic ulcers, nephropathy, and retinopathy, and that it lowers HbA1c. In conclusion, physiologic insulin resensitization has a persuasive scientific basis, significant treatment potential, and likely cost benefits.

For magnetic resonance imaging (MRI) of non-traumatic brachial plexus (BP) lesions, sequences with contrast injection should be considered in the differentiation between tumors, infection, postoperative conditions, and post-radiation changes. The most common non-traumatic inflammatory BP neuropathy is radiation neuropathy. T2-weighted images may help to distinguish neoplastic infiltration showing a high signal from radiation-induced neuropathy with fibrosis presenting a low signal. MRI findings in inflammatory BP neuropathy are usually absent or discrete. Diffuse edema of the BP localized mainly in the supraclavicular part of BP, with side-to-side differences, and shoulder muscle denervation may be found on MRI. BP infection is caused by direct infiltration from septic arthritis of the shoulder joint, spondylodiscitis, or lung empyema. MRI may help to narrow down the list of differential diagnoses of tumors. The most common tumor of BP is metastasis. The most common primary tumor of BP is neurofibroma, which is visible as fusiform thickening of a nerve. In its solitary state, it may be challenging to differentiate from a schwannoma. The most common MRI finding is a neurogenic variant of thoracic outlet syndrome with an asymmetry of signal and thickness of the BP with edema. In abduction, a loss of fat directly related to the BP may be seen. Diffusion tensor imaging is a promising novel MRI sequences; however, the small diameter of the nerves contributing to the BP and susceptibility to artifacts may be challenging in obtaining sufficiently high-quality images.

For magnetic resonance imaging (MRI) of non-traumatic brachial plexus (BP) lesions, sequences with contrast injection should be considered in the differentiation between tumors, infection, postoperative conditions, and post-radiation changes. The most common non-traumatic inflammatory BP neuropathy is radiation neuropathy. T2-weighted images may help to distinguish neoplastic infiltration showing a high signal from radiation-induced neuropathy with fibrosis presenting a low signal. MRI findings in inflammatory BP neuropathy are usually absent or discrete. Diffuse edema of the BP localized mainly in the supraclavicular part of BP, with side-to-side differences, and shoulder muscle denervation may be found on MRI. BP infection is caused by direct infiltration from septic arthritis of the shoulder joint, spondylodiscitis, or lung empyema. MRI may help to narrow down the list of differential diagnoses of tumors. The most common tumor of BP is metastasis. The most common primary tumor of BP is neurofibroma, which is visible as fusiform thickening of a nerve. In its solitary state, it may be challenging to differentiate from a schwannoma. The most common MRI finding is a neurogenic variant of thoracic outlet syndrome with an asymmetry of signal and thickness of the BP with edema. In abduction, a loss of fat directly related to the BP may be seen. Diffusion tensor imaging is a promising novel MRI sequences; however, the small diameter of the nerves contributing to the BP and susceptibility to artifacts may be challenging in obtaining sufficiently high-quality images.

BackgroundPrior comparisons of chemotherapy adverse events (AEs) by age and performance status (PS) are limited by the traditional maximum grade approach, which ignores low-grade AEs and longitudinal changes.Materials and methodsTo compare fatigue and neuropathy longitudinally by age (<65, ≥65 years) and PS (0-1, 2), we analyzed data from a large phase III trial of carboplatin and paclitaxel versus paclitaxel for advanced non-small cell lung cancer (CALGB 9730, n = 529). We performed multivariable (a) linear mixed models to estimate mean AE grade over time, (b) linear regression to estimate area under the curve (AUC), and (c) proportional hazards models to estimate the hazard ratio of developing grade ≥2 AE, as well as traditional maximum grade analyses.ResultsOlder patients had on average a 0.17-point (95% confidence interval [CI], 0.00-0.34; p = .049) higher mean fatigue grade longitudinally compared with younger patients. PS 2 was associated with earlier development of grade ≥2 fatigue (hazard ratio [HR], 1.56; 95% CI, 1.07-2.27; p = .02). For neuropathy, older age was associated with earlier development of grade ≥2 neuropathy (HR, 1.41; 95% CI, 1.00-1.97; p = .049). Patients with PS 2 had a 1.30 point lower neuropathy AUC (95% CI, -2.36 to -0.25; p = .02) compared with PS 0-1. In contrast, maximum grade analyses only detected a higher percentage of older adults with grade ≥3 fatigue and neuropathy at some point during treatment.ConclusionOur comparison of complementary but distinct aspects of chemotherapy toxicity identified important longitudinal differences in fatigue and neuropathy by age and PS that are missed by the traditional maximum grade approach. Clinical trial identification number: NCT00003117 (CALGB 9730) IMPLICATIONS FOR PRACTICE: The traditional maximum grade approach ignores persistent low-grade adverse events (AEs) and changes over time. This toxicity over time analysis of fatigue and neuropathy during chemotherapy for advanced non-small cell

ObjectiveDistal sensory polyneuropathy (DSP) is a disabling consequence of human immunodeficiency virus (HIV), leading to poor quality of life and more frequent falls in older age. Neuropathic pain and paresthesia are prevalent symptoms; however, there are currently no known curative treatments and the longitudinal course of pain in HIV-associated DSP is poorly characterized.MethodsThis was a prospective longitudinal study of 265 people with HIV (PWH) enrolled in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study with baseline and 12-year follow-up evaluations. Since pain and paresthesia are highly correlated, statistical decomposition was used to separate the two symptoms at baseline. Multivariable logistic regression analyses of decomposed variables were used to determine the effects of neuropathy symptoms at baseline on presence and worsening of distal neuropathic pain at 12-year follow-up, adjusted for covariates.ResultsMean age was 56 ± 8 years, and 21% were female at follow-up. Nearly the entire cohort (96%) was on antiretroviral therapy (ART), and 82% had suppressed (≤50 copies/mL) plasma viral loads at follow-up. Of those with pain at follow-up (n = 100), 23% had paresthesia at the initial visit. Decomposed paresthesia at baseline increased the risk of pain at follow-up (odds ratio [OR] 1.56; 95% confidence interval [CI] 1.18, 2.07), and decomposed pain at baseline predicted a higher frequency of pain at follow-up (OR 1.96 [95% CI 1.51, 2.58]).ConclusionsParesthesias are a clinically significant predictor of incident pain at follow-up among aging PWH with DSP. Development of new therapies to encourage neuroregeneration might take advantage of this finding to choose individuals likely to benefit from treatment preventing incident pain.

Destabilizing mutations in small heat shock proteins (sHsps) are linked to multiple diseases; however, sHsps are conformationally dynamic, lack enzymatic function and have no endogenous chemical ligands. These factors render sHsps as classically "undruggable" targets and make it particularly challenging to identify molecules that might bind and stabilize them. To explore potential solutions, we designed a multi-pronged screening workflow involving a combination of computational and biophysical ligand-discovery platforms. Using the core domain of the sHsp family member Hsp27/HSPB1 (Hsp27c) as a target, we applied mixed solvent molecular dynamics (MixMD) to predict three possible binding sites, which we confirmed using NMR-based solvent mapping. Using this knowledge, we then used NMR spectroscopy to carry out a fragment-based drug discovery (FBDD) screen, ultimately identifying two fragments that bind to one of these sites. A medicinal chemistry effort improved the affinity of one fragment by ~50-fold (16 µM), while maintaining good ligand efficiency (~0.32 kcal/mol/non-hydrogen atom). Finally, we found that binding to this site partially restored the stability of disease-associated Hsp27 variants, in a redox-dependent manner. Together, these experiments suggest a new and unexpected binding site on Hsp27, which might be exploited to build chemical probes.

Amyotrophic lateral sclerosis (ALS) is a rare and progressive neurodegenerative disease mainly affecting upper and lower motor neurons but also causing multisystem involvement, in particular, associated with cognitive changes. Minor sensory fibre dysfunction has been described in the past1 and confirmed in recent studies.2 In a multicentre study investigating a population of 88 patients with ALS, the ESTEEM group (a European Telematic Project for quality assurance within Clinical Neurophysiology) reported sensory polyneuropathy (PNP) in 12.5% of the patients, not influenced by age, disease duration and onset region. In this study, we aimed to readdress prevalence of and risk factors for PNP in a larger population of patients with ALS. A large number of variables, including gene mutations, were assessed.

Peripheral neuropathies (PNs) are a type of common disease that hampers the quality of life of affected people. Treatment, in most cases, is just symptomatic and often ineffective. To improve drug discovery in this field, preclinical evidence is warranted. In vivo rodent models allow a multiparametric approach to test new therapeutic strategies, since they can allow pathogenetic and morphological studies different from the clinical setting. However, human readouts are warranted to promptly translate data from the bench to the bedside. A feasible solution would be neurophysiology, performed similarly at both sides. We describe a simple protocol that reproduces the standard clinical protocol of a neurophysiology hospital department. We devised the optimal montage for sensory and motor recordings (neurography) in mice, and we also implemented F wave testing and a short electromyography (EMG) protocol at rest. We challenged this algorithm by comparing control animals (BALB/c mice) with a model of mild neuropathy to grasp even subtle changes. The neurophysiological results were confirmed with neuropathology. The treatment group showed all expected alterations. Moreover, the neurophysiology matched the neuropathological analyses. Therefore, our protocol can be suggested to promptly translate data from the bench to the bedside and vice versa.