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Spinal muscular atrophy (SMA) is associated with developmental disruption of motor axons in ventral roots of the spinal cord alongside motor axon degeneration. The pathogenesis of peripheral axonal change during development is pertinent to understand treatment response. Nerve excitability techniques, stimulating the median motor nerve at the wrist, were utilised to investigate axonal change during neurodevelopment in 24 children with SMA, compared with 71 age-matched controls. Longitudinal axonal response to nusinersen treatment in 18 children was also investigated. Significant differences in axonal development were noted in the youngest children with SMA, signified by reduced compound muscle action potential (CMAP) (P = 0.030), higher axonal threshold (P = 0.016), rheobase (minimal current amplitude of infinite duration, required to generate an action potential) (P = 0.012) and greater changes in depolarising and hyperpolarising threshold electrotonus. Subexcitability increased in all children with SMA, compared to controls. With treatment, nerve excitability changes were observed prominently in young children, with increases in CMAP, reduction in axonal threshold, fanning-in of threshold electrotonus, increase in resting current-threshold slope and reduction in subexcitability. Whilst motor axons continue to mature in SMA, developmental delays in passive and active membrane properties occur especially in early childhood. Concurrently, motor axons actively undergo degeneration. Nusinersen restores the developmental trajectory of motor axons reducing degeneration, especially in children with early treatment initiation. Our findings move the field forward in understanding the developmental aspect of childhood-onset motor neurone diseases and changes in axonal function associated with disease modification. KEY POINTS: Pathomechanisms in spinal muscular atrophy involve concurrent neurodevelopmental and neurodegenerative processes. The greatest delays in maturation of the passive and active properties of the peripheral motor axon are seen in early childhood. Nusinersen facilitates developmental recovery of the motor axon whilst also reducing neurodegeneration. Axonal dysfunction is reversed with SMN repletion particularly when intervention occurs early in development.

Background/purpose To investigate nerve excitability changes in patients with fibromyalgia and the correlation with clinical severity. Methods We enrolled 20 subjects with fibromyalgia and 22 sex and age-matched healthy subjects to receive nerve excitability test and nerve conduction study to evaluate the peripheral axonal function. Results In the fibromyalgia cohort, the sensory axonal excitability test revealed increased superexcitability (%) (P = 0.029) compared to healthy control. Correlational study showed a negative correlation between increased subexcitability (%) (r = −0.534, P = 0.022) with fibromyalgia impact questionnaire (FIQ) score. Computer modeling confirmed that the sensory axon excitability pattern we observed in fibromyalgia cohort was best explained by increased Barrett–Barrett conductance, which was thought to be attributed to paranodal fast K+ channel dysfunction. Conclusion The present study revealed that paranodal sensory K+ conductance was altered in patients with fibromyalgia. The altered conductance indicated dysfunction of paranodal fast K+ channels, which is known to be associated with the generation of pain.

With the help of metrology, we can identify research hotspots and development trends in dynamic electrocardiography, and thereby provide corresponding reference material to aid further theoretical research.All research data derived from the core collection of Web of Science, and all searches were completed on the same day (February 6, 2022). The obtained data were stored in plain text format and imported into CiteSpace for subsequent analysis. Citation analysis and visualization technology were used to draw a visual map of the research elements, using factors such as annual literature volume, country, journal, author, abstract, keywords, and citation.After screening, 2,937 papers were obtained. Research on ambulatory electrocardiography is increasing worldwide every year. Using research hotspots, keyword-clustering time-zone maps, and high-frequency emerging words, the research in this field was roughly divided into two stages, with 2017 as the divider. The first stage primarily focuses on areas such as atrial fibrillation, stroke, autonomic nerve function, catheter ablation, and T-wave alternation. The second stage saw the focus shift to wearable devices, sudden cardiac death, obstructive sleep apnea, feature extraction, cryptogenic stroke, and similar topics.With the development of various wearable technologies, the daily monitoring of healthy people engaged in sporting activities and the development of innovative analysis algorithms providing more accurate data may represent the hotspots and direction of future research.

Metabolic syndrome (MS) was conceptualized to identify people at risk for cardiovascular disease and type 2 diabetes; however, the epidemiology of MS and its combinations of components in older adults remains unclear. Data from the Senior Health Examination Program of the New Taipei City Government in Taiwan in 2014 were obtained for this study. All participants aged 65 years or older and those with a prior history of cardiovascular disease, cerebrovascular disease, or diabetes mellitus were excluded. 29,164 senior citizens were retrieved for this study, and 12,331 (41.28%) of the participants were male. Female participants were more likely to have MS (42.7% vs.31.3%, p

Objective The present study investigates the peripheral neuropathy in Primary Sjögren's syndrome (pSS) using the nerve excitability test to further elucidate how peripheral nerves are affected by the autoantibodies. Methods Each patient received clinical evaluation, examination for anti‐SSA/Ro and anti‐SSB/La antibodies titer, paired motor and sensory nerve excitability test, thermal quantitative sensory test (QST), and nerve conduction study (NCS). Results A total of 40 pSS patients wasenrolled. Motor axonal study of the pSS with positive anti‐SSA/Ro or anti‐SSB/La antibodies (n = 28) was found to have increased stimulus for 50% compound muscle action potential (CMAP) (P

Introduction: A spectrum of non-motor manifestations in amyotrophic lateral sclerosis (ALS) patients has been increasingly recognized, with cognitive and behavioral impairments the most prominent. Evidence suggests that ALS overlaps on a pathological, genetic, and clinical level with frontotemporal dementia (FTD), thereby suggesting a frontotemporal spectrum disorder (ALS-FTSD). Cognitive impairment has been reported in up to 75% of ALS patients, whilst the rate of behavioral dysfunction ranges up to 50%.Areas covered: The present review explores the current understanding of cognitive and behavioral changes in ALS with a particular emphasis on its implications on prognosis and survival.Expert commentary: Further longitudinal studies are needed to clarify the evolution of cognitive impairment in ALS and how this may ultimately influence survival. Improving understanding of cognitive changes has important implications toward the capacity of patients in making critical medical decisions. There is a need to develop a universally accepted and validated cognitive assessment tool to be administered in a multidisciplinary clinic that is efficient and sensitive, as well as being integrated into the design and analysis of future ALS drug trials. In addition, revision of the ALS diagnostic criteria is critically needed that should accommodate cognitive and behavioral symptoms in addition to motor manifestations.

The osseointegration of metallic implants is reliant on a cascade of molecular interactions and the delivery of macromolecules to the implant environment that occurs before substantial bone formation. Early blood vessel formation is a requisite first step in the healing timeline for osteoid formation, where vascular development can be accelerated as a result of controlled hypoxic conditioning. In this study, alginate-derived xerogel films containing varied concentrations of disodium succinate salt which has been shown to induce pseudohypoxia (short-term hypoxic effects while maintaining an oxygenated environment) were developed. Xerogels were characterized for their morphology, succinate release over time and cellular response with osteoblast-mimicking Saos-2 and human umbilical vein endothelial cells (HUVEC). Scanning electron microscopy revealed a multiscale topography that may favour osseointegration and alamarBlue assays indicated no cytotoxic effects during in vitro proliferation of Saos-2 cells. pH measurements of eluted succinate reach 95 % of peak value after 7 h of immersion for all gels containing 10 mM of succinate or less, and 60 % within the first 40 min. In vitro exposure of HUVECs to succinate-conditioned media increased the net concentration of total proteins measured by bicinchoninic acid (BCA) assay and maintains stable vascular endothelial growth factor (VEGF) and extracellular platelet-derived growth factor (PDGF) for vessel formation through comparison of enzyme-linked immunosorbent assays (ELISAs) of the culture media and cell lysate. Tube formation assays also showed a sustained increase in tube diameter across the first 48 h of HUVEC culture when succinate concentrations of 1 and 10 μM in the xerogel. Overall, the succinate-alginate films serve as a prospective organic coating for bone-interfacing implant materials which may induce temporary pseudohypoxic conditions favourable for early angiogenesis and bone regeneration in vivo at succinate concentrations of 1 or 10 μM.

Vasculature is a key component of many biological tissues and helps to regulate a wide range of biological processes. Modeling vascular networks or the vascular interface in organ-on-a-chip systems is an essential aspect of this technology. In many organ-on-a-chip devices, however, the engineered vasculatures are usually designed to be encapsulated inside closed microfluidic channels, making it difficult to physically access or extract the tissues for downstream applications and analysis. One unexploited benefit of tissue extraction is the potential of vascularizing, perfusing, and maturing the tissue in well-controlled, organ-on-a-chip microenvironments and then subsequently extracting that product for in vivo therapeutic implantation. Moreover, for both modeling and therapeutic applications, the scalability of the tissue production process is important. Here we demonstrate the scalable production of perfusable and extractable vascularized tissues in an "open-top" 384-well plate (referred to as IFlowPlate), showing that this system could be used to examine nanoparticle delivery to targeted tissues through the microvascular network and to model vascular angiogenesis. Furthermore, tissue spheroids, such as hepatic spheroids, can be vascularized in a scalable manner and then subsequently extracted for in vivo implantation. This simple multiple-well plate platform could not only improve the experimental throughputs of organ-on-a-chip systems but could potentially help expand the application of model systems to regenerative therapy.

Background Despite the importance of tumor-infiltrating T lymphocytes (TILs) in cancer biology, the relationship between TIL phenotypes and their prognostic relevance for localized non-small-cell lung cancer (NSCLC) has not been well established. Patients and methods Fresh tumor and normal adjacent tissue was prospectively collected from 150 patients with localized NSCLC. Tissue was comprehensively characterized by high-dimensional flow cytometry of TILs integrated with immunogenomic data from multiplex immunofluorescence, T-cell receptor sequencing, exome sequencing, RNA sequencing, targeted proteomics, and clinicopathologic features. Results While neither the magnitude of TIL infiltration nor specific TIL subsets were significantly prognostic alone, the integration of high-dimensional flow cytometry data identified two major immunotypes (IM1 and IM2) that were predictive of recurrence-free survival independent of clinical characteristics. IM2 was associated with poor prognosis and characterized by the presence of proliferating TILs expressing cluster of differentiation 103, programmed cell death protein 1, T-cell immunoglobulin and mucin-domain containing protein 3, and inducible T-cell costimulator. Conversely, IM1 was associated with good prognosis and differentiated by an abundance of CD8+ T cells expressing cytolytic enzymes, CD4+ T cells lacking the expression of inhibitory receptors, and increased levels of B-cell infiltrates and tertiary lymphoid structures. While increased B-cell infiltration was associated with good prognosis, the best prognosis was observed in patients with tumors exhibiting high levels of both B cells and T cells. These findings were validated in patient tumors from The Cancer Genome Atlas. Conclusions Our study suggests that although the number of infiltrating T cells is not associated with patient survival, the nature of the infiltrating T cells, resolved in distinct TIL immunotypes, is prognostically relevant in NSCLC and may inform therapeutic approaches to clinical care.

Three-dimensional (3D) tissue models such as epithelial spheroids or organoids have become popular for pre-clinical drug studies. However, different from 2D monolayer culture, the characterization of 3D tissue models from non-invasive brightfield images is a significant challenge. To address this issue, here we report a Deep-Learning Uncovered Measurement of Epithelial Networks (Deep-LUMEN) assay. Deep-LUMEN is an object detection algorithm that has been fine-tuned to automatically uncover subtle differences in epithelial spheroid morphology from brightfield images. This algorithm can track changes in the luminal structure of tissue spheroids and distinguish between polarized and non-polarized lung epithelial spheroids. The Deep-LUMEN assay was validated by screening for changes in spheroid epithelial architecture in response to different extracellular matrices and drug treatments. Specifically, we found the dose-dependent toxicity of Cyclosporin can be underestimated if the effect of the drug on tissue morphology is not considered. Hence, Deep-LUMEN could be used to assess drug effects and capture morphological changes in 3D spheroid models in a non-invasive manner.Significance of the workDeep learning has been applied for the first time to autonomously detect subtle morphological changes in 3D multi-cellular spheroids, such as spheroid polarity, from brightfield images in a label-free manner. The technique has been validated by detecting changes in spheroid morphology in response to changes in extracellular matrices and drug treatments.

INTRODUCTION Given recent findings of subclinical sensory deficits in colorectal cancer patients before oxaliplatin treatment, in the current study we aimed to identify evidence of subclinical peripheral neuropathy on multimodal testing before chemotherapy commencement. METHODS Clinical, functional, and neurophysiological assessments were undertaken in 93 colorectal cancer patients before chemotherapy. RESULTS There was no neurophysiological evidence of neuropathy, with 92 of 93 sural sensory values within normative reference values for age and no significant abnormalities detected in nerve conduction or nerve excitability studies. Clinical neurological assessment revealed 75.9% of patients with no signs or symptoms, 10.3% with reduction in distal vibration or pinprick sensitivity, and 6.9% with reduction in ankle reflexes only. There was no difference in manual dexterity (using the 9-hole peg-board test) compared with normative data. DISCUSSION The present study has established a low likelihood of significant distal symmetrical polyneuropathy in colorectal cancer patients before initiation of chemotherapy. Muscle Nerve 57: 615-621, 2018.

Peripheral immunity plays a key role in maintaining homeostasis and conferring crucial neuroprotective effects on the injured nervous system, while at the same time may contribute to increased vulnerability to neuropathic pain. Little is known about the reciprocal relationship between entrapment neuropathy and peripheral immunity. This study investigated immune profile in patients with carpal tunnel syndrome (CTS), the most prevalent entrapment neuropathy. All patients exhibited neurophysiological abnormalities in the median nerve, with the majority reporting neuropathic pain symptoms. We found a significant increase in serum CCL5, CXCL8, CXCL10 and VEGF, and in CD4+ central and effector memory T cells in CTS patients, as compared to healthy controls. CCL5 and VEGF were identified as having the highest power to discriminate between patients and controls. Interestingly, and contrary to the prevailing view of CCL5 as a pro-nociceptive factor, the level of circulating CCL5 was inversely correlated with neuropathic pain intensity and median nerve motor latency. In contrast, the level of central memory T cells was positively associated with abnormal neurophysiological findings. These results suggest that entrapment neuropathy is associated with adaptive changes in the homeostasis of memory T cells and an increase in systemic inflammatory modulating cytokines/chemokines, which potentially regulate neuropathic symptoms.

Peripheral neuropathy is a commonly reported adverse effect of oxaliplatin treatment, representing a significant limitation which may require discontinuation of effective therapy. The present study investigated the neuroprotective potential of riluzole in patients undergoing oxaliplatin treatment in a randomised-controlled trial comparing riluzole and placebo-control.Fifty-two patients (17 females, 58.1 ± 12.7 years) receiving oxaliplatin treatment were randomised into either a treatment (50 mg riluzole) or lactose placebo group. The primary outcome measure was the total neuropathy score-reduced (TNSr). Secondary outcome measures include nerve excitability measures, 9-hole pegboard and FACT-GOG NTX questionnaire. Patients were assessed at baseline, pre-cycle 10 or 12, 4-week and 12-week post-treatment.Both the treatment and placebo groups developed objective and patient reported evidence of neurotoxicity over the course of oxaliplatin treatment, although there were no significant differences across any parameters between the two groups. However, across follow-up assessments, the treatment group experienced greater neuropathy, represented by a higher TNSr score at 4-week post-chemotherapy of 8.3 ± 2.7 compared with 4.6 ± 3.6 (p = 0.032) which was sustained at 12-week post-treatment (p = 0.089). Similarly, patients in the treatment group reported worse symptoms with a FACT-GOG NTX score of 37.4 ± 10.2 compared with 43.3 ± 7.4 (p = 0.02) in the placebo group at 4-week post-treatment.This study is the first to provide an objective clinical investigation of riluzole in oxaliplatin-induced peripheral neuropathy employing both functional and neurophysiological measures. Although the recruitment target was not reached, the results do not show any benefit of riluzole in minimising neuropathy and may suggest that riluzole worsens neuropathy associated with oxaliplatin treatment.

Objective Air pollution had been reported to be associated with the reproductive health of women. However, the association of particulate matter (PM) and acid gases air pollution with premenstrual syndrome (PMS) warrants investigation. This study investigated the effects of air pollution on PMS risk. Population We combined data from the Taiwan Air Quality-Monitoring Database and the Longitudinal Health Insurance Database. In total, an observational cohort of 85 078 Taiwanese women not diagnosed as having PMS. Methods Air pollutant concentrations were grouped into four levels based on the concentration quartiles of several types of air pollutants. Main outcome measures We then applied univariable and multivariable Cox proportional hazard regression models to assess PMS risk in association with each pollutant type. Results Women exposed to Q4-level SO2 exhibited a 7.77 times higher PMS risk compared with those to Q1-level SO2 (95% confidence interval [CI] = 6.22–9.71). Women exposed to Q4-level NOx exhibited a 2.86 times higher PMS risk compared with those exposed to Q1-level NOx (95% CI = 2.39–3.43). Women exposed to Q4-level NO exhibited a 3.17 times higher PMS risk compared with women exposed to Q1-level NO (95% CI = 2.68–3.75). Finally, women exposed to Q4-level PM with a ≤2.5-µm diameter (PM2.5) exhibited a 3.41 times higher PMS risk compared with those exposed to Q1-level PM2.5 (95% CI = 2.88–4.04). Conclusions High incidences of PMS were noted in women who lived in areas with higher concentrations of SO2, NOx, NO, NO2 and PM2.5.

Understanding of maturational properties of sensory and motor axons is of central importance for determining the impact of nerve changes in health and in disease in children and young adults.This study investigated maturation of sensory axons using axonal excitability parameters of the median nerve in 47 children, adolescents and young adults (25 males, 22 females; age range 1-25 years) and compared them to concurrent motor studies.The overall pattern of sensory maturation was similar to motor maturation demonstrating prolongation of the strength duration time constant (P 0.001), reduction of hyperpolarising threshold electrotonus (P = 0.002), prolongation of accommodation half-time (P = 0.005), reduction in hyperpolarising current-threshold slope (P = 0.03), and a shift to the right of the refractory cycle curve (P 0.001), reflecting changes in passive membrane properties and fast potassium channel conductances. Sensory axons, however, had a greater increase in strength duration time constant and more attenuated changes in depolarising threshold electrotonus and current-threshold parameters, attributable to a more depolarised resting membrane potential evident from early childhood and maintained in adults. Peak amplitude was established early in sensory axons whereas motor amplitude increased with age (P 0.001), reflecting non-axonal motor unit changes.Maturational trajectories of sensory and motor axons were broadly parallel in children and young adults, but sensory-motor differences were initiated early in maturation.Identifying the evolution of biophysical changes within and between sensory and motor axons through childhood and adolescence is fundamental to understanding developmental physiology and interpreting disease-related changes in immature nerves.

Breast cancer, especially triple-negative breast cancer, is one of the deadliest cancers in women. To date, there is a lack of a good therapeutic regimen for it. PPARγ has been reported to be a tumor suppressor and could be activated by many agonists involved in cancer inhibition. Therefore, the expression of PPARγ in breast cancer was analyzed by online software UALCAN whose data were from the TCGA database. The results revealed that the PPARγ expression was reduced in breast cancer tissues. Furthermore, the methylation in the PPARγ promoter was also assayed and the results indicated that the methylation level in the PPARγ promoter in breast cancer tissue was higher than that in normal tissue. In order to verify the methylation in promoter involved in the regulation of gene PPARγ expression, the 5'-Aza and fluorescence assays were performed and the results proved that methylation in promoter participated in gene PPARγ expression regulation. Pioglitazone, a PPARγ agonist, still was not investigated in breast cancer. Therefore, the effects of pioglitazone on breast cancer cells were tested by cell viability, scratch and transwell assays, and results indicated that the pioglitazone has the inhibition effect on the proliferation and migration of breast cancer cells by PPARγ which was correlated with the JAK2/STAT3 pathway. In order to further confirm the inhibition effect of pioglitazone on breast cancer in vivo, the nude mice model was administrated by gavage with pioglitazone. And the results indicated that pioglitazone could inhibit the growth of breast cancer in the PPARγ overexpression group in vivo. In summary, the expression of gene PPARγ was decreased in breast cancer tissues, which was correlated with its methylation in the promoter region. Moreover, pioglitazone could exert its inhibition on breast cancer proliferation and migration by the JAK2/STAT3 pathway.

Aims/Introduction To elucidate whether axonal changes arise in the prediabetic state and to find a biomarker for early detection of neurophysiological changes. Materials and Methods We enrolled asymptomatic diabetes patients, as well as prediabetic and normoglycemic individuals to test sensory nerve excitability, and we analyzed those findings and their correlation with clinical profiles. Results In nerve excitability tests, superexcitability in the recovery cycle showed increasing changes in the normoglycemic, prediabetes and diabetes cohorts (−19.09 ± 4.56% in normoglycemia, −22.39 ± 3.16% in prediabetes and −23.71 ± 5.15% in diabetes, P = 0.002). Relatively prolonged distal sensory latency was observed in the median nerve (3.12 ± 0.29 ms in normoglycemia, 3.23 ± 0.38 ms in prediabetes and 3.45 ± 0.43 ms in diabetes, P = 0.019). Superexcitability was positively correlated with fasting plasma glucose (r = 0.291, P = 0.009) and glycated hemoglobin (r = 0.331, P = 0.003) in all participants. Conclusions Sensory superexcitability and latencies are the most sensitive parameters for detecting preclinical physiological dysfunction in prediabetes. In addition, changes in favor of superexcitability were positively correlated with glycated hemoglobin for all participants. These results suggest that early axonal changes start in the prediabetic stage, and that the monitoring strategy for polyneuropathy should start as early as prediabetes., We explored early changes of axonal function in prediabetes using axonal excitability test. The changes progressed from normoglycemia, prediabetes and early diabetes. Superexcitability is the most sensitive parameter for sensory axonal dysfunction. Fasting sugar and glycated hemoglobin were correlated with superexcitability in all participants.

This study aimed to investigate the mechanism underlying the inhibitory effect of tumor suppressor gene miR-186 and zinc finger protein 545 (ZNF545) on the proliferation of multiple myeloma (MM) cells. CD138 magnetic beads were used to isolate different types of myeloma cell lines (KM3, U266, RPMI-8226, and H929), which were then infected by lentivirus carrying the miR-186 gene. Using uninfected myeloma cells as the control, MTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, Thiazolyl Blue Tetrazolium Bromide] assay was performed to calculate the rate of cell proliferation at different time points. In addition, the correlation between the expression of Jagged 1 and miR-186 was analyzed by real-time Polymerase Chain Reaction (PCR). Furthermore, the effect of 5-Aza-2-deoxycytidine and acetylase inhibitor Trichomycin A (TSA) on the expression of ZNF545 and proliferation/apoptosis of MM cells was investigated using Reverse Transcription-Polymerase Chain Reaction (RT-PCR), Western blotting (WB), MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] cell proliferation assay, and Annexin V-FITC/PI staining. Compared with the control group, the proliferation of miR-186-overexpressing U266 and RPMI-8226 cells was significantly decreased. In cell cloning experiments, miR-186 decreased the number of U266 and RPMI-8226 clones while reducing the protein expression of Jagged 1. The expression level of ZNF545 in myeloma patients was also reduced to some extent. ZNF545 protein also promoted the apoptosis of myeloma cells. By inhibiting the proliferation of myeloma cells, miR-186 gene and ZNF protein may be used as tumor suppressors in the treatment of myeloma.

Diabetes may impair the capacity for neuroplasticity such that patients experience a slower and poorer recovery after stroke. The current study investigated changes in cortical function in stroke patients with diabetes to determine how this comorbidity may affect poststroke cortical plasticity and thereby functional recovery. From a cohort of 57 participants, threshold-tracking transcranial magnetic stimulation was used to assess cortical function over the ipsilateral and contralesional hemispheres in 7 patients with diabetes after an acute stroke compared with 12 stroke patients without diabetes. Cortical function was also assessed in 8 patients with diabetes without stroke and 30 normal control subjects. After acute stroke, short-interval intracortical inhibition (SICI) was reduced over both motor cortices in stroke patients without diabetes compared with normal control patients, while in stroke patients with diabetes, SICI was only reduced over the contralesional but not the ipsilesional cortex compared with control patients with diabetes. In addition, SICI was significantly reduced in the control patients with diabetes compared with normal control patients. These results have demonstrated the absence of ipsilesional cortical excitability change after diabetic strokes, suggesting impaired capacity for neuroplasticity over this hemisphere as a consequence of a “double-hit” phenomenon because of preexisting alterations in cortical function in nonstroke patients with diabetes. The reliance on reorganization over the contralesional cortex after stroke will likely exert influence on poststroke recovery in patients with diabetes.

// Thomas Sau-Yan Chan 1 , Yuh-Shan Lee 2 , Ilaria Del Giudice 3 , Marilisa Marinelli 3 , Caterina Ilari 3 , Luciana Cafforio 3 , Anna Guarini 4 , Daryl Tan 2 , Colin Phipps 2 , Yeow-Tee Goh 2 , William Hwang 2 , Allan Zhi-Kai Goh 2 , Lisa Lai-Ping Siu 5 , Saliangi Wu 6 , Chun-Yin Ha 7 , Shek-Ying Lin 8 , Chi-Hang Kwok 9 , Chi-Kuen Lau 10 , Kit-Fai Wong 5 , Robin Foa 3 , Yok-Lam Kwong 1 , Eric Tse 1 1 Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China 2 Department of Haematology, Singapore General Hospital, Outram, Singapore 3 Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy 4 Department of Molecular Medicine, Sapienza University, Rome, Italy 5 Department of Pathology, Queen Elizabeth Hospital, Hong Kong, China 6 Department of Medicine, Queen Elizabeth Hospital, Hong Kong, China 7 Department of Medicine, Tuen Mun Hospital, Hong Kong, China 8 Department of Medicine, United Christian Hospital, Hong Kong, China 9 Department of Medicine, Princess Margaret Hospital, Hong Kong, China 10 Department of Medicine, Tseung Kwan O Hospital, Hong Kong, China Correspondence to: Eric Tse, email: ewctse@hku.hk Keywords: chronic lymphocytic leukaemia, Chinese, pathological characteristics, clinical outcomes, prognostication Received: November 14, 2016 Accepted: February 13, 2017 Published: March 09, 2017 ABSTRACT Chronic lymphocytic leukaemia (CLL) is uncommon in Chinese population and its biology, genetics and treatment outcome in Chinese patients have not been comprehensively investigated. In this study, we studied the clinicopathological features and outcome of 212 Chinese patients with newly diagnosed CLL in Hong Kong and Singapore. The median age at diagnosis was 64 years. The majority of patients presented with early-stage disease (Binet stage A, 56.1%). Del(13)(q14) was the most frequent abnormality (41.7%) detected by fluorescence in situ hybridization (FISH) analysis. Del(17p) and TP53 gene mutations were detected in 7.8% and 8.2% of patients, respectively. MYD88 mutations were found at a higher frequency (11.5%) than expected. CLL with unmutated variable region of the immunoglobulin heavy chain genes ( IGHV ) occurred in only 31.2% of cases, and was associated with advanced-stage disease (p

To gain insights into erythromelalgia disease pathophysiology, this study elucidated changes in peripheral axonal excitability and influences of temperature and mexiletine on axonal function., Erythromelalgia (EM) is a rare neurovascular disorder characterized by intermittent severe burning pain, erythema, and warmth in the extremities on heat stimuli. To investigate the underlying pathophysiology, peripheral axonal excitability studies were performed and changes with heating and therapy explored. Multiple excitability indices (stimulus–response curve, strength–duration time constant (SDTC), threshold electrotonus, and recovery cycle) were investigated in 23 (9 EMSCN9A+ and 14 EMSCN9A−) genetically characterized patients with EM stimulating median motor and sensory axons at the wrist. At rest, patients with EM showed a higher threshold and rheobase (P < 0.001) compared with controls. Threshold electrotonus and current–voltage relationships demonstrated greater changes of thresholds in both depolarizing and hyperpolarizing preconditioning electrotonus in both EM cohorts compared with controls in sensory axons (P < 0.005). When average temperature was raised from 31.5°C to 36.3°C in EMSCN9A+ patients, excitability changes showed depolarization, specifically SDTC significantly increased, in contrast to the effects of temperature previously established in healthy subjects (P < 0.05). With treatment, 4 EMSCN9A+ patients (4/9) reported improvement with mexiletine, associated with reduction in SDTC in motor and sensory axons. This is the first study of primary EM using threshold tracking techniques to demonstrate alterations in peripheral axonal membrane function. Taken together, these changes may be attributed to systemic neurovascular abnormalities in EM, with chronic postischaemic resting membrane potential hyperpolarization due to Na+/K+ pump overactivity. With heating, a trigger of acute symptoms, axonal depolarization developed, corresponding to acute axonal ischaemia. This study has provided novel insights into EM pathophysiology.

Objective To explore the benefits of modified-release fampridine on walking distance in MS. Methods This was a randomised double-blind, placebo-controlled crossover trial of fampridine in 25 MS patients. The primary outcome measure was the six minute walk test (6MWT). A p -value Results The pre-specified criterion for statistical significance was met, with a 17m improvement in 6MWT in the treatment arm. In addition, baseline S2 accommodation, a nerve excitability parameter that reflects slow K + channel activity, modified the effect of fampridine. For patients who had abnormally high S2 accommodation values, there was a 28m improvement in the 6MWT ( p =0.04). In contrast, for patients with low S2 values, a 0m improvement was noted ( p =1.0). Conclusion The study provides evidence that fampridine may improve walking distance. Nerve excitability assessment may be useful in selecting those patients who are most likely to gain benefit from fampridine. Significance Fampridine may improve walking distance in MS. Nerve excitability assessment may assist in identifying those patients most likely to respond to fampridine.

Objectives Nonoccupational post-exposure prophylaxis (nPEP) is a strategy to reduce the risk of HIV infection in those with high-risk exposure. This study characterized nPEP awareness among gay, bisexual and other men who have sex with men (MSM) in Metro Vancouver, British Columbia, Canada after a pilot nPEP programme established in 2012. Methods Momentum Health Study participants were MSM aged ≥16 years recruited via respondent-driven sampling (RDS) who completed a computer-assisted self-interview. Stratifying patients by HIV status, we used multivariable logistic regression with backward selection to identify factors associated with nPEP awareness. All analyses were RDS-adjusted. Results A total of 51.9% (112 of 173) of HIV-positive and 48.5% (272 of 500) of HIV-negative participants had heard of nPEP. Only 3% (five of 106) of HIV-negative participants who reported recent high-risk sex used nPEP. Generally, nPEP awareness was higher for participants who engaged in sexual activities with increased HIV transmission potential. Factors associated with greater awareness among HIV-negative participants included recent alcohol use, higher communal sexual altruism, previous sexually transmitted infection diagnosis, and greater perceived condom use self-efficacy. Other factors associated with greater awareness among HIV-negative participants included white race/ethnicity, gay sexual identity, more formal education, lower personal sexual altruism, and Vancouver residence. Greater nPEP awareness among HIV-positive participants was associated with greater perceived agency to ask sexual partners’ HIV status and more frequently reporting doing so, a higher number of lifetime receptive sex partners, and greater access to condoms. Conclusions Following implementation of an nPEP pilot programme, nPEP awareness among HIV-negative MSM was 51% and use was 3%. These data support the need to expand access to and actively promote nPEP services.

To investigate the effects of fampridine on nerve excitability, the present study utilized peripheral axonal excitability techniques in 18 MS patients receiving treatment with fampridine.Studies were performed at baseline and repeated 3months after institution of fampridine at standard dosing.Following treatment with fampridine there were significant changes in axonal excitability for those parameters associated with fast K(+) channels that shifted towards normal control values. Specifically, increases were noted in the peak superexcitability of recovery cycle (fampridine, -25.6±1.6%; baseline -22.8±1.7%; p0.004), peak depolarizing threshold electrotonus (fampridine, 69.1±1.0%; baseline 67.0±1.4%; p0.004), and depolarizing threshold electrotonus between 40 and 60ms after onset of depolarization (fampridine, 52.8±1.3%; baseline 49.9±1.4%; p=0.02).The present study has established that fampridine at standard doses exerts effects on peripheral nerve function that may be mediated by reduction of fast K(+) conductances.Modulation of fast K(+) conductances by fampridine may contribute to the improvement observed in MS symptoms including motor fatigue.

Despite the complexity and structural sophistication that 3D organoid models provide, their lack of vascularization and perfusion limit the capability of these models to recapitulate organ physiology effectively. A microfluidic platform named IFlowPlate is engineered, which can be used to culture up to 128 independently perfused and vascularized colon organoids in vitro. Unlike traditional microfluidic devices, the vascularized organoid-on-chip device with an "open-well" design does not require any external pumping systems and allows tissue extraction for downstream analyses, such as histochemistry or even in vivo transplantation. By optimizing both the extracellular matrix (ECM) and the culture media formulation, patient-derived colon organoids are co-cultured successfully within a self-assembled vascular network, and it is found that the colon organoids grow significantly better in the platform under constant perfusion versus conventional static condition. Furthermore, a colon inflammation model with an innate immune function where circulating monocytes can be recruited from the vasculature, differentiate into macrophage, and infiltrate the colon organoids in response to tumor necrosis factor (TNF)- inflammatory cytokine stimulation is developed using the platform. With the ability to grow vascularized colon organoids under intravascular perfusion, the IFlowPlate platform could unlock new possibilities for screening potential therapeutic targets or modeling relevant diseases.

Evaluate management of challenging malocclusions conservatively (no extractions or orthognathic surgery).Most malocclusions have a predominately environmental etiology. Optimal esthetics and function are restored by aligning the dentition over the apical base of bone at the appropriate vertical dimension of occlusion (VDO). Extra-alveolar (E-A) anchorage is achieved at three intraoral sites: mandibular buccal shelf (MBS), infrazygomatic crest (IZC), and anterior ramus. MBS and IZC bone screws effectively anchor the conservative correction of severe dental and skeletal malocclusions. All bone screw sites are effective for anchoring lever arms to recover impacted teeth. Rather than extracting teeth, E-A anchorage corrects crowding by retracting the posterior segments to increase arch length. Skeletal malocclusion is corrected by aligning teeth over the apical base of bone and restoring the VDO by retracting and posteriorly rotating the dental arches as segments. Challenging dental and skeletal malocclusions can be treated routinely via determinate mechanics anchored with E-A bone screws.

Objectives Diabetic neuropathy is a debilitating complication of diabetes. Animal models of type 1 diabetes (T1DM) suggest that functional and structural changes, specifically axo-glial dysjunction, may contribute to neuropathy development. The present study sought to examine and characterise early sensory axonal function in T1DM patients in the absence of clinical neuropathy. Methods Thirty patients with T1DM (15M:15F) without neuropathy underwent median nerve sensory and motor axonal excitability studies to examine axonal function. A verified mathematical model of human motor and sensory axons was used to elucidate the underlying causes of observed alterations. Results Compared to controls (NC), T1DM patients demonstrated significant axonal excitability abnormalities in sensory and motor axons. These included marked reductions in sensory and motor subexcitability during the recovery cycle (T1DM 7.9 ± 0.4:10.4 ± 0.6%, NC 10.4 ± 0.7:15.4 ± 1.2%, P 0.01) and during hyperpolarizing threshold electrotonus at 10–20 ms (T1DM −75.5 ± 0.8:−69.7 ± 0.8%, NC −78.4 ± 1:−72.7 ± 0.9%, P 0.01). Mathematical modelling demonstrated that these changes were due to reduced nodal Na + currents, nodal/paranodal K + conductances and Na + /K + pump dysfunction, consistent with axo-glial dysjunction as outlined in animal models of T1DM. Conclusions The study provided support for the occurrence of early changes in nodal and paranodal conductances in patients with T1DM. Significance These data indicate that axonal excitability techniques may detect early changes in diabetic patients, providing a window of opportunity for prophylactic intervention in T1DM.

Background: Abnormalities in membrane excitability and Na+ channel function are characteristic of amyotrophic lateral sclerosis (ALS). We aimed to examine the neuroprotective potential, safety and tolerability of the Na+ channel blocker and membrane stabiliser flecainide in ALS. Methods: A double-blind, placebo-controlled, randomised clinical trial of flecainide (200 mg/day) for 32-weeks with a 12-week lead-in phase was conducted in participants with probable or definite ALS recruited from multiple Australian centres (ANZCT Registry number ACTRN12608000338369). Patients were reviewed by a cardiologist to rule out cardiac contraindications. Participants were randomly assigned (1:1) to flecainide or placebo using stratified permuted blocks by a central pharmacy. The primary outcome measure was the slope of decline of the ALS Functional Rating Scale-revised (ALS FRS-r) during the treatment period. Findings: Between March 11, 2008 and July 1, 2010, 67 patients were screened, 54 of whom were randomly assigned to receive flecainide (26 patients) or placebo (28 patients). Four patients in the flecainide group and three patients in the placebo group withdrew from the study. One patient in the flecainide group died during the study, attributed to disease progression. Flecainide was generally well tolerated, with no serious adverse events reported in either group. There was no significant difference in the rate of decline in the primary outcome measure ALS-FRS-r between placebo and flecainide treated patients (Flecainide 0.65 [95% CI 0.49 to 0.98]; Placebo 0.81 [0.49 to 2.12] P = 0.50). However, the rate of decline of the neurophysiological index was significantly reduced in the flecainide group (Flecainide 0.06 [0.01 to 0.11]; Placebo 0.14 [0.09 to 0.19], P = 0.02). Placebo-treated patients demonstrated greater CMAP amplitude reduction during the course of the study in the subset of patients with a reduced baseline CMAP amplitude (Flecainide: −15 ± 12%; Placebo −59 ± 12%; P = 0.03). Flecainide-treated patients maintained stabilized peripheral axonal excitability over the study compared to placebo. Interpretation: This pilot study indicated that flecainide was safe and potentially biologically effective in ALS. There was evidence that flecainide stabilized peripheral axonal membrane function in ALS. While the study was not powered to detect evidence of benefit of flecainide on ALS-FRS-r decline, further studies may demonstrate clinical efficacy of flecainide in ALS.

To define the clinicopathologic features, outcome, and prognostic indicators of myelofibrosis (MF) in Asian patients.Two hundred and seventy consecutive Chinese patients (primary MF, n = 207; post-polycythemia vera MF, n = 27; and post-essential thrombocythemia MF, n = 36) from seven regional referral hospitals were analyzed.The median overall survival (OS) for primary MF was 66 months. Multivariate analysis showed that age65 years (P = 0.02), platelet count100 × 10(9)/l (P = 0.001), and leukemic transformation (P = 0.001) negatively impacted on OS. The median OS of 63 patients with secondary MF was 44 months. In primary MF, the 10-year cumulative risk of leukemic transformation was 28%. On multivariate analysis, unfavorable karyotypes significantly predicted inferior leukemia-free survival (LFS) (P = 0.03). In secondary MF, the 10-year cumulative risk of leukemic transformation was 31%. Circulating blasts ≥1% significantly predicted inferior LFS (P = 0.04). The international prognostic scoring system (IPSS) and dynamic IPSS were not significant survival predictors in our cohort. Eighteen patients underwent allogeneic hematopoietic stem cell transplantation. The median OS post-transplantation was merely 19 months.Platelet count100 × 10(9)/l, unfavorable karyotypes, and circulating blasts1% were negative prognostic indicators. Conclusion Chinese MF patients were similar to Western patients in clinicopathologic features and outcome.

It has been suggested that corticomotoneuronal drive to ankle dorsiflexors is greater than to ankle plantar flexor muscles, despite the finding that plantar flexors are no less active than TA during walking and standing. The present study was undertaken to determine whether there was differential involvement of distal lower limb muscles in amyotrophic lateral sclerosis (ALS), to elucidate pathophysiological mechanisms of selective muscle involvement. Prospective studies were undertaken in 52 ALS patients, including clinical assessment, disease staging (revised ALS functional rating scale), Medical Research Council sum score, and a scale of upper motor neurone (UMN) dysfunction. Motor unit number estimates (MUNE) and compound muscle action potentials (CMAP) from ankle dorsiflexors and plantar flexors were used to provide objective measures. A novel ‘split leg index’ was calculated as follows: SLI = CMAPDF ÷ CMAPPF. In ALS, there was significantly greater reduction of MUNE and CMAP amplitude recorded from plantar flexors when compared to dorsiflexors, suggesting preferential involvement of plantar flexor muscles, underpinning a ‘split leg’ appearance. The SLI correlated with clinical plantar flexor strength (R= −0.56, p

Objectives There is accumulating evidence of dysfunction of spinal circuits in the pathogenesis of amyotrophic lateral sclerosis (ALS). Methods The present study was undertaken to characterise the pathophysiological changes in segmental motoneuronal excitability in 28 ALS patients, using recruitment curves of the soleus H-reflex and M-wave, compared with clinical assessments of upper motor neuron (UMN) and lower motor neuron dysfunction. Results H-reflex recruitment curves established that H max / M max and slope ( H θ / M θ ) ratios predicted clinical UMN dysfunction ( p H θ / M θ were driven by reduced M θ . Assessment of H max / M max was similar in the ALS and control groups, and was affected by overlap of the H and M recruitment curves in ALS patients. Conclusion Changes in the slope ratio ( H θ / M θ ) in ALS suggested that alterations in peripheral motor nerve excitability following UMN damage may affect the recorded H-reflex. Increased collision of reflex discharges with antidromically-conducted motor impulses may be exacerbated in ALS due to preferential loss of large-caliber α-motoneurones, which may explain the similarities in H max / M max between groups. Significance Findings from the present study provide further insight into the pathophysiology of ALS, specifically the relative contributions of premotoneuronal and segmental motoneuronal dysfunction.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an inflammatory neuropathy, classically characterised by a slowly progressive onset and symmetrical, sensorimotor involvement. However, there are many phenotypic variants, suggesting that CIDP may not be a discrete disease entity but rather a spectrum of related conditions. While the abiding theory of CIDP pathogenesis is that cell-mediated and humoral mechanisms act together in an aberrant immune response to cause damage to peripheral nerves, the relative contributions of T cell and autoantibody responses remain largely undefined. In animal models of spontaneous inflammatory neuropathy, T cell responses to defined myelin antigens are responsible. In other human inflammatory neuropathies, there is evidence of antibody responses to Schwann cell, compact myelin or nodal antigens. In this review, the roles of the cellular and humoral immune systems in the pathogenesis of CIDP will be discussed. In time, it is anticipated that delineation of clinical phenotypes and the underlying disease mechanisms might help guide diagnostic and individualised treatment strategies for CIDP.

Objective The aim of this study was to evaluate changes in sensory axonal excitability in the distal nerve in patients with cervical radiculopathy. Methods The patients were classified by the findings of cervical MRI into two subgroups: 22 patients with C6/7 root compression and 25 patients with cervical cord and root compression above/at C6/7. Patients were investigated using conventional nerve conduction studies (NCS) and nerve excitability testing. Sensory nerve excitability testing was undertaken with stimulation at the wrist and recording from digit II (dermatome C6/7). The results were compared with healthy controls. Both preoperative and postoperative tests were performed if the patient underwent surgery. Results Sensory axonal excitability was significantly different in both cohorts compared with healthy controls, including prolonged strength-duration time constant, reduced S2 accommodation, increased threshold electrotonus hyperpolarisation (TEh (90–100 ms)), and increased superexcitability. The changes in these excitability indices are compatible with axonal membrane hyperpolarisation. In five patients who underwent surgery, the postoperative sensory excitability was tested after 1 week, and showed significant changes in TE (TEh (90–100 ms) and TEh slope, p Conclusions The present study demonstrated distal nerve axonal hyperpolarisation in patients with cervical radiculopathy. These findings suggest that the hyperpolarised pattern might be due to Na + -K + ATPase overactivation induced by proximal ischaemia, or could reflect the remyelinating process. Distal sensory axons were hyperpolarised even though there were no changes in NCS, suggesting that nerve excitability testing may be more sensitive to clinical symptoms than NCS in patients with cervical radiculopathy.

Objective Potassium (K + ) has been implicated as a factor in the development of uraemic neuropathy. This study was undertaken to investigate whether hyperkalaemia plays a causal role in axonal dysfunction in end-stage kidney disease (ESKD). Methods Median motor nerve excitability studies were undertaken in four haemodialysis patients during a modified dialysis session. The serum K + level was "clamped" (fixed) for the first 3h of dialysis, whilst allowing all other solutes to be removed, this was followed by dialysis against low dialysate K + for a further 4h. Blood chemistry and nerve excitability studies were undertaken prior to, during and following dialysis. Results were compared to results from the same patients during routine dialysis sessions. Results All patients demonstrated significant nerve excitability abnormalities reflective of nerve membrane depolarization in pre-dialysis recordings ( p + remained elevated (5.0mmol/L) and nerve excitability remained highly abnormal, despite the significant clearance of other uraemic toxins. In contrast, studies undertaken during routine dialysis sessions demonstrated significant improvement in both serum K + and nerve function after 3h. Conclusions The current study has established a causal relationship between serum K + and axonal membrane depolarization in haemodialysis patients. Significance From a clinical perspective, strict K + control may help improve nerve function in ESKD.

Over the past 20 years, the most notable advance in understanding Guillain–Barre syndrome (GBS) has been the identification of an axonal variant. This advance arose chiefly through studies undertaken in East Asian countries and comprised two major aspects: first, the immunopathogenesis of axonal GBS related to anti-ganglioside antibodies and molecular mimicry of Campylobacter jejuni ; and second, the observation that distinct electrophysiological patterns of axonal GBS existed, reflecting reversible conduction failure (RCF). As a consequence, the pathophysiology of acute motor axonal neuropathy (AMAN) has perhaps become better understood than acute inflammatory demyelinating polyneuropathy. Despite these more recent advances, a critical issue remains largely unresolved: whether axonal GBS is more common in Asia than in Europe or North America. If it is more common in Asia, then causative factors must be more critically considered, including geographical differences, issues of genetic susceptibility, the role of antecedent infections and other potential triggering factors. It has become apparent that the optimal diagnosis of AMAN requires serial electrophysiological testing, to better delineate RCF, combined with assessment for the presence of anti-ganglioside antibodies. Recent collaborative approaches between Europe and Asia have suggested that both the electrophysiological pattern of AMAN and the seropositivity for anti-ganglioside antibodies develop similarly. Separately, however, current electrodiagnostic criteria for AMAN limited to a single assessment appear inadequate to identify the majority of cases. As such, diagnostic criteria will need to be revised to improve the diagnostic sensitivity for AMAN.

Neurotoxicity is a significant clinical side effect of immunosuppressive treatment used in prophylaxis for rejection in solid organ transplants. This study aimed to provide insights into the mechanisms underlying neurotoxicity in patients receiving immunosuppressive treatment following renal transplantation. Clinical and neurophysiological assessments were undertaken in 38 patients receiving immunosuppression following renal transplantation, 19 receiving calcineurin inhibitor (CNI) therapy and 19 receiving a calcineurin-free (CNI-free) regimen. Groups were matched for age, gender, time since transplant and renal function and compared to normal controls (n = 20). The CNI group demonstrated marked differences in nerve excitability parameters, suggestive of nerve membrane depolarization (p < 0.05). Importantly, there were no differences between the two CNIs (cyclosporine A or tacrolimus). In contrast, CNI-free patients showed no differences to normal controls. The CNI-treated patients had a higher prevalence of clinical neuropathy and higher neuropathy severity scores. Longitudinal studies were undertaken in a cohort of subjects within 12 months of transplantation (n = 10). These studies demonstrated persistence of abnormalities in patients maintained on CNI-treatment and improvement noted in those who were switched to a CNI-free regimen. The results of this study have significant implications for selection, or continuation, of immunosuppressive therapy in renal transplant recipients, especially those with pre-existing neurological disability.

Limited evidence to date has demonstrated changes in excitability that develops over the contralateral motor cortex after a cerebellar infarct. As such, the present study investigated changes in excitability over the contra- (contraM1) and ipsilateral motor cortices (ipsiM1), in patients with acute cerebellar infarct, to determine whether the changes may have functional relevance. Paired-pulse transcranial magnetic stimulation, combined with detailed clinical assessment, was undertaken in ten patients presenting with acute unilateral cerebellar infarct. Studies were undertaken within 1 week of ictus and followed longitudinally at 3-, 6-, and 12-month periods. Comparisons were made with 15 age-matched controls. Immediately following a stroke, short-interval intracortical inhibition (SICI) was significantly reduced over the contraM1 in all patients (P = 0.01), while reduced over the ipsiM1 in those with severe functional impairment (P = 0.01). Moreover, ipsiM1 SICI correlated with impairment (r = 0.69, P = 0.03), such that less SICI was observed in those patients with most impairment. Cortical excitability changes persisted over the follow-up period in the context of clinical improvement. Following an acute cerebellar infarct, excitability abnormalities develop over both motor cortices, more prominently in patients with severe functional impairment. The cortical changes, particularly over the ipsilateral motor cortex, may represent a functionally relevant plastic process that may guide future therapeutic strategies to better facilitate recovery.

Riluzole, a benzothiazole derivative, has been shown to be effective in prolonging survival in amyotrophic lateral sclerosis. The mechanisms by which riluzole exerts neuroprotective effects in amyotrophic lateral sclerosis remains to be fully elucidated, although inhibition of glutamatergic transmission and modulation of Na+ channel function have been proposed. In an attempt to determine the mechanisms by which riluzole exerts neuroprotective effects, in particular to dissect the relative contributions of inhibition of glutamatergic transmission and Na+ channel modulation, the present study utilized a combination of cortical and peripheral axonal excitability approaches to monitor changes in excitability and function in patients with amyotrophic lateral sclerosis. Cortical assessment was undertaken by utilising the threshold tracking transcranial magnetic stimulation (TMS) technique and combined with peripheral axonal excitability studies in 25 patients with amyotrophic lateral sclerosis. Studies were performed at baseline and repeated when patients were receiving riluzole 100 mg/day. At the time of second testing all patients were tolerating the medication well. Motor evoked potential and compound muscle action potential responses were recorded over the abductor pollicis brevis muscle. At baseline, features of cortical hyperexcitability were evident in patients with amyotrophic lateral sclerosis, indicated by marked reduction in short interval intracortical inhibition ( P < 0.001) and cortical silent period duration ( P < 0.001), as well as an increase in the motor evoked potential amplitude ( P < 0.01). Riluzole therapy partially normalized cortical excitability by significantly increasing short interval intracortical inhibition (short interval intracortical inhibitionbaseline 0.5 ± 1.8%; short interval intracortical inhibitionON riluzole 7.9 ± 1.7%, P < 0.01). In contrast, riluzole did not exert any modulating effect on cortical silent period duration ( P = 0.45) or motor evoked potential amplitude ( P = 0.31). In terms of peripheral nerve function, axonal excitability studies established that, relative to control subjects, patients with amyotrophic lateral sclerosis had significant increases in depolarizing threshold electrotonus [amyotrophic lateral sclerosisbaseline TEd (90–100 ms) 49.1 ± 1.8%; controlsTEd (90–100 ms) 45.2 ± 0.6%, P < 0.01] and superexcitability (amyotrophic lateral sclerosisbaseline 30.1 ± 2.3%; control subjects 23.4 ± 1.0%, P < 0.01) at baseline. Following institution of riluzole therapy there was a significant reduction in superexcitability (amyotrophic lateral sclerosisbaseline 30.1 ± 2.3%; amyotrophic lateral sclerosisON riluzole 27.3 ± 2.3%, P < 0.05) and refractoriness at 2 ms (amyotrophic lateral sclerosisbaseline 98.7 ± 10.7%; amyotrophic lateral sclerosisON riluzole 67.8 ± 9.3%, P < 0.001). In conclusion, the present study has established that riluzole exerts effects on both central and peripheral nerve function, interpreted as partial normalization of cortical hyperexcitability and reduction of transient Na+conductances. Taken together, these findings suggest that the neuroprotective effects of riluzole in amyotrophic lateral sclerosis are complex, with evidence of independent effects across both compartments of the nervous system. * Abbreviations : ALS : amyotrophic lateral sclerosis ALSFRS-R : Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised SICI : short interval intracortical inhibition

OBJECTIVE Pharmacological agents for diabetic peripheral neuropathy (DN) target a number of mechanisms, including sodium channel function and γ-aminobutyric acid–minergic processes. At present, prescription is undertaken on a trial-and-error basis, leading to prolonged medication trials and greater healthcare costs. Nerve-excitability techniques are a novel method of assessing axonal ion channel function in the clinical setting. The aim of this study was to determine the effects of axonal ion channel dysfunction on neuropathy-specific quality-of-life (QoL) measures in DN. RESEARCH DESIGN AND METHODS Fifty-four patients with type 2 diabetes mellitus underwent comprehensive neurologic assessment, nerve-conduction studies, and nerve-excitability assessment. Neuropathy severity was assessed using the Total Neuropathy Score. Neuropathy-specific QoL was assessed using a DN-specific QoL questionnaire (Neuropathy-Specific Quality of Life Questionnaire [NeuroQoL]). Glycosylated hemoglobin and BMI were recorded in all patients. RESULTS NeuroQoL scores indicated significant QoL impairment (mean 9.08 ± 5.93). Strength-duration time constant (SDTC), an excitability parameter reflecting sodium channel function, was strongly correlated with QoL scores (r = 0.545; P < 0.005). SDTC was prolonged in 48.6% of patients who experienced neuropathic symptoms. A significant correlation was also noted between SDTC and neuropathy severity (r = 0.29; P < 0.05). This relationship was strengthened when looking specifically at patients with clinically graded neuropathy (r = 0.366; P < 0.05). CONCLUSIONS The current study has demonstrated an association between markers of sodium channel function and QoL in DN. The study demonstrates that excitability techniques may identify patients in whom altered sodium channel function may be the dominant abnormality. The findings suggest that excitability techniques may have a role in clinical decision making regarding neuropathic treatment prescription.

Autoantibodies to nodal/paranodal proteins have been reported in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN). To determine the frequency of anti-paranodal antibodies in our cohort of CIDP patients and to validate the presence anti-nodal antibodies in MMN, sera were screened for IgG against human neurofascin 155, contactin-1, neurofascin 186 and gliomedin using ELISA. In CIDP patients, 7% were anti-NF155 IgG4 positive and 7% were anti-CNTN1 IgG4 positive. Positive results were confirmed using cell based assays and indirect immunofluorescence on teased nerve fibres. We did not detect IgG autoantibodies against these nodal/paranodal antigens in MMN patients.

This study investigated sensory and motor nerve excitability properties to elucidate the development of diabetic neuropathy. A total of 109 type 2 diabetes patients were recruited, and 106 were analyzed. According to neuropathy severity, patients were categorized into G0, G1, and G2+3 groups using the total neuropathy score-reduced (TNSr). Patients in the G0 group were asymptomatic and had a TNSr score of 0. Sensory and motor nerve excitability data from diabetic patients were compared with data from 33 healthy controls. Clinical assessment, nerve conduction studies, and sensory and motor nerve excitability testing data were analyzed to determine axonal dysfunction in diabetic neuropathy. In the G0 group, sensory excitability testing revealed increased stimulus for the 50% sensory nerve action potential (P

Introduction Patients diagnosed with amyotrophic lateral sclerosis (ALS) generally have a limited medical history and a normal body mass index, raising the possibility of a premorbid ALS phenotype. Methods The prevalence of cardiometabolic factors was analyzed in 58 ALS patients via comprehensive cardiovascular assessments and compared with Australian population norms. Results ALS patients had good cardiac fitness and no reported cardiovascular events. Average blood pressure, heart rate, PR interval, and corrected QT interval were in the normal range. There were significantly fewer obese women in the ALS cohort (13.6%, P

SUMMARYThe medical records of 84 patients with stool cultures positive forClostridium difficileduring the period August 2007 to June 2009 were retrospectively reviewed. A case of confirmed (toxigenic)C. difficileinfection (CDI) was defined by the presence of symptoms (fever, diarrhoea, abdominal discomfort or distension, ileus) and the presence of toxigenicC. difficile. Patients with compatible clinical symptoms and stool cultures positive for non-toxigenicC. difficileisolates were defined as probable (non-toxigenic) CDI cases. Of these 84 patients, 50 (59·5%) were diagnosed as confirmed CDI and 34 (40·5%) as probable CDI. Thirteen (15·5%) of the 84 patients died during their hospital stay. Usage of proton pump inhibitors was a significant independent risk factor for CDI (OR 3·21,P = 0·014). Of the 50 isolates associated with confirmed CDI, seven (8·3%) carried binary toxin genes (cdtAB), and six (7·1%) had a deletion in thetcdCgene. The mortality rate in confirmed CDI patients with isolates exhibiting deletion in thetcdCgene (2/6, 33·3%), those with isolates harbouring binary toxin genes (2/7, 28·6%), and those with isolates containing mutations ingyrA(2/7, 28·6%) andgyrB(1/2, 50%) was higher than the overall mortality rate (10/50, 20%) in patients with confirmed CDI.

Objective To elucidate longitudinal changes in axonal function in amyotrophic lateral sclerosis (ALS) patients, and to relate such changes with motor unit loss and functional impairment. Methods 37 ALS patients (age, 53.7±1.7years; 22 males) were studied using axonal excitability techniques at baseline and 12weeks follow-up. Results Longitudinal measurements across excitability parameters suggested increasing K + channel dysfunction, with further increases in depolarising threshold electrotonus (90–100ms, baseline, 46.8±1.0%; follow-up, 48.7±0.8%; P =0.02) and superexcitability (baseline, −24.0±1.2%; 12weeks, −26.0±1.2%; P =0.04). Patients with preserved compound muscle action potential (CMAP) amplitude at follow-up developed more severe changes in axonal excitability than those in whom CMAP decreased from baseline, suggesting that the most pronounced disease effects were on motor axons immediately prior to axonal loss in ALS patients. Fine motor decline was associated with more severe changes in axonal excitability, suggesting that functional impairment was related to axonal dysfunction. Conclusions Longitudinal changes in axonal excitability in ALS patients suggest increasing K + channel dysfunction in motor axons. Significance Axonal excitability studies enable investigation of longitudinal changes in axonal ion channel dysfunction, and thereby the processes that potentially contribute to axonal degeneration in ALS.