Painful peripheral neuropathy and cancer

Peripheral neuropathy (PN) is very prevalent in cancer patients and a leading cause of pain related to cancer. However, the underlying pathophysiological mechanisms vary significantly. Peripheral neuropathy can be a direct or an indirect complication of cancer or cancer-related treatment, or a pre-existing comorbidity not related to cancer. PN might also occur as a paraneoplastic neurological syndrome. Such syndromes are immune-mediated manifestations that usually precede the diagnosis of cancer or cancer's relapse. Pain is very prevalent in paraneoplastic peripheral neuropathies and, therefore, merits attention

Behavioral therapy approaches for the management of low back pain: An up-to-date systematic review

Low back pain is one of the most common causes for seeking medical treatment and it is estimated that one in two people will experience low back pain at some point during their lifetimes. Management of low back pain includes pharmacological and non-pharmacological approaches. Non-pharmaceutical treatments include interventions such as acupuncture, spinal manipulation, and psychotherapy. The latter is especially important as patients who suffer from low back pain often have impaired quality of life and also suffer from depression. Depressive symptoms can appear because back pain limits patients' ability to work and engage in their usual social activities. The aim of this systematic review was to overview the behavioral approaches that can be used in the management of patients with low back pain. Approaches such as electromyography (EMG) biofeedback, cognitive behavioral therapy, and mindfulness-based stress reduction are discussed as non-pharmacological options in the management of low back pain

The role of vitamin B6 in peripheral neuropathy: a systematic review

Introduction: Vitamin B6 is a water-soluble vitamin that is naturally present in many foods and is accessible in many dietary supplements. The three natural forms are pyridoxine, pyridoxal, and pyridoxamine. Both vitamin B6 deficiency and high B6 intake have been described as risk factors for developing peripheral neuropathy (PN). The aim of this systematic review is to characterize and comprehensively describe B6-related PN. Method: A systematic, computer-based search was conducted using the PubMed database. Twenty articles were included in this review. Results: Higher vitamin B6 levels, which usually occur following the taking of nutritional supplements, may lead to the development of a predominantly, if not exclusively, sensory neuropathy of the axonal type. After pyridoxine discontinuation, such patients subjectively report improved symptoms. However, although low vitamin B6 levels can be seen in patients suffering from peripheral neuropathy of various etiologies, there is no firm evidence that low B6 levels have a direct causal relationship with PN. Many studies suggest subjective improvement of neuropathy symptoms in patients suffering from PN of various etiologies after receiving B6 supplementation; however, no data about B6 administration as a monotherapy exist, only as part of a combination treatment, usually with other vitamins. Therefore, the potential therapeutic role of B6 cannot be confirmed to date. Supplementation with vitamin B6, even as part of a nutritional multivitamin supplement, has not been proven harmful at permitted daily doses in patients who already suffer from PN. Conclusion: Current scientific evidence supports a neurotoxic role of B6 at high levels. Although some studies suggest that low B6 is also a potential risk factor, further studies in this area are needed

Ionic lanthanum passage across cerebral endothelium exposed to hyperosmotic arabinose

Hyperosmotic media infused into the cerebral circulation open the blood-brain barrier to protein and colloid. The mechanism whereby such substances cross the affected vessels is still disputed. We describe here the transendothelial route taken by ionic lanthanum (La 3+ ), a small electron-dense tracer which, unlike colloidal lanthanum, can be administered to the living animal. In adult rats, 2.9 ml of hyperosmotic (1.4 M) arabinose was infused into the internal carotid artery as a 30-s bolus, followed by 5 mM LaCl 3 . To find the extravasated La 3+ , which is invisible by light microscopy, horseradish peroxidase (HRP) was injected simultaneously into the femoral vein. The hyperosmotic treatment resulted in exudation of both HRP and La 3+ primarily around cerebral arterioles. The La 3+ crossed arterioles through successive tight junctions between endothelial cells. Although the tight junctions were not discernibly opened, they must have become permeable because the extracellular pools between successive tight junctions were penetrated by the La 3+ . These pools are normally inaccessible to La 3+ . Luminal and abluminal pits and cytoplasmic vesicles, some of them containing La 3+ , formed intraendothelial clusters. Their role, if any, in the transfer of ion remains remains uncertain.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47227/1/401_2004_Article_BF00685347.pd

Neurofilament light as a blood biomarker for neurodegeneration in Down syndrome.

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.BACKGROUND: Down syndrome (DS) may be considered a genetic form of Alzheimer's disease (AD) due to universal development of AD neuropathology, but diagnosis and treatment trials are hampered by a lack of reliable blood biomarkers. A potential biomarker is neurofilament light (NF-L), due to its association with axonal damage in neurodegenerative conditions. METHODS: We measured blood NF-L concentrations in 100 adults with DS using Simoa NF-light® assays, and we examined relationships with age as well as cross-sectional and longitudinal dementia diagnosis. RESULTS: NF-L concentrations increased with age (Spearman's rho = 0.789, p < 0.001), with a steep increase after age 40, and they were predictive of dementia status (p = 0.022 adjusting for age, sex, and APOE4), but they showed no relationship with long-standing epilepsy or premorbid ability. Baseline NF-L concentrations were associated with longitudinal dementia status. CONCLUSIONS: NF-L is a biomarker for neurodegeneration in DS with potential for use in future clinical trials to prevent or delay dementia.This work was funded by a Wellcome Trust Strategic Award (grant number 098330/Z/12/Z) conferred upon The London Down Syndrome (LonDownS) Consortium (Chief Investigator, Andre Strydom)

Pain in platin-induced neuropathies: A systematic review and meta-analysis

INTRODUCTION: Platin-induced peripheral neuropathy (PIPN) is a common cause of PN in cancer patients. The aim of this paper is to systematically review the current literature regarding PIPN, with a particular focus on epidemiological and clinical characteristics of painful PIPN, and to discuss relevant management strategies. METHODS: A systematic computer-based literature search was conducted on the PubMed database. RESULTS: This search strategy resulted in the identification of 353 articles. After the eligibility assessment, 282 articles were excluded. An additional 24 papers were identified by scanning the reference lists. In total, 95 papers met the inclusion criteria and were used for this review. The prevalence of neuropathic symptoms due to acute toxicity of oxaliplatin was estimated at 84.6%, whereas PN established after chemotherapy with platins was estimated at 74.9%. Specifically regarding pain, the reported prevalence of pain due to acute toxicity of oxaliplatin was estimated at 55.6%, whereas the reported prevalence of chronic peripheral neuropathic pain in PIPN was estimated at 49.2%. CONCLUSION: Peripheral neuropathy is a common complication in patients receiving platins and can be particularly painful. There is significant heterogeneity among studies regarding the method for diagnosing peripheral neuropathy. Nerve conduction studies are the gold standard and should be performed in patients receiving platins and complaining of neuropathic symptoms post-treatment

Using interictal seizure-free EEG data to recognise patients with epilepsy based on machine learning of brain functional connectivity

Most seizures in adults with epilepsy occur rather infrequently and as a result, the interictal EEG plays a crucial role in the diagnosis and classification of epilepsy. However, empirical interpretation, of a first EEG in adult patients, has a very low sensitivity ranging between 29-55%. Useful EEG information remains buried within the signals in seizure-free EEG epochs, far beyond the observational capabilities of any specialised physician in this field. Unlike most of the existing works focusing on either seizure data or single-variate method, we introduce a multi-variate method to characterise sensor level brain functional connectivity from interictal EEG data to identify patients with generalised epilepsy. A total of 9 connectivity features based on 5 different measures in time, frequency and time frequency domains have been tested. The solution has been validated by the K-Nearest Neighbour algorithm, classifying an epilepsy group (EG) vs healthy controls (HC) and subsequently with another cohort of patients characterised by non-epileptic attacks (NEAD), a psychogenic type of disorder. A high classification accuracy (97%) was achieved for EG vs HC while revealing significant spatio temporal deficits in the frontocentral areas in the beta frequency band. For EG vs NEAD, the classification accuracy was only about 73%, which might be a reflection of the well-described coexistence of NEAD with epileptic attacks. Our work demonstrates that seizure-free interictal EEG data can be used to accurately classify patients with generalised epilepsy from HC and that more systematic work is required in this direction aiming to produce a clinically useful diagnostic method

Novel genotype-phenotype and MRI correlations in a large cohort of patients with SPG7 mutations

Objective: To clinically, genetically, and radiologically characterize a large cohort of SPG7 patients. Methods: We used data from next-generation sequencing panels for ataxias and hereditary spastic paraplegia to identify a characteristic phenotype that helped direct genetic testing for variations in SPG7. We analyzed MRI. We reviewed all published SPG7 mutations for correlations. Results: We identified 42 cases with biallelic SPG7 mutations, including 7 novel mutations, including a large multi-exon deletion, representing one of the largest cohorts so far described. We identified a characteristic phenotype comprising cerebellar ataxia with prominent cerebellar dysarthria, mild lower limb spasticity, and a waddling gait, predominantly from a cohort of idiopathic ataxia. We report a rare brain MRI finding of dentate nucleus hyperintensity on T2 sequences with SPG7 mutations. We confirm that the c.1529C>T allele is frequently present in patients with long-standing British ancestry. Based on the findings of the present study and existing literature, we confirm that patients with homozygous mutations involving the M41 peptidase domain of SPG7 have a younger age at onset compared to individuals with mutations elsewhere in the gene (14 years difference, p T compound heterozygous mutations are associated with a younger age at onset compared to homozygous cases (5.4 years difference, p < 0.022). Conclusions: Mutant SPG7 is common in sporadic ataxia. In patients with British ancestry, c.1529C>T allele represents the most frequent mutation. SPG7 mutations can be clinically predicted by the characteristic hybrid spastic-ataxic phenotype described above, along with T2 hyperintensity of the dentate nucleus on MRI

Platelets Alter Gene Expression Profile in Human Brain Endothelial Cells in an In Vitro Model of Cerebral Malaria

Platelet adhesion to the brain microvasculature has been associated with cerebral malaria (CM) in humans, suggesting that platelets play a role in the pathogenesis of this syndrome. In vitro co-cultures have shown that platelets can act as a bridge between Plasmodium falciparum-infected red blood cells (pRBC) and human brain microvascular endothelial cells (HBEC) and potentiate HBEC apoptosis. Using cDNA microarray technology, we analyzed transcriptional changes of HBEC in response to platelets in the presence or the absence of tumor necrosis factor (TNF) and pRBC, which have been reported to alter gene expression in endothelial cells. Using a rigorous statistical approach with multiple test corrections, we showed a significant effect of platelets on gene expression in HBEC. We also detected a strong effect of TNF, whereas there was no transcriptional change induced specifically by pRBC. Nevertheless, a global ANOVA and a two-way ANOVA suggested that pRBC acted in interaction with platelets and TNF to alter gene expression in HBEC. The expression of selected genes was validated by RT-qPCR. The analysis of gene functional annotation indicated that platelets induce the expression of genes involved in inflammation and apoptosis, such as genes involved in chemokine-, TREM1-, cytokine-, IL10-, TGFβ-, death-receptor-, and apoptosis-signaling. Overall, our results support the hypothesis that platelets play a pathogenic role in CM

Differentially expressed microRNAs in experimental cerebral malaria and their involvement in endocytosis, adherens junctions, FoxO and TGF-β signalling pathways

Cerebral malaria (CM) is the most severe manifestation of infection with Plasmodium, however its pathogenesis is still not completely understood. microRNA (miRNA) have been an area of focus in infectious disease research, due to their ability to affect normal biological processes, and have been shown to play roles in various viral, bacterial and parasitic infections, including malaria. The expression of miRNA was studied following infection of CBA mice with either Plasmodium berghei ANKA (causing CM), or Plasmodium yoelii (causing severe but non-cerebral malaria (NCM)). Using microarray analysis, miRNA expression was compared in the brains of non-infected (NI), NCM and CM mice. Six miRNA were significantly dysregulated between NCM and CM mice, and four of these, miR-19a-3p, miR-19b-3p, miR-142-3p and miR-223-3p, were further validated by qPCR assays. These miRNA are significantly involved in several pathways relevant to CM, including the TGF-β and endocytosis pathways. Dysregulation of these miRNA during CM specifically compared with NCM suggests that these miRNA, through their regulation of downstream targets, may be vitally involved in the neurological syndrome. Our data implies that, at least in the mouse model, miRNA may play a regulatory role in CM pathogenesis.This work was funded by the National Health and Medical Research Council (#1099920 for GEG). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.S