关键词： Oxaliplatin   Neuropathy   Hereditary   Risk factors   Charcot-Marie-tooth disease   Chemotherapy  

摘要： Oxaliplatin therapy can be complicated by chemotherapy-induced peripheral neuropathy (CIPN). Other neurotoxic chemotherapies have been linked to single nucleotide variants (SNV) in Charcot-Marie-Tooth disease (CMT) genes. Whether oxaliplatin carries increased risks of CIPN due to SNV in CMT-associated genes is unknown. 353 patients receiving oxaliplatin in NCCTG N08CB were serially evaluated for CIPN using a validated patient-reported outcome (PRO) instrument, the CIPN20 questionnaire (sensory scale). 49 canonical CMT-associated genes were analyzed for rare and common SNV by nextgen sequencing. The 157 patients with the highest and lowest susceptibility to CIPN (cases and controls) harbored 270 nonsynonymous SNV in CMT-associated genes (coding regions). 143 of these were rare, occurring only once ("singletons"). CIPN cases had 0.84 singletons per patient compared with 0.98 in controls. An imbalance in favor of cases was noted only in few genes including PRX, which was previously highlighted as a candidate CIPN gene in patients receiving paclitaxel. However, the imbalance was only modest (5 singleton SNV in cases and 2 in controls). Therefore, while singleton SNV were common, they did overall not portend an increased risk of CIPN. Furthermore, testing CMT-associated genes using recurrent non-synonymous SNV did not reveal any significant association with CIPN. Genetic analysis of patients from N08CB provides clinical guidance that oxaliplatin chemotherapy decisions should not be altered by the majority of SNV that may be encountered in CMT-associated genes when common genetic tests are performed, such as exome or genome sequencing. Oxaliplatin's CIPN risk appears unrelated to CMT-associated genes.

关键词： Attitudes   Care   End of life   Neurology   Reliability   Validity  

摘要： Background Knowing the opinions of patients with Progressive Neurological Diseases (PNDs) and their family members on end-of-life care can help initiate communication and the drawing up of a care plan. The aim of this paper is to describe the creation and psychometric properties of the newly developed APND-EoLC questionnaire (the Attitudes of Patients with Progressive Neurological Disease to End of Life Care questionnaire). Methods Following focus group discussion, four main areas of interest were identified: patients' and family members' attitudes towards end-of-life care, factors influencing decisions about treatment to prolong patients' life, concerns and fears regarding dying, and opinions on the system of care. The created questions were divided into domains based on factor analysis and psychometric properties were evaluated by sample of 209 patients with PND and 118 their family members. Results The final version of the scale contains a total of 28 questions divided into six domains (end-of-life control, keeping patients alive, trust in doctors/treatment, trust in social support, sense of suffering, and dependence/loss of control) and five individual questions determining views of the care system with specified response options. Construct validity was verified by confirmatory factor analysis for each evaluated area individually. Appropriate psychometric properties were identified in the questionnaire. Conclusions The APND-EoLC questionnaire can be recommended for use in both research and clinical practice.

关键词： Traumatic brain injury   Methamphetamine   Addiction   Interplay   Neurological outcomes  

摘要： Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality in the world. TBI causes permanent physical, cognitive, social, and functional impairments. Substance use and intoxication are established risk factors for TBI. Data are emerging that also suggest that brain injury might be a risk factor for substance use. Methamphetamine (METH), a highly addictive psychostimulant, has not been thoroughly investigated in the context of TBI exposure. The interplay between the two has been of interest as their pathophysiology intertwines on many levels. However, the knowledge concerning the association between TBI-METH and the impact of chronic METH use on short and long-term TBI outcomes is equivocal at best. In this review of the literature, we postulate that, when combined, these two conditions synergize to result in more significant neuronal damage. As such, chronic exposure to METH before brain trauma may accentuate the pathophysiological signs of injury, worsening TBI outcomes. Similarly, individuals with a history of TBI would be more vulnerable to METH misuse and harmful effects. We, therefore, review the most recent preclinical and clinical data tackling the significant overlap in the pathophysiology of TBI and METH at three levels: the structural level, the biochemical level, and the cellular level. We also highlight some controversial results of studies investigating the outcomes of the interaction between TBI and METH.

关键词： Prostaglandin D2 synthase   Sleep disorders   Neurodegenerative diseases   Daytime sleepiness  

摘要： Background: Prostaglandin D2 (PGD2) induces sleep and may play a role in sleep and neurological disorders. We investigated PGD synthase (PGDS) levels in various sleep and neurological disorders. Methods: Sixty-three patients with neurological or sleep disorders (Parkinson's disease with excessive daytime sleepiness (PDS), n = 19;PD without sleepiness (PDWS), n = 14;Alzheimer's disease (AD), n = 10;narcolepsy (NA), n = 10;sleep apnea syndrome (SAS), n = 10) and 21 healthy controls were included in this study. Plasma lipocalin-type PGDS (L-PGDS) and glutathione-dependent hematopoietic PGDS (H-PGDS) levels were assessed using an enzyme-linked immunosorbent assay. Results: H-PGDS levels were not significantly different among the groups. Compared with healthy controls, the PDWS, PDS and AD groups had higher levels of L-PGDS. Neither H-PGDS nor L-PGDS levels correlated with scores on the Epworth Sleepiness Scale or Pittsburgh Sleep Quality Index in any group. Conclusion: We found higher levels of L-PGDS in patients with neurodegenerative diseases such as PD and AD. Whether increased L-PGDS levels reflect underlying sleepiness or the pathophysiology of neurodegenerative diseases needs further study.

关键词： Paraneoplastic syndrome   Immune checkpoint inhibitor   Anti-PD-1 inhibitor   Nivolumab, anti-Hu antibody   Neurologic immune related adverse events  

摘要： We present an illustrative case of a 62-year-old woman with small cell lung cancer who developed progressive worsening of pre-existing anti-Hu antibody associated sensory neuronopathy after treatment with programmed cell death-1 (PD-1) inhibitor, nivolumab. We review the literature and identify 6 reported cases to understand the clinical outcomes of patients with anti-Hu paraneoplastic neurologic syndrome (PNS) treated with anti-PD-1 treatment. The PNS clinical spectrum comprised of encephalitis, a combination of sensory neuronopathy and anti-NMDAR encephalitis, isolated sensory neuronopathy, and encephalomyelitis. Immune checkpoint inhibitor have the potential to worsen pre-existing anti-Hu PNS and may promote the development of anti-Hu PNS.

关键词： Neurotransmission   Brain Reward Cascade (BRC)   Opioid Use Disorder (OUD)   Endorphinergic mechanisms   Dopamine release and homeostasis   Genetic testing of addiction liability   Reward Deficiency Syndrome (RDS)   Endorphinergic deficiency syndrome   Opioid deficiency syndrome   Dopamine deficiency syndrome   Precision Addiction Management (PAM)  

摘要： The consensus of the current literature strongly supports the concept that brain neurotransmitters, and second messengers involved in the net release of dopamine in the mesolimbic region, especially the Nucleus Accumbens (NAc), is directly linked to motivation, anti-stress, incentive salience (wanting), and well-being. The role of dopamine in terms of alcohol withdrawal symptomology, cocaine craving behavior, dopamine -condensation products (TIQs), and more recently, the genetic aspects of drug-seeking and pro-dopamine regulation, provide compelling evidence of the relevant molecular neurological correlates of dopaminergic /endorphinergic mechanisms in reward circuitry due to genetic polymorphisms and epigenetic insults. In the face of an Americans opioid epidemic, the clinical consensus is to treat Opioid Use Disorder (OUD) with life-long opioid substitution therapy. However, the authors suggest a paradigm shift involving novel modalities like targeting the endorphinergic system linked to dopamine release at the NAc, in terms of the induction of required "dopamine homeostasis." Utilizing the known genetic - environmental interaction theorem P = G + E, the authors provide a clear rationale for the adoption of genetic risk testing coupled with endorphinergic/dopamine regulation to address dysfunction across the brain reward circuitry. The goal of altering resting-state, functional connectivity may require a gentle "neurotransmitter fix" vis enkephalinase inhibition to overcome or combat - self-induction of acute dopamine release via psychoactive substance misuse resulting in chronic dopamine down-regulation. As subsets of reward deficiency, we are poised to provide novel, genetically guided therapy for endorphinergic, opioidergic, and dopaminergic deficiencies and related syndromes, utilizing "Precision Addiction Management.

摘要： Lung-protective ventilation I We recommend a lung-protective ventilation strategy consisting of low tidal volumes (6-8 mL/kg), high positive end-expiratory pressure i ( I PEEP) (at least 8 cm H i I SB 2 sb i I 0) and recruitment manoeuvres after ventilator disconnections in potential lung donors (strong recommendation i , I moderate-certainty evidence) i . All 3 studies showed an improved lung procurement rate with implementation of their comprehensive lung donor management strategies, and 1 of the 3 studies showed increased recipient survival.[28] The committee considered potential drawbacks not explored in these studies. Given that the evidence for a benefit from lung-protective ventilation is greatest for lung donation, we considered narrowing our recommendations to potential lung donors only. Achieving donor management goals before deceased donor procurement is associated with more organs transplanted per donor. [Extracted from the article]

关键词： Nicotine   ROS   autophagy   melatonin  

摘要： Purpose: The aim of this study was to explore the mechanism of neurological changes underlying the toxicity of nicotine. Materials and methods: Rat pheochromocytoma 12 (PC12) cells and human neuroglia (HM) cells were used. The ROS levels of the cells were detected by the FACScan. Autophagy flux was monitored by a tandem monomeric RFP-GFP-tagged LC3 lentivirus. The autophagic proteins LC3, SQSTM1/p62 and Beclin1 were detected by western blot assay. In order to evaluate the effects of nicotine and melatonin on the morphological changes of neurons, primary cortical neurons were obtained and immunocytochemistry of TUBB3 tubulin were conducted. Results: Nicotine increased the levels of reactive oxygen species (ROS) in PC12 and HM cells in a concentration-dependent manner. Microscopy showed increased autophagic flux in nicotine-treated PC12 cells. Subsequent western blotting results showed that nicotine induced increase in the levels of LC3B-II and Beclin1, and decreased SQSTM1/p62 in a concentration-dependent manner. Finally, nicotine treatment reduced the length of TUBB3-positive axons and dendrites. Melatonin, a mitochondrially targeted antioxidant, reduced the ROS level, and blocked autophagy activation and the morphologic structural changes induced by nicotine. Conclusions: Our results suggested that the role of nicotine in neuronal toxicity maybe through the induction of ROS and the subsequent activation of autophagy. These effects could be restored by melatonin.

关键词： neurological disorders   Parkinson's disease   Alzheimer's disease   glioblastoma   epilepsy   multiple sclerosis   nose-to-brain   blood brain barrier   nanoformulations  

摘要： Although the global prevalence of neurological disorders such as Parkinson's disease, Alzheimer's disease, glioblastoma, epilepsy, and multiple sclerosis is steadily increasing, effective delivery of drug molecules in therapeutic quantities to the central nervous system (CNS) is still lacking. The blood brain barrier (BBB) is the major obstacle for the entry of drugs into the brain, as it comprises a tight layer of endothelial cells surrounded by astrocyte foot processes that limit drugs' entry. In recent times, intranasal drug delivery has emerged as a reliable method to bypass the BBB and treat neurological diseases. The intranasal route for drug delivery to the brain with both solution and particulate formulations has been demonstrated repeatedly in preclinical models, including in human trials. The key features determining the efficacy of drug delivery via the intranasal route include delivery to the olfactory area of the nares, a longer retention time at the nasal mucosal surface, enhanced penetration of the drugs through the nasal epithelia, and reduced drug metabolism in the nasal cavity. This review describes important neurological disorders, challenges in drug delivery to the disordered CNS, and new nasal delivery techniques designed to overcome these challenges and facilitate more efficient and targeted drug delivery. The potential for treatment possibilities with intranasal transfer of drugs will increase with the development of more effective formulations and delivery devices.