摘要： The nociceptin opioid peptide (NOP) receptor and its endogenous ligand nociceptin/orphanin FQ (N/OFQ) are the fourth members of the opioid receptor and opioid peptide families. Although they have considerable sequence homology to the other family members, they are not considered opioid per se because they do not have pharmacological profiles similar to the other family members. The number of NOP receptors in the brain is higher than the other family members, and NOP receptors can be found throughout the brain. Because of the widespread distribution of NOP receptors, N/OFQ and other peptide and small molecule agonists and antagonists have extensive CNS activities. Originally thought to be anti-opioid, NOP receptor agonists block some opioid activities, potentiate others, and modulate other activities not affected by traditional opiates. Because the effect of receptor activation can be dependent upon site of administration, state of the animal, and other variables, the study of NOP receptors has been fraught with contradictions and inconsistencies. In this article, the actions and controversies pertaining to NOP receptor activation and inhibition are discussed with respect to CNS disorders including pain (acute, chronic, and migraine), drug abuse, anxiety and depression. In addition, progress towards clinical use of NOP receptor-directed compounds is discussed.

关键词： circadian rhythm   chronopharmacology   neurological diseases  

摘要： The importance of circadian rhythm dysfunctions in the pathophysiology of neurological diseases has been highlighted recently. Chronopharmacology principles imply that tailoring the timing of treatments to the circadian rhythm of individual patients could optimize therapeutic management. According to these principles, chronopharmacology takes into account the individual differences in patients' clocks, the rhythmic changes in the organism sensitivity to therapeutic and side effects of drugs, and the predictable time variations of disease. This review examines the current literature on chronopharmacology of neurological diseases focusing its scope on epilepsy, Alzheimer and Parkinson diseases, and neuropathic pain, even if other neurological diseases could have been analyzed. While the results of the studies discussed in this review point to a potential therapeutic benefit of chronopharmacology in neurological diseases, the field is still in its infancy. Studies including a sufficiently large number of patients and measuring gold standard markers of the circadian rhythmicity are still needed to evaluate the beneficial effect of administration times over the 24-hour day but also of clock modulating drugs.

关键词： DNA damage   Nucleotide excision repair   Transcriptional arrest   Neurodegeneration   R-loop   Gene length  

摘要： Human genetic syndromes deficient in nucleotide excision repair (NER), such as xeroderma pigmentosum and Cockayne syndrome, may present neurological abnormalities and premature aging symptoms. Unrepaired endogenously generated DNA damage that hampers transcription is a strong candidate that contributes to the development of these severe effects in neuronal tissue. Endogenous lesions include those generated due to byproducts of cellular metabolisms, such as reactive oxygen species. This review presents much of the evidence on the mechanisms related to neurodegenerative processes associated with DNA damage responses. The primary focus is on the effects of the transcription machinery, including the accumulation of DNA center dot RNA hybrids (R-loops) that, in turn, influence DNA damage and repair metabolism. Moreover, several neuronal tissues present higher expression of long genes, a genomic subset more affected by DNA lesions, which may explain part of the neurological abnormalities in these patients. Also, neuronal tissues have different DNA repair capabilities that might result in different neurological consequences, as observed in patients and NER deficient animal models. The better understanding of how the accumulation of transcription blocking lesions can lead to neurological abnormalities and premature aging-like phenotypes may assist us in finding potential biomarkers and therapeutic targets that might improve the lives of these patients, as well as other neurological disorders in the general population.

关键词： Cardiac arrest   Coma   Prognosis   Short-latency somatosensory evoked poitentials (SSEPs)   Electroencephalogram   Pupillary light reflex  

摘要： Aim: To assess if, in comatose resuscitated patients, the amplitude of the N20 wave (N20amp) of somatosensory evoked potentials (SSEP) can predict 6-months neurological outcome. Setting: Multicentre study in 13 Italian intensive care units. Methods: The N20amp in microvolts (mu V) was measured at 12 h, 24 h, and 72 h from cardiac arrest, along with pupillary reflex (PLR) and a 30-min EEG classified according to the ACNS terminology. Sensitivity and false positive rate (FPR) of N20amp alone or in combination were calculated. Results: 403 patients (age 69[58-68] years) were included. At 12 h, an N20amp >3 mV predicted good neurological outcome (Cerebral Performance Categories [CPC] 1-2) with 61[50-72]% sensitivity and 11[6-18]% FPR. Combining it with a benign (continuous or nearly continuous) EEG increased sensitivity to 91[82-96]%. For poor outcome (CPC 3-5), an N20Amp similar to 0.38 mV, similar to 0.73 mV and similar to 1.01 mV at 12 h, 24 h, and 72 h, respectively, had 0% FPR with sensitivity ranging from 61[51-69]% and 82[76-88]%. Sensitivity was higher than that of a bilaterally absent N20 at all time points. At 12 h and 24 h, a highly malignant (suppression or burst-suppression) EEG and bilaterally absent PLR achieved 0% FPR only when combined with SSEP. A combination of all three predictors yielded a 0[0-4]% FPR, with maximum sensitivity of 44[36-53]%. Conclusion: At 12 h from arrest, a high N20Amp predicts good outcome with high sensitivity, especially when combined with benign EEG. At 12 h and 24 h from arrest a low-voltage N20amp has a high sensitivity and is more specific than EEG or PLR for predicting poor outcome.

关键词： Traumatic brain injury   Microglia   KCNQ1OT1   ceRNA   miR-873-5p  

摘要： Background: Microglia-induced neuroinflammation is one of the main characteristics of traumatic brain injury (TBI). Presently, we aim to investigate the role of long non-coding RNA (lncRNA) KCNQ1 overlapping transcript 1 (KCNQ1OT1) in TBI-induced neurological deficits and the related mechanism. Methods: An in-vivo TBI model was established in mice, and in-vitro experiments were carried out on BV2 microglia. Then the neurological functions, microglial activation, inflammatory cytokines, and proteins were detected. Results: Our data indicated that KCNQ1OT1 was markedly overexpressed in the cerebral tissues of TBI mice, accompanied by a higher level of the cytokines (including IL-1 beta, IL-6, and TNF alpha). However, knocking down KCNQ1OT1 relieved neurological deficits, neuron loss, and blood-brain barrier damage. Besides, overexpressing miR-873-5p enhanced the "M2'' polarization of microglia by repressing the TRAF6-mediated p38 and NF-kappa B pathways. In contrast, downregulating KCNQ1OT1 repressed microglial neuroinflammation by attenuating the "M1'' polarization of microglia and promoting "M2'' polarization of microglia, and inactivating the p38 and NF-kappa B pathway. Conclusions: Mechanistically, KCNQ1OT1 functioned as a competitive endogenous RNA (ceRNA) by sponging miR-873-5p, which targeted the 3' untranslated region (UTR) of TRAF6. Overall, our data confirmed that downregulating lncRNA KCNQ1OT1 exerted neuroprotective effects on TBI mice by modulating the miR-873-5p-TRAF6-p38/NF-kappa B axis.

关键词： depression   neurological disorders   psychometrics   screening  

摘要： Background and purpose There is concern that the Patient Health Questionnaire-9 (PHQ-9) depression scale may be impacted by the presence of somatic symptoms (differential item functioning [DIF]) in patients with neurological conditions. We evaluated the PHQ-9 for the presence and impact of DIF in large clinical samples of neurological patients. Methods We conducted a cross-sectional study of patients seen at the Cleveland Clinic Cerebrovascular, Headache, Movement Disorder, and Neuromuscular clinics who completed the PHQ-9 and patient-reported disease severity measures as part of standard care between 29 July 2008 and 21 February 2013. We evaluated PHQ-9 items for DIF with respect to disease-specific severity for each condition. Salient DIF impact was characterized as a difference between DIF-adjusted and unadjusted PHQ-9 scores. Results Included in the study were 2112 patients with stroke, 8221 with migraine, 440 with amyotrophic lateral sclerosis (ALS), and 5022 with Parkinson disease (PD). Several PHQ-9 items demonstrated DIF with respect to disease-specific severity, although salient DIF was present in very few patients (stroke, n = 0;migraine, n = 1;ALS, n = 13;PD, n = 1). Conclusions PHQ-9 items function consistently across disease severity, with salient levels of DIF impact found only for a very small proportion of people. These results suggest that the PHQ-9 provides a consistent measure of depression severity among people with neurological conditions associated with somatic symptoms that overlap with depression.

关键词： eye‐   movement control   modified ranking scale   paraneoplastic neurological syndromes   saccadic eye movement   smooth pursuit  

摘要： Background and purpose Paraneoplastic neurological syndromes with Hu-antibodies (Hu-PNS) are immune-mediated disorders in patients with malignancies, most frequently small cell lung cancer, affecting both the peripheral and central nervous system (CNS). In Hu-PNS, brainstem and cerebellar involvement are common. Here, we assessed whether eye-movement disturbances can be used for diagnosis and monitoring of CNS involvement in Hu-PNS. Methods Twenty-nine patients with Hu-PNS (17 females;mean age, 63.2 years,) and 14 healthy age-matched controls (seven females;mean age, 60.2 years) were included. Saccadic and smooth pursuit eye movements in response to visual stimuli were recorded with video-oculography. Eye movements were scored quantitatively (number of correction saccades, saccadic intrusions, and saccades during fixation period) and qualitatively by two eye-movement experts. In 20 patients, up to three follow-up measurements were made during subsequent hospital visits with fixed 4-week intervals. Disease course was assessed using the modified Rankin Scale. Results Eye movements were disturbed in 26 of 29 Hu-PNS patients, with horizontal eye movements being in general more impaired. Moreover, in 12 of the 14 Hu-PNS patients without clinical CNS involvement, eye movements were disturbed. Changes in eye-movement control over a period of up to 12 weeks were significantly correlated with the clinical response to treatment (rho = 0.52, p = 0.02). Conclusions Hu-PNS often affects eye-movement control, also in the absence of CNS signs or symptoms. Eye-movement recordings in Hu-PNS patients might be a useful tool to objectively monitor progression and treatment efficacy in Hu-PNS patients.

关键词： Applicants   Diversity   Ethnic   Gender   Neurosurgery residency   Racial   Residents  

摘要： OBJECTIVE: To assess trends in gender, racial, and ethnic diversity of applicant pools and subsequent resident cohorts in neurosurgical residency programs in the United States. METHODS: Applicant and residency data from 2009 to 2018 were analyzed from the Electronic Residency Application Service, Journal of the American Medical Association, and National Resident Matching Program to evaluate trends in diversity. RESULTS: There was no statistically significant difference between applicant sex from 2009 to 2013 compared with 2014 to 2018 (P > 0.05). From 2009 to 2018, the percentage of female residents saw a statistically significant increase from 12.9% to 17.5% but remained less reflective of women's representativeness in the United States (50.8%). The percentage of Black and Hispanic applicants decreased across the observed period (4% and 1%, respectively). While Black people represented 5.2% of the resident pool in 2009, this decreased to 4.95% by 2018. Hispanic residents saw a <2% net increase (5.5% to 7.2%) in resident representation but still fell behind when compared with census statistics. The application pool did not see a significant change in the percentage of White and Asian applicants;however, the percentage of residents did decrease slightly over the observed decade. CONCLUSIONS: Current efforts to improve racial and ethnic diversity have not been sufficient in generating parity in the recruitment and retention of racially under-represented groups in neurosurgery. Although the presence of women in applicant and resident pools has increased,

关键词： Coronavirus   Neurology   Cerebrovascular stroke   Inflammation  

摘要： As the current understanding of COVID-19 continues to evolve, a synthesis of the literature on the neurological impact of this novel virus may help inform clinical management and highlight potentially important avenues of investigation. Additionally, understanding the potential mechanisms of neurologic injury may guide efforts to better detect and ameliorate these complications. In this review, we synthesize a range of clinical observations and initial case series describing potential neurologic manifestations of COVID-19 and place these observations in the context of coronavirus neuro-pathophysiology as it may relate to SARS-CoV-2 infection. Reported nervous system manifestations range from anosmia and ageusia, to cerebral hemorrhage and infarction. While the volume of COVID-19-related case studies continues to grow, previous work examining related viruses suggests potential mechanisms through which the novel coronavirus may impact the CNS and result in neurological complications. Namely, animal studies examining the SARS-CoV have implicated the angiotensin-converting-enzyme-2 receptor as a mediator of coronavirus-related neuronal damage and have shown that SARS-CoV can infect cerebrovascular endothelium and brain parenchyma, the latter predominantly in the medial temporal lobe, resulting in apoptosis and necrosis. Human postmortem brain studies indicate that human coronavirus variants and SARS-CoV can infect neurons and glia, implying SARS-CoV-2 may have similar neurovirulence. Additionally, studies have demonstrated an increase in cytokine serum levels as a result of SARS-CoV infection, consistent with the notion that cytokine overproduction and toxicity may be a relevant potential mechanism of neurologic injury, paralleling a known pathway of pulmonary injury. We also discuss evidence that suggests that SARS-CoV-2 may be a vasculotropic and neurotropic virus. Early reports suggest COVID-19 may be associated with severe neurologic complications, and several plaus