Acute nitrous oxide-induced neuropathy mimicking Guillain-Barré syndrome.

The early clinical features of nitrous oxide (N2 O)-induced neuropathy were mimicking that of Guillain-Barré syndrome (GBS). We aimed to explore clinical and laboratory characteristics of N2 O-induced neuropathy in comparison with GBS. We retrospectively reviewed data of 15 patients with N2 O-induced neuropathy and compared them with 15 GBS patients. The age of the N2 O-induced neuropathy group was significantly younger than that in the GBS group (22 ± 5 vs 45 ± 17). Paresthesia was more common in N2 O-induced neuropathy group (100% vs 53.3%). The proportion of distal upper limbs weakness was lower than that in GBS group (20.0% vs 93.3%). There was no significant difference in the distal weakness of the lower limbs (100% vs 80.0%). The incidence of motor conduction block and compound muscle action potential amplitude reduction in upper limbs was lower than that in GBS group (6.7% vs 60.0%; 26.7% vs 80.0%). The sensory nerve action potential amplitude drop in the lower limbs was more severe than that in GBS group (53.3% vs 0). The increase of Mean corpuscular volume (MCV) was more pronounced compared to GBS group (96.97 ± 6.00 vs 88.55 ± 5.41). High homocysteine levels were more common in N2 O-related group [29.80(11.60, 70.50) vs 14.35(9.22, 19.30)]. Typical clinical features of the acute N2 O neuropathy appears to be a myeloneuropathy, affecting the lower limbs more than the upper limbs, mixed axonal-demyelinating electrophysiological performance, higher homocysteine level, and larger MCV and common posterior spinal cord involvement in cervical segment.

MicroRNA-216a inhibits neuronal apoptosis in a cellular Parkinson's disease model by targeting Bax.

The study found that microRNAs play an important role in Parkinson's disease (PD). However, the function of MicroRNA-216a (miR-216a) in PD is unclear. Therefore, this experiment aimed to investigate the pathogenesis of miR-216a in PD. Using the toxicity of MPP+ to polyhexamine neurons, apoptosis of SH-SY5Y neuroblastoma cells was induced at different time by MPP+ to construct a stable acute PD cell model. The effects of DNA breakage, mitochondrial membrane potential (A ^ m), caspase-3 activity and nucleosome enrichment on cell apoptosis were detected by flow cytometry, TUNEL. MPP+ increased the toxic effects of dopaminergic neurons in a PD model. The introduction of miR-216a inhibited MPP + -induced neuronal apoptosis. The main manifestations were the decreased levels of positive rate of Tunel cells, caspase 3 activity and nucleosome enrichment factor. Bax was a direct target of miR-216a. In addition, Bax overexpression reversed the effects of miR-216a on neural cells. Bax downstream factors were also involved in miR-216a regulation of MPP + -triggered neuronal apoptosis. miR-216a regulated the progression of PD by regulating Bax, and miR-216a may be a potential target for PD.

SIRT3 Acts as a Neuroprotective Agent in Rotenone-Induced Parkinson Cell Model.

SIRT3 is a member of Sirtuins family, which belongs to NAD(+) dependent class III histone deacetylases. Emerging evidence suggests that SIRT3 plays a pivotal role in regulating mitochondrial function. Mitochondrial dysfunction is a main pathogenesis of Parkinson's disease (PD). Here, we have investigated the protective effect of SIRT3 for PD cell model. The rotenone-induced human neuroblastoma SH-SY5Y cells damage was used as PD cell model. The lentiviral vectors were used to over-expression or knockdown SIRT3 expression. The cell viability was analyzed using MTT method. The apoptosis, reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were measured by flow cytometer. Superoxide dismutase (SOD) and glutathione (GSH) were detected by using automated microplate reader. The accumulation of α-synuclein was determined by immunofluorescence staining. SIRT3 knockdown significantly worsen rotenone-induced decline of cell viability (p < 0.01) and enhanced cell apoptosis (p < 0.01), exacerbated the decrease of SOD (p < 0.05) and GSH (p < 0.05), and augmented the accumulation of α-synuclein (p < 0.05). While SIRT3 overexpression dramatically increased cell viability (p < 0.01), and decreased cell apoptosis (p < 0.01), prevented the accumulation of α-synuclein (p < 0.05), suppressed the reducing of SOD (p < 0.05) and GSH (p < 0.01), decreased ROS generation (p < 0.05), and alleviated MMP collapse (p < 0.01) induced by rotenone. SIRT3 has neuroprotective effect in PD cell model and could be developed into a therapeutic agent for PD patients.

Recombinant VLP-Z of JC Polyomavirus: A Novel Vector for Targeting Gene Delivery.

Virus-like particle (VLP) of JC polyomavirus (JCPyV) is capable of packaging and delivering exogenous DNA into human cells and can be used for mediating therapeutic gene expression. However, many human cells express the JCPyV receptor. Thus, wild-type VLP can transduce a wide range of human cells nonspecifically. This study tested the feasibility of using a modified VLP with a IgG binding domain (Z domain) of protein A in its capsid for targeted gene delivery. The Z domain of protein A isolated from the membrane of Staphylococcus aureus was inserted into the NH3-terminus of VP1, the major JCPyV capsular protein. The recombinant VLP-Z was produced using Escherichia coli. Electron-microscopic analysis showed that VLP-Z has a viral-like structure. A hemagglutination test showed that VLP-Z has hemagglutination activity. VP(1) was detected in the nuclei of HeLa cells by immunostaining after VLP-Z inoculation, suggesting that VLP-Z is viable and can enter the cell nucleus. Inoculating HeLa cells with pEGFP-N(1) plasmid packaged in VLP-Z has resulted in enhanced green fluorescent protein expression in the cells. In addition, a binding assay showed that VLP-Z was able to bind IgG through the interaction of the Z domain in VLP-Z and IgG. These data suggest that VLP-Z could be armed with cell-specific antibody and be used to deliver therapeutic genes to target cells.

Sex-dependent interactions between prodromal intestinal inflammation and LRRK2 G2019S in mice promote endophenotypes of Parkinson's disease.

Gastrointestinal (GI) disruptions and inflammatory bowel disease (IBD) are commonly associated with Parkinson's disease (PD), but how they may impact risk for PD remains poorly understood. Herein, we provide evidence that prodromal intestinal inflammation expedites and exacerbates PD endophenotypes in rodent carriers of the human PD risk allele LRRK2 G2019S in a sex-dependent manner. Chronic intestinal damage in genetically predisposed male mice promotes α-synuclein aggregation in the substantia nigra, loss of dopaminergic neurons and motor impairment. This male bias is preserved in gonadectomized males, and similarly conferred by sex chromosomal complement in gonadal females expressing human LRRK2 G2019S. The early onset and heightened severity of neuropathological and behavioral outcomes in male LRRK2 G2019S mice is preceded by increases in α-synuclein in the colon, α-synuclein-positive macrophages in the colonic lamina propria, and loads of phosphorylated α-synuclein within microglia in the substantia nigra. Taken together, these data reveal that prodromal intestinal inflammation promotes the pathogenesis of PD endophenotypes in male carriers of LRRK2 G2019S, through mechanisms that depend on genotypic sex and involve early accumulation of α-synuclein in myeloid cells within the gut.

Molecular signatures underlying neurofibrillary tangle susceptibility in Alzheimer's disease.

Tau aggregation in neurofibrillary tangles (NFTs) is closely associated with neurodegeneration and cognitive decline in Alzheimer's disease (AD). However, the molecular signatures that distinguish between aggregation-prone and aggregation-resistant cell states are unknown. We developed methods for the high-throughput isolation and transcriptome profiling of single somas with NFTs from the human AD brain, quantified the susceptibility of 20 neocortical subtypes for NFT formation and death, and identified both shared and cell-type-specific signatures. NFT-bearing neurons shared a marked upregulation of synaptic transmission-related genes, including a core set of 63 genes enriched for synaptic vesicle cycling. Oxidative phosphorylation and mitochondrial dysfunction were highly cell-type dependent. Apoptosis was only modestly enriched, and the susceptibilities of NFT-bearing and NFT-free neurons for death were highly similar. Our analysis suggests that NFTs represent cell-type-specific responses to stress and synaptic dysfunction. We provide a resource for biomarker discovery and the investigation of tau-dependent and tau-independent mechanisms of neurodegeneration.

Nursing effects of finger exercise on cognitive function and others for cerebral ischemic stroke patients.

OBJECTIVE: To investigate the nursing effects of finger exercise training on cognitive function and others for patients with cerebral ischemic stroke (CIS). METHODS: A total of 200 patients with CIS were selected in this prospective study. According to the random number table method, they were divided into control group (n=100, routine nursing) and research group (n=100, routine nursing combined with finger exercise training). Various scales were used to evaluate the cognitive function, hand function, upper limb motor function, wrist flexor muscle tone, degree of neurological impairment and ability of daily living (ADL) in the two groups before and after intervention. And the incidence of mild vascular cognitive impairment (VCI) after intervention was compared. RESULTS: After intervention, Montreal Cognitive Assessment (MoCA), Mini Mental State Examination (MMSE), hand function, Fugl-meyer Assessment (FMA) and ADL scores in both groups were significantly increased, and those in the research group were significantly higher than those in the control group (all P<0.05). There were opposite trends in the Neurologic Functional Defect (NIHSS) and Modified Ashworth Scale (MAS) for wrist flexor scores (all P<0.05). The incidence of mild VCI in the research group was significantly lower than that in the control group (P<0.05). CONCLUSION: On the basis of early rehabilitation nursing, combined finger exercise training can improve cognitive function, hand function, upper limb function and ADL for patients with CIS.

Effects of a new magnesium-rich artificial cerebrospinal fluid on contractile 5-hydroxytryptamine and endothelin receptors in rat cerebral arteries.

Objectives Cerebral vasospasm after subarachnoid haemorrhage (SAH) is associated with cerebrovascular contractile receptor upregulation resulted from haemolysis in the subarachnoid space. This study developed a new magnesium-rich artificial cerebrospinal fluid (MACSF) formula and investigated its effects on receptor-mediated contraction in rat basilar arteries. Methods Clear and haemorrhagic cerebrospinal fluid (CSF) were collected from patients with hydrocephalus or SAH. MACSF was freshly prepared using clinical intravenous injections. Rat basilar arteries were segmented and incubated with clear CSF, haemorrhagic CSF or MACSF. The contractile responses were studied by myograph. The messenger ribonucleic acid (mRNA) and protein expression of 5-hydroxytryptamine 1B (5-HT1B), endothelin subtype B (ETB) and endothelin subtype A (ETA) receptors were evaluated by real-time polymerase chain reaction (PCR) and Western blot analyses. Results Haemorrhagic CSF exposure shifted the contractile curves induced by 5-hydroxytryptamine (5-HT), sarafotoxins 6c (S6c) and endothelin-1 (ET-1) leftward with increased maximal contraction values. Furthermore, mRNA and protein expression were markedly elevated for 5-HT1B, ETB and ETA receptors on arteries exposed to haemorrhagic CSF. However, the contractile responses to 5-HT, S6c or ET-1 and expression of 5-HT1B, ETB and ETA receptors in rat cerebral arteries exposed to MACSF remained unaffected compared to those exposed to clear CSF. Besides, unlike normal saline which can inactive in-vitro vessels, MACSF can maintain their physiological activity. Conclusion Haemorrhagic CSF induces upregulation of 5-HT1B, ETB and ETA receptors in rat cerebral arteries. However, MACSF can maintain in-vitro rat basilar arteries in good physiological activity and normal expression of contractile 5-HT and ET receptors.

Study of Cbl-b dynamics in peripheral blood lymphocytes isolated from patients with multiple sclerosis.

E3 ubiquitin ligase Casitas B cell lymphoma-b (Cbl-b) has been recently highlighted as a negative regulator of T-cell activation and which dysfunction usually results in autoimmunity. To present, however, the possible involvement of Cbl-b in multiple sclerosis (MS), an autoimmune demyelinating disease mediated by T-helper 1 (Th1) cells is still unclear. To clarify this, using reverse transcriptase polymerase chain reaction (RT-PCR) and Western blot analyses, we thus investigated the levels of Cbl-b mRNA and protein in peripheral blood T-lymphocytes isolated from 11 MS patients in acute relapse phase and 20 cases in remission phase. 16 healthy subjects were used as normal control. Cbl-b mRNA and protein levels were found both significantly down-regulated in peripheral blood lymphocytes isolated from MS patients (P<0.0001). Interestingly, this decrease of Cbl-b protein but not mRNA levels was significantly more marked in samples of relapsed patients than that of remitted cases (P<0.0001). In addition, it was shown that Cbl-b mRNA levels being inversely correlated with the frequency of MS clinical relapses (P<0.0001). Altogether, the data show for the first time that Cbl-b dynamics in peripheral blood T-lymphocyte subset and which possible relationship with the clinical onsets during MS.

SIRT3 Protects Rotenone-induced Injury in SH-SY5Y Cells by Promoting Autophagy through the LKB1-AMPK-mTOR Pathway.

SIRT3 is a class III histone deacetylase that modulates energy metabolism, genomic stability and stress resistance. It has been implicated as a potential therapeutic target in a variety of neurodegenerative diseases, including Parkinson's disease (PD). Our previous study demonstrates that SIRT3 had a neuroprotective effect on a rotenone-induced PD cell model, however, the exact mechanism is unknown. In this study, we investigated the underlying mechanism. We established a SIRT3 stable overexpression cell line using lentivirus infection in SH-SY5Y cells. Then, a PD cell model was established using rotenone. Our data demonstrate that overexpression of SIRT3 increased the level of the autophagy markers LC3 II and Beclin 1. After addition of the autophagy inhibitor 3-MA, the protective effect of SIRT3 diminished: the cell viability decreased, while the apoptosis rate increased; α-synuclein accumulation enhanced; ROS production increased; antioxidants levels, including SOD and GSH, decreased; and MMP collapsed. These results reveal that SIRT3 has neuroprotective effects on a PD cell model by up-regulating autophagy. Furthermore, SIRT3 overexpression also promoted LKB1 phosphorylation, followed by activation of AMPK and decreased phosphorylation of mTOR. These results suggest that the LKB1-AMPK-mTOR pathway has a role in induction of autophagy. Together, our findings indicate a novel mechanism by which SIRT3 protects a rotenone-induced PD cell model through the regulation of autophagy, which, in part, is mediated by activation of the LKB1-AMPK-mTOR pathway.

Expression of TLR4 and TLR9 mRNA in Lewis rats with experimental allergic neuritis.

OBJECTIVE: Experimental autoimmune neuritis (EAN) is a T cell-mediated animal model of the Guillain-Barré syndrome characterized by inflammation and demyelination of the peripheral nervous system (PNS). The key pathogenesis of EAN is the imbalance between Th1- and Th2-type immune response. Toll-like receptor (TLR) is a receptor of the innate immune system. It can recognize the antigen by pathogen-associated molecular patterns, and activate the antigen-presenting cells, producing costimulating molecules to activate T cells. In this study, we observed the expression of mRNA of TLR4 and TLR9 in EAN rats. METHODS: Male Lewis rats were immunized with the component of PNS myelin sheath protein P0 180-199 (100 microg) and Freund's complete adjuvant (CFA). The clinical signs of rats and the pathological changes in the sciatic nerves were observed. The rats in the immunized group and the control group were sacrificed on day 7, 16, 24 and 33 after immunization. To observe the histopathological changes, sciatic nerve was embedded in paraffin, sectioned and stained with HE and Weil's stain. The mRNA expression of TLR4 and TLR9 in spleen, sciatic nerve, peripheral blood monocytes and lymph nodes was detected by reverse transcriptase PCR dynamically. RESULTS: The EAN group reached the peak of the clinical score at day 16 after the immunization, and the clinical manifestation obviously improved at day 33 after the immunization. The mRNA expression of TLR4 peaked at day 16, then decreased gradually, but at day 33, it was still higher than that of the CFA control group (p < 0.05); there were significant differences among the four time points (p < 0.05). The mRNA expression of TLR9 was upregulated during the entire course of EAN compared to the CFA and the control group (p < 0.05). CONCLUSIONS: TLR4 and TLR9 may play a role in the pathogenesis of EAN by taking part in the activation phage and effector phage.

Autophagy-lysosome dysfunction is involved in Aß deposition in STZ-induced diabetic rats.

ß-Amyloid (Aß) deposition has a central role in the pathogenesis of Alzheimer disease (AD). Previous studies have indicated that as a risk factor for AD, diabetes mellitus (DM) could induce Aß deposition in the brain, but the mechanism is not fully elucidated. Autophagy-lysosome is a cellular pathway involved in protein and organelle degradation. In the present study, we used streptozotocin (STZ)-induced diabetic rats to investigate whether autophagy-lysosome is related to Aß1-42 clearance in DM. We found that DM rats had a longer escape latency and less frequent entry into the target zone than that of the control group (p<0.05) in the Morris water maze test. Meanwhile, hippocampal neuron damage and apoptosis (p<0.05) were found in the DM rats. The Aß1-42 expression in the hippocampus significantly increased in the DM group compared with the control group (p<0.05). The markers of autophagy, beclin-1 and LC3 II, were increased (p<0.05), whereas LC3 I was decreased (p<0.05), and the ratio of LC3 II / I was increased as the time advanced (p<0.01). LAMP1 and LAMP2, which are the markers of lysosome function, were decreased in the hippocampus of DM rats (p<0.05). The Aß1-42 deposition was correlated with beclin-1, LC3 II, and LC3 I positively (p<0.05), but with LAMP1 and LAMP2 negatively (p<0.05). These findings indicate that DM activated autophagy, but lysosome function was impaired. Autophagy-lysosome dysfunction may be involved in the Aß deposition in diabetic cognitive impairment.

Sleep Deprivation Induced Plasma Amyloid-ß Transport Disturbance in Healthy Young Adults.

BACKGROUND: Sleep is an important physiological process and beneficial in the removal of brain metabolites and functional recovery. Prior studies have shown that sleep disorders are significant risk factors for Alzheimer's disease (AD). OBJECTIVE: The present study was designed to characterize the effect of short-term total sleep deprivation (TSD) on plasma amyloid-ß (Aß) concentrations. METHODS: A clinical trial was conducted between March 1, 2016, and April 1, 2016. Twenty volunteers (age 27.3±3.4 years) with normal cognitive function and sleeping habits were recruited from the local population. Participants underwent 24 h of TSD. Periprocedural blood samples were collected to compare the changes of plasma Aß42, Aß40, low-density lipoprotein receptor-related protein (sLRP-1), soluble receptors for advanced glycation end products (sRAGE), and serum superoxide dismutase (SOD) and malonaldehyde (MDA). RESULTS: TSD increased morning plasma Aß40 levels by 32.6% (p < 0.001) and decreased the Aß42/Aß40 ratio by 19.3% (p < 0.001). A positive relationship was found between TSD duration and plasma Aß40 level (r = 0.51, p < 0.001) and Aß40/Aß42 ratio (r = 0.25, p = 0.003). Plasma concentrations of sLRP1 (p = 0.018) and sRAGE (p = 0.001) decreased significantly after TSD. Aß40 and Aß42 plasma concentrations correlated with plasma levels of sLRP1 and sRAGE. Serum SOD decreased after TSD (p = 0.005), whereas serum MDA was increased (p = 0.001). CONCLUSION: Sleep deprivation can lead to an elevation of plasma Aß40 and decrease of the Aß42/Aß40 ratio. The underlying mechanisms may be related to increased oxidative stress and impaired peripheral Aß clearance as pathomechanisms of AD.

Celastrol protects human neuroblastoma SH-SY5Y cells from rotenone-induced injury through induction of autophagy.

Celastrol, an active component found in the Chinese herb tripterygium wilfordii has been identified as a neuroprotective agent for neurodegenerative diseases including Parkinson's disease (PD) through unknown mechanism. Celastrol can induce autophagy, which plays a neuroprotective role in PD. We tested the protective effect of celastrol on rotenone-induced injury and investigated the underlying mechanism using human neuroblastoma SH-SY5Y cells. The SH-SY5Y cells were treated with celastrol before rotenone exposure. The cells survival, apoptosis, accumulation of α-synuclein, oxidative stress and mitochondrial function, and autophagy production were analyzed. We found celastrol (500 nM) pre-treatment enhanced cell viability (by 28.99%, P<0.001), decreased cell apoptosis (by 54.38%, P<0.001), increased SOD and GSH (by 120.53% and 90.46%, P<0.01), reduced accumulation of α-synuclein (by 35.93%, P<0.001) and ROS generation (by 33.99%, P<0.001), preserved MMP (33.93±3.62%, vs. 15.10±0.71% of JC-1 monomer, P<0.001) and reduced the level of cytochrome C in cytosol (by 45.57%, P<0.001) in rotenone treated SH-SY5Y cells. Moreover, celastrol increased LC3-II/LC3 I ratio by 60.92% (P<0.001), indicating that celastrol activated autophagic pathways. Inhibiting autophagy by 3-methyladenine (3-MA) abolished the protective effects of celastrol. Our results suggested that celastrol protects SH-SY5Y cells from rotenone induced injuries and autophagic pathway is involved in celastrol neuroprotective effects.

Methylphenidate improves spatial memory of spontaneously hypertensive rats: evidence in behavioral and ultrastructural changes.

The purpose of this study was to investigate the effects of methylphenidate on the spatial learning and memory ability and synaptic ultrastructure in the hippocampal CA3 region of the spontaneously hypertensive rat, a rat model of attention deficit hyperactivity disorder. The methylphenidate group and model group were respectively administered the drug (10mg/kg, i.p.) and saline 30 min before place navigation on 6 consecutive days, a control group of Wistar Kyoto rats were administered saline in the same way. Transmission electron microscopic and imaging analyses were then used to detect and analyze any microstructural changes. The performance of the model rats treated with the drug was the best in the probe test. In addition, three parameters including the length of the active zone, the thickness of the postsynaptic density and the synaptic curvature were measured to show the significant synaptic configuration changes in the methylphenidate group in comparison to the model group. Therefore, these ultrastructural changes in the hippocampal CA3 region may be one of the mechanisms by which methylphenidate improves the spatial memory ability of spontaneously hypertensive rats. The Wistar Kyoto rats showed a significantly decreased latency for finding the platform from the second day in spite of a floating characteristic, while in the probe test, their performance was close to that of the model rats. Finally, morphological evidence suggested the model rats to have a cognitive impairment in comparison to the control group and their better performance was possibly due to the physiological hyper-response of WKY in the water maze tasks.

[Creativity and personality analysis in 302 medical students using personality questionnaires].

OBJECTIVE: To evaluate the creativity of medical students and study their personality characteristics using personality questionnaires. METHODS: This investigation was conducted among 310 medical students using 16 Personality Factor Questionnaire (16PF) and Eysenck Personality Questionnaire (EPQ). RESULTS: A total of 302 students completed the questionnaires. The male and female students showed significant differences in two sub-factors with similar creativity. Four subfactors were identified to positively or inversely correlate to the creativity. The number of male students without either high or low scores was greater than that of female students. The incidences of abnormal scores in 16PF showed significant difference between students with typical EPQ scores and those with atypical scores for introversion-extroversion. CONCLUSIONS: These medical students do not show high creativity in this study. Compared with the male medical students, the female students are more likely to have extroverted personality, and their scores for 16 basic personality factors easily exceed the normal ranges, suggesting the necessity of mental health education. The students with at least 5 abnormal scores in 16PF may show a typical introversion-extroversion personality, and individual psychological counseling can be considered when necessary.