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To solve the problem of spacecraft attitude manoeuvre planning under dynamic multiple mandatory pointing constraints and prohibited pointing constraints, a systematic attitude manoeuvre planning approach is proposed that is based on improved policy gradient reinforcement learning. This paper presents a succinct model of dynamic multiple constraints that is similar to a real situation faced by an in-orbit spacecraft. By introducing return baseline and adaptive policy exploration methods, the proposed method overcomes issues such as large variances and slow convergence rates. Concurrently, the required computation time of the proposed method is markedly reduced. Using the proposed method, the near optimal path of the attitude manoeuvre can be determined, making the method suitable for the control of micro spacecraft. Simulation results demonstrate that the planning results fully satisfy all constraints, including six prohibited pointing constraints and two mandatory pointing constraints. The spacecraft also maintains high orientation accuracy to the Earth and Sun during all attitude manoeuvres. [ABSTRACT FROM AUTHOR]

Abstract: The 3′-untranslated regions (3′-UTRs) of growth-associated protein 43 (GAP-43), which is crucial for neural development and axonal regeneration, are highly conserved among vertebrates. Previous studies in mammals have identified one U-rich cis element within GAP-43 3′-UTR and several trans factors that regulate its mRNA stability. However, much less is known in lower vertebrates. The Xenopus GAP-43 3′-UTR, despite its high similarity with those in higher vertebrates, contains unique CU-rich sequences, suggesting the existence of novel cis elements and trans factors. In current study, we isolated four proteins bound to GAP-43 3′-UTR from juvenile frog brain using affinity purification. Mass spectrometry identified Hu antigen D (HuD) and poly(C) binding protein 2 (αCP2) as the proteins forming 48- and 44-kDa ribonucleoprotein complexes, respectively. We validated the association between αCP2 and GAP-43 3′-UTR in vivo. After confirming the post-transcriptional effects of αCP2 on GAP-43 expression, we demonstrated that αCP2 directly inhibited the translation of GAP-43 gene, without affecting its mRNA stability. αCP2 overexpression led to decreased level of GAP-43 protein and significantly inhibited axonal outgrowth in primarily cultured neurons. Our study therefore provided insights on novel functions of αCP2 in vertebrate nervous system during development and new mechanisms of post-transcriptional regulation for GAP-43 gene. [Copyright &y& Elsevier]

Phosphorylation of the cAMP response element binding protein (CREB) by cAMP-dependent kinase (PKA) is critical to memory formation. However, activation of PKA can also increase tau phosphorylation, which may contribute to memory impairment. Therefore, the regulation of PKA may be part of the mechanism by which glucocorticoids (GCs) influence memory. Additionally, the cellular response to GCs may be affected by the presence of human tau. The goal of this paper was to study GCs-mediated regulation of PKA as well as CREB and tau phosphorylation in wild-type HEK293 cells and HEK293 cells stably expressing human tau441 (HEK293/tau441 cells). By using dexamethasone (DEX) as GCs, we found that DEX induced a tau-dependent selective decrease in the level of PKA RIIβ subunit protein. The observed decrease in RIIβ expression was not due to alterations of mRNA levels and was reversed by inhibiting the proteasome with lactacystin. Moreover, the decrease in RIIβ did not diminish the co-localization of the catalytic subunit of PKA with tau and might contribute to the DEX-induced increase in tau phosphorylation at Ser-214. DEX also induced a tau-dependent decrease in CREB phosphorylation that could not be reversed by activating PKA with forskolin. Taken together, these results show that human tau protein may alter the GCs-mediated regulation of PKA activity and CREB phosphorylation. [ABSTRACT FROM AUTHOR]

Abstract: The present study shows that JAK2-STAT3 inflammatory signaling mediates thrombin-stimulated microglia activation. In rat primary microglia, thrombin rapidly activated JAK2 and induced phosphorylation of STAT3. In addition, thrombin increased transcription of the inflammation-associated genes tumor necrosis factor (TNF)-α, inducible nitric oxide synthase (iNOS), production of TNF-α, NO and induced neurodegeneration of dopaminergic neurons in mesencephalic cultures. AG490, a JAK inhibitor, markedly reduced activation of JAK2 and STAT3 in thrombin-treated microglia. AG490 also inhibited thrombin-induced transcription and expression of TNF-α, iNOS and/or NO release, moreover rescued dopaminergic neurons. These results suggest that JAK2-STAT3 signaling pathway plays a critical role in mediating thrombin-induced activation of microglia and degeneration of dopaminergic neurons. [Copyright &y& Elsevier]

Abstract: The neuroprotective effects of erythropoietin on 1-methyl-4-phenylpyridinium (MPP+)-induced oxidative stress and apoptosis in cultured PC12 cells as well as the underlying mechanism were investigated. Treatment of PC12 cells with MPP+ caused the loss of cell viability, which was associated with the elevation in apoptotic rate, the formation of reactive oxygen species and the disruption of mitochondrial transmembrane potential. It was also shown that MPP+ significantly induced upregulation of Bax/Bcl-2 ratio and activation of caspase-3. In contrast, erythropoietin reversed these phenotypes and had its maximum protective effect at 1 U/ml. The effect of erythropoietin was mediated by the phosphatidylinositol 3-kinase (PI3K) signaling pathway since erythropoietin failed to rescue cells from MPP+ insult in the presence of the PI3K inhibitor, LY 294002. In addition, the downstream effector of PI3K, Akt, was activated by erythropoietin, and Akt activation was inhibited by LY 294002. Furthermore, the effect of erythropoietin on reactive oxygen species levels was also blocked by LY 294002. These results show that erythropoietin may provide a useful therapeutic strategy for the treatment of oxidative stress-induced neurodegenerative diseases such as Parkinson disease. [Copyright &y& Elsevier]

Objective. To explore the efficacy and safety of pramipexole sustained release (SR) versus pramipexole immediate release (IR) in treating nocturnal symptoms in levodopa-treated Chinese patients with advanced Parkinson's disease (PD) and sleep disturbances. Method. SUSTAIN was an open-label, randomised, active-controlled parallel group exploratory pilot study (NCT03521635). A total of 98 patients were randomly allocated (1 : 1) to either pramipexole SR (n = 49) or pramipexole IR (n = 49) groups. The primary endpoint was a change from baseline in PD Sleep Scale 2nd version (PDSS-2) total score at 18 weeks. A reduction in score represents improvement. Secondary endpoints included Nocturnal Hypokinesia Questionnaire, Scales for Outcomes in PD Sleep Scale, Early Morning Off (EMO), Epworth Sleepiness Scale, PD Questionnaire-8, and responder rates as measured by PDSS-2 total score (<18), EMO scores (≥1 point change), Clinical Global Impression Improvement scale, and Patient Global Impression-Improvement scale. Other endpoints included motor complications (MDS-UPDRS part IV) score. Adverse events were evaluated for each group. Results. The mean pramipexole dose for both groups was 1.5 mg/day at week 18, and the mean changes in PDSS-2 total score for pramipexole SR and IR were –13.7 (95% CI –16.0 to –11.4) and –14.4 (–16.8 to –12.0) (difference of 0.7; p = 0.688). Change from baseline for both groups achieved the minimal clinical important difference threshold (MCID = –3.44). No significant difference was observed in change from baseline for other measures of sleep-related disturbances or responder rates. For motor complications, a greater improvement in MDS-UPDRS part IV score was observed in pramipexole SR over IR (–3.4 vs –2.3; treatment group difference: –1.1; p = 0.036). Both groups had comparable safety profiles. Conclusion. In Chinese patients with advanced PD and sleep disturbances, pramipexole SR and IR have similar benefits in the treatment of nocturnal symptoms and safety, and an improvement from baseline in nocturnal symptoms was observed regardless of pramipexole formulation. [ABSTRACT FROM AUTHOR]

Extensive changes occur at transcriptional level after traumatic spinal cord injury (SCI). In this study, we performed a large scale screening of expression changes of long (>200 nt) RNA transcripts including both coding and non-coding RNA species in a rat contusion SCI model. We validated significant down-regulation of one long non-coding RNA (lncSCIR1) at 1, 4, and 7 days postinjury. lncSCIR1 knockdown promoted astrocyte proliferation and migration in vitro . We further validated the strong association between lncSCIR1 knock down and the expression changes of four mRNAs after injury. Our data indicated that lncSCIR1 down-regulation might play a detrimental role in the pathophysiology of traumatic SCI and thereby provided new insights into the studies of potential therapeutic targets for traumatic central nervous system (CNS) injuries. [ABSTRACT FROM AUTHOR]

Although the etiology of Alzheimer's disease (AD) is not fully understood, multiple lines of evidence suggests the importance of amyloid-β (Aβ) in the initiation/progression of the disease. Aβ has been shown to induce neuronal apoptosis via the sphingomyelin/ceramide pathway. This study was designed to elucidate whether the sphingosine kinase-1 (SPK1), a critical regulator of the ceramide/sphingosine 1-phosphate rheostat, plays a pivotal role in the regulation of death and survival of differentiated neuro-2a cells in response to beta-amyloid peptide fragment 25-35 (Aβ25-35). These results show that the expression of SPK1 was markedly decreased in Aβ25-35-induced neurotoxicity, as evidenced by the decreased cell viability and the increased apoptotic rate. Overexpression of SPK1 significantly attenuated Aβ25-35-induced neurotoxicity, whereas silencing the expression of SPK1 exacerbated it. Moreover, overexpression of SPK1 can significantly attenuate Aβ25-35-induced upregulation of Bax and rehabilitate the level of Bcl-2; concomitantly, it can ameliorate mitochondrial ultrastructure. These studies demonstrate that overexpression of SPK1 may moderate Aβ25-35-induced neurotoxicity by regulating the Bcl-2/Bax ratio and improving mitochondrial ultrastructure. Based on these findings, SPK1 is a potential therapeutic target for AD. [ABSTRACT FROM AUTHOR]

Aims Anesthesia is related to cognitive impairment and the risk for Alzheimer's disease. Hypothermia during anesthesia can lead to abnormal hyperphosphorylation of tau, which has been speculated to be involved in anesthesia-induced cognitive impairment. The aim of this study was to investigate whether maintenance of the tau phosphorylation level by body temperature control during anesthesia could reverse the cognitive dysfunction in C57BL/6 mice. Methods Eighteen-month-old mice were repeatedly anesthetized during a 2-week period with or without maintenance of body temperature, control mice were treated with normal saline instead of anesthetics. Tau phosphorylation level in mice brain was detected on western blot, and cognitive performance was measured using the Morris water maze ( MWM). Results After anesthesia-induced hypothermia in old mice, tau was hyperphosphorylated and the cognitive performance, measured on MWM, was impaired. When body temperature was controlled during anesthesia, however, the tau hyperphosphorylation was completely avoided, and there was partial recovery in cognitive impairment measured on the MWM. Conclusion Hyperphosphorylation of tau in the brain after anesthesia is an important event, and it might be, although not solely, responsible for postoperative cognitive decline. [ABSTRACT FROM AUTHOR]

Ciliary neurotrophic factor (CNTF) is a pleiotropic cytokine that has been fully studied for its structure, receptor, and signaling pathways and its multiplex effects on neural system, skeletal muscle, and weight control. Recent research demonstrates that CNTF also plays an important role in neurogenesis and the differentiation of neural stem cells. In this article, we summarize the general characteristics of CNTF and its function on neural stem cells, which could be a valuable therapeutic strategy in treating neurological disorders. [ABSTRACT FROM AUTHOR]

Background: Depression is a common non-motor symptom in patients with Parkinson's disease (PD). There are many kinds of antidepressants being used, such as tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and Dopamine agonists which are suggested as alternative antidepressants for the treatment of depression in PD. Which one should we choose first? Literatures have shown inconsistent results. Methods: We conducted a network meta-analysis of randomized controlled trials to compare the efficacy and acceptability of therapeutic methods for the treatment of depression in Parkinson's disease. Results: We used the odds ratios (OR) as effect size firstly and the results indicated no statistical significance between each compared intervention. Then we used the logarithm of the individual odds ratios as effect size. With efficacy of TCAs as the standard of comparison, the degree of incoherence (a measure of how closely the entire network fits together) was small (ω =  4.824827e-05). The logor were: SSRIs −0.69 (95% CI −1.28– −0.10); Pramipexole −0.73 (−1.71– −0.26); Pergolide −1.97 (−3.67– 0.27); SNRIs −0.86 (−1.86– 0.15); Placebo −1.24 (−1.99– −0.50). With Placebo as the standard of comparison, the logor were: TCAs 1.24 (0.50– 1.99); SSRIs 0.55 (−0.03– 1.13); Pramipexole 0.51 (−0.12– 1.15); Pergolide −0.73 (−2.25– 0.80); SNRIs 0.38 (−0.42– 1.19); TCAs, pramipexole, pergolide and SNRIs showed better profile of acceptability, leading to significant fewer discontinuations than that of SSRIs. Conclusions: There is insufficient evidence to support antidepressant efficacy for SSRIs, pramipexole, pergolide and SNRIs. TCAs might be the best choice when starting antidepressant treatment in patients of Parkinson's disease because it has the most favorable balance between benefits and acceptability, followed by pramipexole and SNRIs, SSRIs might be the last choice. [ABSTRACT FROM AUTHOR]

Abstract: Preventing or reducing tau hyperphosphorylation is considered to be a therapeutic strategy in the treatment of Alzheimer’s disease (AD). Rapamycin may be a potential therapeutic agent for AD, because the rapamycin-induced autophagy may enhance the clearance of the hyperphosphorylated tau. However, recent rodent studies show that the protective effect of rapamycin may not be limited in the autophagic clearance of the hyperphosphorylated tau. Because some tau-related kinases are targets of the mammalian target of rapamycin (mTOR), we assume that rapamycin may regulate tau phosphorylation by regulating these kinases. Our results showed that in human neuroblastoma SH-SY5Y cells, treatment with rapamycin induced phosphorylation of the type IIα regulatory (RIIα) subunit of cAMP-dependent kinase (PKA). Rapamycin also induced nuclear translocation of the catalytic subunits (Cat) of PKA and decreases in tau phosphorylation at Ser214 (pS214). The above effects of rapamycin were prevented by pretreatment with the mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) inhibitor U0126. In addition, these effects of rapamycin might not depend on the level of tau expression, because similar results were obtained in both the non-tau-expressing wild type human embryonic kidney 293 (HEK293) cells and HEK293 cells stably transfected with the longest isoform of recombinant human tau (tau441; HEK293/tau441). These findings suggest that rapamycin decreases pS214 via regulation of PKA. Because tau phosphorylation at Ser214 may prime tau for further phosphorylation by other kinases, our findings provide a novel possible mechanism by which rapamycin reduces or prevents tau hyperphosphorylation. [Copyright &y& Elsevier]

Lipoxins have emerged as mediators of key events in endogenous anti-inflammation and resolution. However, the implication of these novel lipid mediators on neuroinflammation has not been investigated. Microglia is the major cells involved in brain tissue damage during infection and neurodegenerative diseases. One of the major features shared by neuroinflammation conditions is the increased production of reactive oxygen species (ROS) generated by NADPH oxidase activation. In this study, we have examined whether aspirin-triggered lipoxin A (ATL) modulates ROS generation in BV2 cells. Pre-treatment of BV2 cells with ATL blocked ROS production triggered by LPS in the time-dependent and concentration-dependent manner. ATL inhibited the translocation of the cytoplasmic NADPH oxidase subunit p47 to the cell membrane as well as NADPH oxidase activity. Taken together, these results demonstrate that ATL suppresses NADPH oxidase-mediated ROS generation in BV2 microglia cells, strongly indicating that ATL may play an important role against the development and progression of neuroinflammtion. [ABSTRACT FROM AUTHOR]

Abstract: In the absence of a cure for Parkinson''s disease, development of preventive medications for this devastating disease is particularly encouraged. Dl-3-n-butylphthalide (NBP), an established natural antioxidant for clinical stroke treatment in China, can reportedly reduce beta-amyloid-induced neuronal toxicity in cultured neuronal cells, and attenuate neurodegenerative changes in aged rats. However, whether or not NBP confers neuroprotection in parkinsonian models is still unknown. In this study, we investigated the effects of NBP in rotenone models for Parkinson''s diseases. In a cellular model, pretreatment with NBP enhanced cell viability by decreasing nuclear fragmentation, retaining mitochondrial membrane potential, and preventing reactive oxygen species (ROS) from generation. In a rodent model, 2-week treatment with NBP was able to ameliorate apomorphine-evoked rotations by 48% and rescue dopaminergic (DA) neurons by 30% and striatal DA terminal by 49%. Furthermore, NBP upregulated the vesicular monoamine transporter 2 gene expression in vitro and in vivo. Together, NBP protects DA neurons likely by reducing oxidative stress, offering an alternative neuroprotective medication for Parkinson''s disease. [Copyright &y& Elsevier]

Abstract: The 5-hydroxytryptamine 7 (5-HT7) receptor is the most recently classified member of the serotonin receptor family. The localization of 5-HT7 receptors and the biological activity of its ligands have suggested that 5-HT7 receptors might be involved in the pathogenesis of epilepsy. In the present study, we investigated the correlation between temporal lobe epilepsy and 5-HT7 receptors using pilocarpine-induced rat models of temporal lobe epilepsy and surgical samples of temporal neocortex from intractable epilepsy patients. An analysis of electroencephalogram (EEG) and behavioral changes before and after the treatment of SB269970 hydrochloride (a selective 5-HT7 receptor antagonist, 10mg/kg, i.p.) and AS19 (a selective 5-HT7 receptor agonist, 10mg/kg, s.c.) demonstrated that in epileptic rats the activation of 5-HT7 receptors could increase the number of seizures, which could be reduced by a 5-HT7 receptor antagonist. Moreover, the expression of 5-HT7 receptors was higher in the epilepsy group compared with the nonepileptic group in both rat and human brain tissues. The present results suggested that 5-HT7 receptors participate in the pathogenesis of temporal lobe epilepsy, and a 5-HT7 receptor antagonist may be used as a therapeutic alternative for temporal lobe epilepsy. [Copyright &y& Elsevier]

Context. Tetramine is an illegal rat poison that has resulted in a number of accidental mass poisonings in China. Objective. To investigate the long term outcome of tetramine poisoning. Materials and methods. A survey of epileptic attacks in 370 patients in the Hubei province of P. R. China who had survived tetramine poisoning in the last decade was undertaken by means of telephone calls, letters, and interviews. Data describing the initial acute episode was gathered from medical and public health records. Results. Among the 370 patients surveyed (188 males, 182 females, age range 10 to 71 y), 352 experienced seizures during the initial poisoning. One hundred fifty-eight individuals are currently seizure-free, after an average medication period of 2.93 years. The other patients have recurrent epilepsy, including 156 with tonic-clonic seizures and 39 with partial seizures. Six patients have other neurological problems. Discussion and conclusion. Tetramine, a rat poison sometimes ingested by mistake, blocks GABA receptors and causes seizures. These seizures can persist for years after the initial poisoning, even when no seizures are present initially. Sodium valproate, which has the ability to increase the amount of GABA in the CNS, would be a reasonable choice for the treatment of epilepsy caused by tetramine poisoning. [ABSTRACT FROM AUTHOR]

Abstract: Physical and psychological stress can alter the immune system in both humans and animals. Stress is a known risk factor for numerous human diseases, such as infectious and autoimmune diseases, and cancer. Toll-like receptors (TLRs) play a pivotal role in the induction of innate and adaptive immune response. Our previous studies have shown that TLR4 deficiency prevents stress-induced splenocyte reduction. However, the role of TLR2 in stress-mediated lymphocyte reduction is unknown. In this study, we investigated the effects of TLR2 ligands on stress-induced lymphocyte reduction. We also defined whether the phosphoinositide 3-kinases (PI3Ks)/Akt pathway contributes to TLR2-mediated lymphocyte numbers altered by stress. Our data have shown that stimulation of TLR2 by TLR2 ligands peptidoglycan (PGN) or Pam3CSK4 (Pam3) attenuates stress-induced reduction in lymphocyte numbers. However, TLR2 ligand-induced protection from stress-induced lymphocyte reduction is lost in TLR2 deficiency in mice. Furthermore, stimulation of TLR2 by PGN induces protection from stress-induced reduction in the number of splenocytes through PI3K. Moreover, PGN dramatically increases the level of phosphorylation of Akt through a PI3K-dependent manner. Moreover, we found that stimulation of TLR2 by PGN induced protection from stress-induced reduction in splenocyte numbers is abolished in β-arrestin 2 deficient mice. In addition, PGN-induced immune protection in stress-induced changes of cytokine levels appears to require β-arrestin 2, a multifunctional adaptor and signal transducer. Collectively, our study thus demonstrates that stimulation of TLR2-mediated PI3K signaling attenuates splenocyte reduction induced by stress, and that β-arrestin 2 modulates TLR2-mediated immune response following stress. [Copyright &y& Elsevier]

Several studies have shown functional improvements, neuroprotective, and neuroregenerative effects after mesenchymal stem cells transplantation to parkinsonian animal models. However, questions remain about the safety, feasibility, and long-term efficacy of this approach. In this study, we investigated migration, therapeutic, tumorigenesis, and epileptogenic effects of human umbilical cord mesenchymal stromal cells (HUMSCs) 1 year after transplantation into rotenone-induced hemiparkinsonian rats. Our data indicated that DiI-labeled HUMSCs migrated in the lesioned hemisphere, from corpus striatum (CPu) to substantia nigra. By integrating with host cells and differentiating into NSE, GFAP, Nestin, and tyrosine hydroxylase-positive cells, HUMSCs prevented 48.4% dopamine neurons from degeneration and 56.9% dopamine terminals from loss, both correlating with improvement of apomorphine-induced rotations. The CD50 and CD97 value of pentylenetetrazol and semiquantitative immunohistochemical analysis of proliferating cell nuclear antigen (PCNA), β-catenin, C-myc, and NF-κB expression showed no significant difference between HUMSCs transplanted and untransplanted groups, whereas the expressions of Bcl-2 and P53 in the grafted CPu were upregulated by 281% and 200% compared to ungrafted CPu. The results of this long-term study suggest that HUMSCs transplantation, 1 of the most potential treatments for Parkinson''s disease, is an effective and safe approach. [Copyright &y& Elsevier]

Abstract: Dopaminergic neurons are lost mainly through apoptosis in Parkinson''s disease. Insulin like growth factor-1 (IGF-1) inhibits apoptosis in a wide variety of tissues. Here we have shown that IGF-1 protects PC12 cells from toxic effects of 1-methyl-4-phenylpyridiniumion (MPP+). Treatment of PC12 cells with recombinant human IGF-1 significantly decreased apoptosis caused by MPP+ as measured by acridine orange/ethidium bromide staining. IGF-1 treatment induced sustained phosphorylation of glycogen synthase kinase-3beta (GSK-3beta) as shown by western blot analysis. The anti-apoptotic effect of IGF-1 was abrogated by LY294002, which indirectly inhibits phosphorylation of GSK-3beta. Lithium chloride (LiCl), a known inhibitor of GSK-3beta, also blocked MPP+-induced apoptosis. Finally, although IGF-1 enhanced phosphorylation of extracellular signal-regulated kinases ERK1 and 2 (ERK1/2), PD98059, a specific inhibitor of ERK1/2, did not alter the survival effect of IGF-1. Thus, our findings indicate that IGF-1 protects PC12 cells exposed to MPP+ from apoptosis via the GSK-3beta signaling pathway. [Copyright &y& Elsevier]

Abstract: Toll-like receptor 2 (TLR2), a key immune receptor in the TLR family, is widely expressed in various systems, including the immune and nervous systems and plays a critical role in controlling innate and adaptive immune responses. We previously reported that opioids inhibit cell growth and trigger apoptosis. However, the underlying mechanism by which TLR2 mediates apoptosis in response to opioids is not yet known. Here we show that chronic morphine treatment in primary neurons dramatically increased the expression of TLR2 at both the messenger RNA and protein levels. In addition, TLR2 deficiency significantly inhibited chronic morphine-induced apoptosis in primary neurons. Activation of caspase-3 after morphine treatment is impaired in TLR2 deficient primary neurons. Moreover, morphine treatment failed to induce an increased level of phosphorylated glycogen synthase kinase 3 beta (GSK3β) in TLR2 deficient primary neurons, suggesting an involvement of GSK3β in morphine-mediated TLR2 signaling. These results thus demonstrate that opioids prime neurons to undergo apoptosis by inducing TLR2 expression. Our data suggest that inhibition of TLR2 is capable of preventing opioids-induced damage to neurons. [Copyright &y& Elsevier]

Abstract: The hallmarks of Parkinson''s disease (PD) are the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of intracellular inclusion bodies in surviving neurons. Although the specific etiology and pathogenesis of sporadic PD remains unknown, neuronal death was proven to be associated with mitochondrial dysfunction and protein misfolding. However, molecular links between mitochondrial dysfunction and protein misfolding remains obscure. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a classical glycolytic enzyme, is responsible for carbohydrate metabolism under normal circumstances. When translocated to the nucleus, GAPDH promotes neuron apoptosis in several neurodegenerative disorders. But it seems that GAPDH translocation is not the sole mechanism responsible for neuronal apoptosis. We found that rotenone, a common mitochondrial complex I inhibitor used to produce experimental parkinsonism, cannot only induce GAPDH translocation but also trigger intermolecular disulfide bonding and result in the formation of intracytoplasmic aggregates of GAPDH. This suggests a link between mitochondrial dysfunction and protein misfolding, and sheds light on the pathophysiology of Lewy body formation in Parkinson''s disease. [Copyright &y& Elsevier]

Background: Rasagiline is a monoamine oxidase-B inhibitor used for Parkinson's disease (PD) treatment, but its effectiveness on Chinese patients is unclear. This study aimed to evaluate the efficacy and safety of rasagiline monotherapy in Chinese patients with early PD. Methods: A 26-weeks, randomized, double-blind, placebo-controlled study has been performed at 15 sites in China and enrolled outpatients (≥35 years old) with idiopathic PD without a history of using any dopaminergic drugs. Participants were randomized 1:1 to receive rasagiline 1 mg once daily or placebo. The primary endpoint was the change of the Unified Parkinson's Disease Rating Scale (UPDRS) total score from baseline to 26 weeks treatment. Secondary endpoints included changes in UPDRS subscale scores from part I to III. Health status was assessed with the PD Questionnaire (PDQ)-39 and EuroQol-Five-Dimension (EQ-5D) questionnaire. Safety profile was collected until 30 weeks after randomization. Results: A total of 130 patients (n = 65/group) were recruited, and 127 (rasagiline, n = 64; placebo, n = 63) were included in the full analysis set. Baseline characteristics were comparable between the two groups. The decrease in the mean UPDRS total score was greater in the rasagiline group than in the placebo group (− 3.18 ± 0.95 vs. − 0.18 ± 0.98, P = 0.025), and the mean UPDRS part I non-motor symptoms score (− 0.54 ± 0.15 vs. -0.08 ± 0.15, P = 0.003) were significantly decreased in the rasagiline group compared with placebo treated patients. An improvement trend was observed in the active treatment group for the subscales evaluation with parts II and III, while the difference to placebo was not statistically significant. Life quality assessed by the EQ-5D visual analog scale improved in the rasagiline group but worsened in placebo treated patients. The overall incidence of treatment-emergent adverse events (AEs) was slightly lower in the rasagiline group (41.5%) than in the placebo group (46.2%). Conclusions: Rasagiline is effective, safe, and well tolerated as monotherapy for the treatment of Chinese PD patients. Trial registration: Clinicaltrials.gov: NCT01556165. Registered 13 Mar 2012. [ABSTRACT FROM AUTHOR]

Background: The use of adjunct rasagiline in levodopa-treated patients with Parkinson's disease and motor fluctuations is supported by findings from large-scale clinical studies. This study is to investigate the efficacy and safety of adjunct rasagiline in Chinese patients with Parkinson's disease, as a product registration study. Methods: This 16-week, randomized, double-blind, parallel-group, multicenter, placebo-controlled study of rasagiline 1 mg/day included levodopa-treated patients with Parkinson's disease and motor fluctuations. The primary efficacy endpoint was mean change from baseline in total daily OFF time over 16 weeks. Secondary endpoints were Clinical Global Impressions – Improvement (CGI-I), and change in Unified Parkinson's Disease Rating Scale (UPDRS) Activities of daily living (ADL) and Motor scores. Patient well-being (EQ-5D), and the frequency of adverse events were also assessed. Results: In total, 324 levodopa-treated patients were randomized to rasagiline 1 mg/day (n = 165) or placebo (n = 159). Over 16 weeks, rasagiline statistically significantly reduced the mean [95% confidence interval] total daily OFF time versus placebo (− 0.5 h [− 0.92, − 0.07]; p = 0.023). There were also statistically significant improvements versus placebo in CGI-I (− 0.4 points [− 0.61, − 0.22]; p < 0.001), UPDRS-ADL OFF (− 1.0 points [− 1.75, − 0.27]; p = 0.008), and UPDRS-Motor ON (− 1.6 points [− 3.05, − 0.14]; p = 0.032) scores, as well as the EQ-5D utility index (p < 0.05). Rasagiline was safe and well tolerated. Conclusions: In levodopa-treated Chinese patients with Parkinson's disease and motor fluctuations, adjunct rasagiline 1 mg/day statistically significantly reduced OFF time, and improved daily function and overall well-being, versus placebo. Consistent with findings in other countries, adjunct rasagiline was proven efficacious and well tolerated in Chinese patients. Trial registration number: NCT01479530. Registered 22 November 2011. [ABSTRACT FROM AUTHOR]

A letter to the editor that reports a Chinese fatal familial insomnia patient from China with an early onset age and a rapid disease course is presented.