Association analyses of apolipoprotein E genotypes and cognitive performance in patients with Parkinson's disease.

BACKGROUND: Cognitive impairment is a common non-motor symptom of Parkinson's disease (PD). The apolipoprotein E (APOE) ε4 genotype increases the risk of Alzheimer's disease (AD). However, the effect of APOEε4 on cognitive function of PD patients remains unclear. In this study, we aimed to understand whether and how carrying APOEε4 affects cognitive performance in patients with early-stage and advanced PD. METHODS: A total of 119 Chinese early-stage PD patients were recruited. Movement Disorder Society Unified Parkinson's Disease Rating Scale, Hamilton anxiety scale, Hamilton depression scale, non-motor symptoms scale, Mini-mental State Examination, Montreal Cognitive Assessment, and Fazekas scale were evaluated. APOE genotypes were determined by polymerase chain reactions and direct sequencing. Demographic and clinical information of 521 early-stage and 262 advanced PD patients were obtained from Parkinson's Progression Marker Initiative (PPMI). RESULTS: No significant difference in cognitive performance was found between ApoEε4 carriers and non-carriers in early-stage PD patients from our cohort and PPMI. The cerebrospinal fluid (CSF) Amyloid Beta 42 (Aß42) level was significantly lower in ApoEε4 carrier than non-carriers in early-stage PD patients from PPMI. In advanced PD patients from PPMI, the BJLOT, HVLT retention and SDMT scores seem to be lower in ApoEε4 carriers without reach the statistical significance. CONCLUSIONS: APOEε4 carriage does not affect the cognitive performance of early-stage PD patients. However, it may promote the decline of CSF Aß42 level and the associated amyloidopathy, which is likely to further contribute to the cognitive dysfunction of PD patients in the advanced stage.

Carpets with visual cues can improve gait in Parkinson's disease patients: may be independent of executive function.

BACKGROUND: Gait impairment is common in Parkinson's disease (PD) patients, which greatly reduces their quality of life. Executive dysfunction is associated with gait impairment. Compensatory strategies, including visual cues, have been shown to be effective in improving PD gait. In this study, we aimed to understand whether carpets with visual cues could improve PD gait, and how the improvement varies across patients with different executive function state. METHODS: We designed carpets with chessboard and stripe cues. A total of 65 Chinese PD patients were recruited. Movement Disorder Society Unified Parkinson's Disease Rating Scale, L-dopa equivalent daily dosage, Hoehn & Yahr stage, Frontal Assessment Battery, Mini Mental State Examination Scale, Hamilton Anxiety Scale, and Hamilton Depression Scale were evaluated. Gait parameters including stride length, gait speed and fall risk were recorded by a wearable electronic device. RESULTS: The stride length and gait speed were significantly improved and the fall risk was significantly mitigated when PD patients walked on carpets with chessboard and stripe patterns. Further analysis showed the amelioration of gait parameters was independent of executive dysfunction. CONCLUSIONS: Our study demonstrates that carpets with visual cues can improve the gait of PD patients even in those with mild executive dysfunction.

[Corrigendum] Knockdown of HOXA10 reverses the multidrug resistance of human chronic mylogenous leukemia K562/ADM cells by downregulating P­gp and MRP­1.

Following the publication of the above article, an interested reader drew to the authors' attention that, in Fig. 2 on p. 1408, the microscopic images shown for the light scope images (upper row) and the green fluorescence images (lower row) appeared to be overlapping, such that these images appeared to have been derived from the same original sources even though they were intended to portray the results from differently performed experiments. After having re­examined their figures, the authors realized that this figure was assembled incorrectly. The revised version of Fig. 2, showing the correct data for all four experimental panels, is shown below. Note that the errors made during the assembly of these figures did not affect the overall conclusions reported in the paper. All the authors agree with the publication of this corrigendum, and are grateful to the Editor of International Journal of Molecular Medicine for allowing them the opportunity to publish this. They also apologize to the readership for any inconvenience caused. [International Journal of Molecular Medicine 37: 1405­1411, 2016; DOI: 10.3892/ijmm.2016.2539].

Isolated unilateral oculomotor palsy caused by pure midbrain infarction: a case report.

Purpose: Multiple etiologies may cause oculomotor nerve palsies. Identification of different etiologies is very important for subsequent treatment. Midbrain infarction is a rare cause of oculomotor nerve palsy. Materials and methods: We herein present a case of isolated unilateral oculomotor paresis caused by pure midbrain infarction. Results: Her pupillary sphincter and inferior rectus muscles were selectively spared. The symptoms were completely relieved after two months of antiplatelet therapy. We proposed that fibers from Edinger-Westphal nucleus and inferior rectus nucleus do not course through the paramedian area of the midbrain. Conclusions: Our report adds to the understanding of fascicles arrangement in the midbrain.

A series of fluorescent dyes based on 4-phenylacetylene-1,8-naphthalimide: Synthesis, theoretical calculations, photophysical properties and application in two-color imaging and dynamic behavior monitoring of lipid droplets and lysosomes.

A series of fluorescent dyes (NapPAs) based on 4-phenylacetylene-1,8-naphthalimide were synthesized and characterized, whose conjugated structures were extended by the introduction of phenylethynyl. Furthermore, changes in the photophysical properties of the dyes when substituents with varying electron richness were introduced at the p-position of phenylacetylene were studied. The theoretical calculation of the dye molecules was carried out by B3LYP functional and 6-31G(d,p) basis set, and the effects of different substituents at the p-position of phenylacetylene on the electronic structure and photophysical properties of the dyes were studied by theoretical calculation results. Theoretical calculations provided a reliable means of predicting the properties of dyes, which could help in the design of more efficient and novel dyes. To verify the practicability of the dyes, two dyes with excellent photophysical properties (large Stokes shift, high polarity-viscosity sensitivity, good biocompatibility) were selected as fluorescent probes for visualization of LDs and two-color imaging of LDs and lysosomes. Cell imaging showed that NapPA-LDs and NapPA-LDs-Lyso serve as excellent imaging tools to monitor the dynamic changes, movements, and behaviors of LDs and lysosomes in real time. Notably, NapPA-LDs-Lyso held promise as a potential tool to study the interaction between LDs and lysosomes.

Viscosity & SO2-sensitive dual colorimetric effect fluorescent sensor enabled imaging detection within plant onion and biological system.

The biological microenvironment includes important parameters such as viscosity, polarity, temperature, oxygen content and pH. In particular, abnormal cell viscosity is associated with the development of major diseases. Sulphur dioxide (SO2) serves not only as an essential atmospheric pollutant but also an influential signalling molecule in biological cells, predisposing individuals to increased respiratory disease. In this work, we designed and synthesized a novel fluorescent probe CouCN-V&S with dual response to micro environmental viscosity and SO2. The probe monitored viscosity and SO2 separately through dual emission channels with a difference of 135 nm. The probe responded sensitively to SO2 (<1s) and exhibited satisfactory immunity to interference and pH stability. The probe was successfully applied to imaging cellular, intra-zebrafish viscosity and SO2 changes. Interestingly, we took onion epidermal cells as model and explored the capability of probe CouCN-V&S to image SO2 in plant cells for the first time.

Effect of different substituents on the fluorescence properties of precursors of synthetic GFP analogues and a polarity-sensitive lipid droplet probe with AIE properties for imaging cells and zebrafish.

The green fluorescent protein (GFP) is a purely natural specialty protein that has been widely used to design synthetic fluorescent probes. In the present work we designed and synthesized a series of fluorescent compounds akin to GFP precursors by a one-step method, and investigated the luminescence properties of the fluorescent compounds by varying the substituents. We presented the first systematic summary of the photophysical data including extinction coefficients and fluorescence quantum yields for this class of fluorescent dyes. We also carried out density functional theory (DFT) calculations for these dyes to investigate the effect of electronic effects due to different substituents. These studied optical properties may provide a reference for later probe design. More interestingly, we have developed a polarity-sensitive lipid droplet probe T-LD with AIE properties on this basis. The probe exhibited not only favorable pH stability and kinetic stability in terms of optical properties, but also solvent discolouration and polarity-sensitive properties, and was able to label intracellular lipid droplets. We successfully applied the probe for intracellular lipid droplet level monitoring and zebrafish imaging.

π-Extended BTD Derivatives: Synthesis, Photophysical Properties, and Applications in Biological Systems Imaging for Discriminating Living and Dead Cells.

Here, π-Extended BTD derivatives were successfully synthesized by Heck coupling reaction, which exhibited the the advantages of simplicity and efficiency, wild substrate scope, easily available substrates and high yield. The fluorescent probe PEG-BTDAr targeting LDs was successfully prepared by the nucleophilic substitution reaction between the Heck coupling reaction product 3 h and Amino polyethylene glycol monomethyl ether (Mn=2000). PEG-BTDAr exhibited the advantages of high selectivity, good stability and pH resistance. The use of PEG as a substrate gave PEG-BTDAr good biocompatibility. It was worth mentioning that PEG-BTDAr could not only track LDs in cells under different physiological conditions, but also distinguish between living and dead cells in biological systems.

Gene-wide significant association analyses of DNMT1 genetic variants with Parkinson's disease.

Background: DNA methylation plays an important role in Parkinson's disease (PD) pathogenesis. DNA methyltransferase 1 (DNMT1) is critical for maintaining DNA methylation in mammals. The link between DNMT1 polymorphisms and PD remains elusive. Methods: The DNMT1 gene contained a total of 28 single nucleotide polymorphisms (SNPs). Four representing tag-SNPs (rs16999593, rs2162560, rs11880553, and rs9305012) were identified and genotyped in a Han Chinese population comprising 712 PD patients and 696 controls. Association analyses were performed at gene-wide significance (p < 1.8 × 10-3). Results: Rs9305012, but not the other 3 tag-SNPs, was gene-wide significantly associated with PD risk (p = 0.8 × 10-3). The rs9305012/C was a protective allele against PD (p = 1.5 × 10-3, OR 0.786, 95% CI 0.677-0.912). No significant association was observed in individual genders or PD subtypes. Haplotypes of the 4 tag-SNPs showed a significant overall distribution difference between PD patients and controls (p < 1 × 10-4). The 3-allele ACC module in the order of rs2162560, rs11880553, and rs9305012 was the highest-risk haplotype associated with PD (p < 1 × 10-4, OR 2.439, 95% CI 1.563-3.704). Rs9305012 displayed certain probability to affect transcription factor binding and target gene expression based on functional annotation analyses. Conclusion: The DNMT1 variant rs9305012 together with its haplotypes may gene-wide significantly modulate PD susceptibility. Our results support a role of DNMT1 in PD pathogenesis and provide novel insights into the genetic connection in between.

Reduced platelet 5-HT content is associated with rest tremor in Parkinson's disease.

INTRODUCTION: Parkinson's disease (PD) is highly heterogeneous in manifestations and pathogenesis. Serotonergic neurotransmitter system dysfunction is frequently implicated in PD tremor. Serotonin (5-HT) content in platelets is highly correlated with that in cerebrospinal fluid. In this study, we aimed to understand whether and how platelet 5-HT content reflects tremor in PD. METHOD: A total of 139 Chinese PD patients met with inclusion criteria were recruited. Motor and non-motor scores, and disease severity were evaluated. Patients were classified into subtypes of tremor-dominant (TD) and non-tremor-dominant (NTD). Peripheral platelets were isolated, and platelet 5-HT levels were measured. RESULTS: Platelet 5-HT content was lower in PD patients of TD subtype than in NTD subtype. Multifactor risk analysis showed that this lower content was independently associated with the TD phenotype. Platelet 5-HT level was inversely correlated with total tremor score, rest tremor amplitude score, rest tremor constancy score, and index of rest tremor, but not with postural tremor score, and kinetic tremor score. CONCLUSION: The cross-sectional study demonstrates that reduced platelet 5-HT content is associated with PD rest tremor. Our results support the involvement of serotonergic disturbance in PD rest tremor and indicate that 5-HT reduction can be manifested in peripheral platelets.

A novel fluorescent probe with ACQ-AIE conversion by alkyl chain engineering for simultaneous visualization of lipid droplets and lysosomes.

The AIE bio-probes have attracted extensive attention because of their good brightness, long-term in situ retention ability, photostability and low cytotoxicity. Recently, the transformation of ACQ to AIE has become very popular, which is very important for the further development of AIE probes. Herein, a series of novel dyes (NR-Lyso-Ⅰ, NR-Lyso-Ⅱ, NR-Lyso-III, NR-Lyso-IV) were designed and synthesized. It was found that alkylation of 4-aminonaphthalimide could achieve the transformation of the dye from ACQ to AIE effect due to the growth of carbon chain. Moreover, the AIE probe NR-Lyso-IV exhibited dual-state emission (DSE) and large Stokes shift (＞100 nm), excellent selectivity, photostability, and low cytotoxicity, which was able to simultaneous visualize the lipid droplets (LDs) and lysosomes of HeLa cells and zebrafish.

Neck pain and absence of cranial nerve symptom are clues of cervical myelopathy mimicking stroke: Two case reports.

BACKGROUND: Cervical myelopathy is a potential stroke imitator, for which intravenous thrombolysis would be catastrophic. CASE SUMMARY: We herein present two cases of cervical myelopathy. The first patient presented with acute onset of right hemiparesis and urinary incontinence, and the second patient presented with sudden-onset right leg monoplegia. The initial diagnoses for both of them were ischemic stroke. However, both of them lacked cranial nerve symptom and suffered neck pain at the beginning of onset. Their cervical spinal cord lesions were finally confirmed by cervical computed tomography. A literature review showed that neck pain and absence of cranial nerve symptom are clues of cervical myelopathy. CONCLUSION: The current report and the review remind us to pay more attention to these two clues in suspected stroke patients, especially those within the thrombolytic time window.

Case report: Blepharospasm in peak-dose dyskinesia may benefit from amantadine in Parkinson's disease.

Introduction: Blepharospasm is uncommon in Parkinson's disease, especially in the peak-dose dyskinesia period. Case presentation: We herein present the case of a patient with PD who developed blepharospasm in the peak-dose dyskinesia period. The symptom was improved by taking amantadine. Conclusion: The current report expands the phenomenology of peak-dose dykinesia in PD to include dystonic blepharospasm. This complication of levodopa therapy may respond to amantadine despite the dystonic appearance of movements.

Viscosity-Sensitive Solvatochromic Fluorescent Probes for Lipid Droplets Staining.

Lipid droplets (LDs) are simple intracellular storage sites for neutral lipids and exhibit important impact on many physiological processes. For example, the changes in the polar microenvironment inside LDs could affect physiological processes, such as lipid metabolism and storage, protein degradation, signal transduction, and enzyme catalysis. Herein, a new fluorescent chemo-sensor (Couoxo-LD) was formulated by our molecular design strategy. The probe could be applied to effectively label intracellular lipid droplets. Intriguingly, Couoxo-LD demonstrated positive sensitivity to both polarity and viscosity, which might be attributed to its D-π-A structure and the twisted rotational behavior of the carbon-carbon double bond (TICT). Additionally, Couoxo-LD was successfully implemented in cellular imaging due to its excellent selectivity, pH stability, and low biotoxicity. In HeLa cells, the co-localization curve between Couoxo-LD and commercial lipid droplet dyes overlapped at 0.93. The results indicated that the probe could selectively sense LDs in HeLa cells. Meanwhile, Couoxo-LD can be applied for in vivo imaging of zebrafish.

Parkinsonism-Hyperpyrexia Syndrome and Dyskinesia-Hyperpyrexia Syndrome in Parkinson's Disease: Two Cases and Literature Review.

Parkinsonism-hyperpyrexia syndrome (PHS) and dyskinesia-hyperpyrexia syndrome (DHS) are rare but exhibit life-threatening complications in Parkinson's disease (PD). We herein presented two cases of PD patients and performed a comprehensive and comparative literature review for these two syndromes. The first case was diagnosed as PHS with cerebral salt wasting syndrome caused by abrupt withdrawal of antiparkinsonian medication. Her symptoms were gradually remitted with reinstitution of the medication. The second one was an early-stage PD patient diagnosed as DHS in association with abuse of antiparkinsonian drugs. Her symptoms were gradually remitted with reduced dosage of dopaminergic drugs. Results of literature reviews revealed a total of 56 and 13 cases of PHS and DHS, respectively, and they were more likely to occur in elderly and long-term PD patients. These two syndromes showed different female-to-male ratio, similar mortality, and different recovery time. There were stark differences between PHS and DHS, including triggers (abrupt drug stoppage versus drug abuse), symptoms (worsened tremor and rigidity versus continuous dyskinesia), and treatment (drug reinstitution versus drug reduction). In summary, our reports and the review provide new insights into PHS and DHS in association with PD and may facilitate rapid discrimination of the syndromes for timely and proper treatment to reduce mortality.

Preparation of oxime compound lipid droplet-specifically labeled fluorescent probe and its application in cell imaging.

Fluorescent probes can facilitate our further comprehension of the functional and physiological roles of LDs and thus promote the development of effective therapeutic approaches. Oxime compounds are widely used due to their good crystallinity and high reactivity. However, the majority oximes fluorescent probes are usually employed for the detection of HCIO, and the application of oximes in fluorescently labeled LDS is poorly reported. In this paper, three kinds of LDs fluorescent probes (NAP-a, NAP-b and NAP-c) with D-π-A structure were synthesized by simple synthesis method with 1,8-naphthalimide as fluorescent matrix and oxime group as electron donor. These probes were highly sensitive to polarity, and possessed good photostability and low cytotoxicity. Co-staining experiments showed that these probes could target LDs and the fluorescence image was green. These probes NAP-a, NAP-b and NAP-c possessed high Pearson coefficient (HeLa cells: 0.91, 0.95, 0.86) and Manders coefficient (HeLa cells: 0.91, 0.96, 0.86) with Nile Red. Interestingly, the dynamic variations in their size, shape and distribution could be clearly observed in the oleic acid-treated cell model of LDs. Imaging of zebrafish was performed and green fluorescence was collected in zebrafish. These excellent properties make oxime compound fluorescent probes a promising fluorescent probes for studying LDs and metabolic diseases. This study opens up a new way for the preparation of LDs fluorescent probe.

A novel and fast-responsive two-photon fluorescent probe with modified group for monitoring endogenous HClO accompanied by a large turn-on signal and its application in zebrafish imaging.

Hypochlorous acid (HClO) plays a critical role in physiological activities of maintaining the stable oxidation balance of organisms, which was proved to relate to some serious diseases. In this work, 4-nitrobenzenesulfonylhydrazide based fast-responsive two-photon fluorescent probe CoPh-ClO was designed and synthesized reasonably, which possessed low cytotoxicity, good anti-interference characteristics, a large Stokes shift (85 nm), and good two-photon performance. In addition, probe CoPh-ClO was successfully applied to detect exogenous HClO in living HeLa cells and endogenous HClO in living RAW264.7 cells respectively. Moreover, we successfully achieved tissues imaging with a deep penetration depth of 65 µm and zebrafish imaging accompanied with a high contrast (about 45-fold). Interestingly, the introduce of benzene ring between fluorophore and reaction site made probe CoPh-ClO more sensitive (only 20 s) with a large turn-on signal. The probe CoPh-ClO was modified and possessed better stability (more than 10 mins) even in excessive HClO. All of mentioned above merits demonstrated that CoPh-ClO could be a promising imaging tool for monitoring HClO in various physiological processes, and the introduction of benzene ring would provide a new perspective for the development of multi-function probes.

A novel and stable fluorescent probe for tracking Hg2+ with large Stokes shift and its application in cell imaging.

Giving the fact that mercury ions (Hg2+) is highly toxic, migratory and bioaccumulative and even very small amounts of mercury can cause serious damage to health, resulting in many diseases, such as abdominal pain, renal failure, nervous system damage. The content of mercury in drinking water quality standard of our country has been strictly limited. Therefore, it is of good research interest to develop a stable fluorescent probe capable of detecting the presence of mercury in biological cells. In this study, a novel fluorescent probe based on isophoronitriles scaffold, DNC-Hg, was designed and synthesized for monitoring mercury ion in living HeLa cells. The good properties of the probe may be attributed to the unique strong electron-absorbing group in the structural design, the good conjugation effect, and the mature Hg2+ recognition site. The probe exhibited good selectivity and stability, large Stokes shift(174 nm) and low cytotoxicity. Furthermore, this stable probe DNC-Hg could be used for cellular imaging.

A lysosomal targeted fluorescent probe based on coumarin for monitoring hydrazine in living cells with high performance.

A lysosomal targeted fluorescent probe based on coumarin for monitoring hydrazine (N2H4) in living cells was designed and synthesised. The novel fluorescent probe Cou-Lyso-N2H4, in response to N2H4, exhibited good selectivity, low cytotoxicity, and lysosomal localization, which could be suitable for studying the harmfulness of N2H4 in subcellular organelles during various physiological processes.