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Introduction: Only two studies investigated the associations between peak width of skeletonized mean diffusivity (PSMD) and age-related cognitive alterations, whereas none of the studies investigated the association with vascular risk factors., Methods: We evaluated 801 stroke- and dementia-free elderlies with baseline and 3-year follow-up assessments. Regression analyses were used to assess the association between age-related cognitive functions and PSMD. Simple mediation models were used to study the mediation effect of PSMD between vascular risk factors and age-related cognitive outcomes., Results: PSMD was negatively associated with processing speed at baseline and negatively associated with processing and memory scores at 3-year follow-up. The association between vascular risk factors and age-related cognition was mediated by PSMD, as well as other diffusion tensor imaging markers., Discussion: PSMD is preferred over other diffusion tensor imaging markers as it is sensitive to age-related cognitive alterations and calculation is fully automated. PSMD is proposed as a research tool to monitor age-related cognitive alterations., (© 2019 The Authors.)

Background The poor viability of transplanted mesenchymal stem cells (MSCs) hampers their therapeutic efficacy for ischemic heart disease. Micro RNA s are involved in regulation of MSC survival and function. The present study was designed to investigate the molecular effects of mi R -15a/15b on MSC survival, focusing on the role of vascular endothelial growth factor receptor 2. Methods and Results We first harvested donor luc(Luciferase)- MSC s (5×10 5 ) isolated from the luciferase transgenic mice with FVB background. Luc- MSC s were transfected with miR-15a/15b mimics or inhibitors and cultured under oxygen glucose deprivation condition for 12 hours to mimics the harsh microenvironment in infarcted heart; they were subjected to MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide?Thiazolyl Blue Tetrazolium Bromide) assay, bioluminescence imaging, quantitative reverse transcription-polymerase chain reaction, transferase-mediated deoxyuridine triphosphate-digoxigenin nick-end labeling assay, and flow cytometry. Furthermore, the levels of vascular endothelial growth factor receptor 2, protein kinase B, p(Phosphorylate)-protein kinase B, Bcl-2, Bax, and caspase-3 proteins were available by Western blotting assay. In vivo, acute myocardial infarction was induced in 24 mice by coronary ligation, with subsequent receipt of Luc- MSC s, Luc- MSC s+miR-15a/15b inhibitors, or PBS treatment. The therapeutic procedure and treatment effects were tracked and assessed using bioluminescence imaging and echocardiographic measurement. Next, ex vivo imaging and immunohistochemistry were conducted to verify the distribution of MSC s. We demonstrated that miR-15a/15b targeted vascular endothelial growth factor receptor 2 to modulate MSC survival, possibly via phosphatidylinositol 3-kinase/protein kinase B signaling pathway, which was proved by bioluminescence imaging, immunohistochemistry analysis, and echocardiographic measurement. Conclusions Luc- MSC s could be followed dynamically in vitro and in vivo by bioluminescence imaging, and the role of mi R -15a/b could be inferred from the loss of signals from luc- MSC s. This finding may have practical clinical implications in mi R -15a/15b-modified MSC transplantation in treating myocardial infarction.

Background: Debate continues about whether percutaneous closure of patent foramen ovale (PFO) is a better strategy for the treatment of patients with cryptogenic stroke in comparison with medical therapy alone. We performed an updated meta-analysis of 6 randomized controlled trials (RCTs) to assess the effectiveness and safety of percutaneous closure of PFO as secondary prevention for patients with previous cryptogenic stroke compared to medical therapy., Materials and Methods: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, conference proceedings, and Internet-based resources were retrieved in March 2018 for eligible RCTs. The primary effectiveness outcome was recurrent strokes., Results: Six studies meeting our selection criteria were identified. Among 3560 participants, 1889 patients were assigned to PFO closure and 1671 patients to medical therapy. There were no significant differences among the baseline characteristics. The pooled incidence of recurrent strokes was 1.96% in the PFO closure group and 4.60% in the medical therapy group (Relative risk [RR] .39, 95% confidence interval [CI] .18-.82, P = .01). Newly detected atrial fibrillation occurred in 77 of 1844 (4.18%) patients in the PFO closure group and in 12 of 1667 (.72%) patients in the medical therapy group (RR 4.56, 95% CI 2.21-9.41, P <.0001). There was no difference in terms of serious adverse events, total mortality or bleeding between 2 groups., Conclusions: Our updated meta-analysis suggests that in patients with PFO and cryptogenic stroke, the rate of recurrent stroke is significantly reduced with percutaneous closure of PFO compared to the medical therapy., (Copyright © 2018. Published by Elsevier Inc.)

Study Design: Prospective observational study., Objective: To test the hypothesis that different types of surgical frame and the patient's body mass index (BMI) can affect pulmonary compliance, intra-abdominal pressure (IAP), and oxygenation., Summary of Background Data: The oxygenation index (PaO2/FiO2) and IAP are known to be associated with BMI when patients are in the supine position. However, there are few reports on the correlation between BMI, the oxygenation index, and IAP in the prone position, especially when a Jackson surgical table is used., Methods: Thirty-seven adult patients were divided into two groups according to BMI: normal-weight patients (n = 19, BMI: 18.5-24.9 kg m) and overweight patients (n = 18, BMI ≥ 25 kg m). After the induction of general anesthesia, patients were turned to the prone position onto either a Jackson surgical table (Mizuho OSI) or a general surgical table (MAQUET; foam pad, China). The patient's IAP, peak airway pressure, pulmonary dynamic compliance (Cdyn), and oxygenation index were recorded., Results: In overweight patients, there was a greater increase in peak airway pressure and a greater decrease in Cdyn observed when a general surgical table was used compared with the Jackson surgical table. When the Jackson surgical table was used, there was a greater increase in the oxygenation index and a greater decrease in IAP. There was a significant negative correlation between the oxygenation index and BMI and a significant positive correlation between IAP and BMI in the prone position., Conclusion: Turning patients from the supine to the prone position during anesthesia results in an increase in the oxygenation index and a decrease in IAP. Both of these factors are dependent upon the type of surgical frame used and the patient's BMI. The reduction in IAP was particularly significant when a Jackson surgical table was used for overweight patients., Level of Evidence: 4.

Objective: To investigate the time expression profile of serum monocyte chemoattractant protein (MCP)-1, and regulated upon activation, normal T cell expressed and secreted (RANTES) after minor intracerebral hemorrhage (ICH)., Methods: This study was carried out in the Department of Neurology in the Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, China. Fifteen consecutive hospitalized patients with minor ICH were enrolled from July 2008 to December 2008. The patients` serum levels of MCP-1 and RANTES were measured by enzyme-linked immunosorbent assay (ELISA) on days 1-3, 7, 14, and 30 after the onset of ICH, and compared with that of 10 controls., Results: The serum MCP-1 levels increased immediately on days 1-3 (p=0.000) after onset, and then decreased slightly on day 7 (p=0.001), and day 14 (p=0.000); after day 14, the levels continued to increase and reached their highest levels on day 30 (p=0.000). No statistical differences in MCP-1 levels were found between any time points. The RANTES levels at any time point did not differ significantly from the controls. The levels of MCP-1 and RANTES were not correlated with the serum C-reactive protein (CRP) levels, brain hematoma volumes, acute neurologic impairment, or 3-month outcome., Conclusion: The persistent elevation of serum MCP-1 levels after minor ICH may contribute to the acute damage and the repair following an ICH.

In the title salt, C(6)H(9)N(2) (+)·NO(3) (-), the 2-amino-5-methyl-pyridinium cation and the nitrate anion are cyclically linked through pyridinium and amine N-H⋯O hydrogen bonds [graph set R(4) (3)(12)]. These units are extended into a zigzag chain structure lying parallel to the a axis, through a second cyclic R(2) (2)(8) association involving amine N-H⋯O and aromatic C-H⋯O hydrogen bonds to nitrate O-atom acceptors.

In the title complex, [Cu(C(16)H(15)NO(3))(C(10)H(8)N(2))]·3H(2)O, the Cu(II) atom is five coordinated by O,N,O'-donor atoms of the Schiff base ligand and by two N atoms of the 2,2'-bipyridine ligand in a distorted square-pyramidal geometry. In the crystal, mol-ecules are linked into a two-dimensional network parallel to (011) by O-H⋯O hydrogen bonds.

Focal cerebral cortical infarction after distal middle cerebral artery occlusion causes β-amyloid deposition and secondary neuronal degeneration in the ipsilateral ventroposterior nucleus of the thalamus. Several studies suggest that autophagy is an active pathway for β-amyloid peptide generation. This study aimed to investigate the role of autophagy in thalamic β-amyloid deposition and neuronal degeneration after cerebral cortical infarction in hypertensive rats. At 7 and 14days after middle cerebral artery occlusion, neuronal death and β-amyloid deposits were evident in the ipsilateral ventroposterior nucleus, and the activity of β-site amyloid precursor protein (APP)-cleaving enzyme 1, required for β-amyloid peptide generation, was elevated in the thalamus. In correlation, both the number of cells showing punctate microtubule-associated protein 1A light chain 3 fluorescence and levels of light chain 3-II protein, an autophagosome marker, were markedly increased. Notably, most of the cells that over-expressed β-site APP-cleaving enzyme 1 displayed punctate light chain 3 staining. Furthermore, the inhibition of autophagy with 3-methyladenine significantly reduced the thalamic neuronal damage, β-amyloid deposits, and β-site APP-cleaving enzyme 1 activity. These results suggest that autophagosomes accumulate within thalamic cells after cerebral cortical infarction, which is associated with thalamic β-amyloid deposition and secondary neuronal degeneration via elevation of β-site APP-cleaving enzyme 1 level., (© 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.)

The M(3) subtype of muscarinic acetylcholine receptors (M(3)-mAChR) plays a protective role in myocardial ischemia and microRNAs (miRNAs) participate in many cardiac pathophysiological processes, including ischemia-induced cardiac injury. However, the role of miRNAs in M(3)-mAChR mediated cardioprotection remains unexplored. The present study was designed to identify miRNAs that are involved in cardioprotective effects of M(3)-mAChR against myocardial ischemia and elucidate the underlying mechanisms. We established rat model of myocardial ischemia and performed miRNA microarray analysis to identify miRNAs involved in the cardioprotection of M(3)-mAChR. In H9c2 cells, the viability, intracellular free Ca(2+) concentration ([Ca(2+)]i), intracellular reactive oxygen species (ROS), miR-376b-5p expression level, brain derived neurophic factor (BDNF) and nuclear factor kappa-B (NF-κB) levels were measured. Our results demonstrated that M(3)-mAChR protected myocardial ischemia injury. Microarray analysis and qRT-PCR revealed that miR-376b-5p was significantly up-regulated in ischemic heart tissue and the M(3)-mAChRs agonist choline reversed its up-regulation. In vitro, miR-376b-5p promoted H(2)O(2)-induced H9c2 cell injuries measured by cells viability, [Ca(2+)]i and ROS. Western blot and luciferase assay identified BDNF as a direct target of miR-376b-5p. M(3)-mAChR activated NF-κB and thereby inhibited miR-376b-5p expression. Our data show that a novel M(3)-mAChR/NF-κB/miR-376b-5p/BDNF axis plays an important role in modulating cardioprotection. MiR-376b-5p promotes myocardial ischemia injury possibly by inhibiting BDNF expression and M(3)-mAChR provides cardioprotection at least partially mediated by the downregulation of miR-376b-5p through NF-κB. These findings provide new insight into the potential mechanism by which M(3)-mAChR provides cardioprotection against myocardial ischemia injury.

Cerebral infarction can cause secondary degeneration of thalamus and delay functional recovery. However, the mechanisms underlying secondary degeneration are unclear. The present study aimed to determine the occurrence and contribution of autophagy to the thalamic degeneration after cerebral infarction. Focal cerebral infarction was induced by distal middle cerebral artery occlusion (MCAO). Autophagic activation, Beclin 1 expression and amyloid β (Aβ) deposits were determined by immunofluorescence, immunoblot and electron microscopy. Secondary damage to thalamus was assessed with Nissl staining and immunofluorescence analysis. Apoptosis was determined using TUNEL staining. The contribution of autophagy to the secondary damage was evaluated by shRNA-mediated downregulation of Beclin 1 and the autophagic inhibitor, 3-methyladenine (3-MA). The potential role of Aβ in autophagic activation was determined with N-[N-(3, 5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT). The results showed that the conversion of LC3-II, the formation of autophagosomes, and the levels of activated cathepsin B and Beclin 1 were significantly increased in the ipsilateral thalamus at 7 and 14 days after MCAO (p < 0.05 or 0.01). Both Beclin 1 knockdown and 3-MA treatment significantly reduced LC3-II conversion and autophagosome formation, which were accompanied by obvious decreases in neuronal loss, gliosis and apoptosis in the ipsilateral thalamus (p < 0.05 or 0.01). Additionally, DAPT treatment markedly reduced Aβ deposits, which coincided with decreases in LC3-II conversion and autophagosome formation (p < 0.01). These results suggest that inhibition of autophagy by Beclin 1 knockdown can attenuate the secondary thalamic damage after focal cerebral infarction. Furthermore, Aβ deposits may be involved in the activation of autophagy.

The metal ion copper is a cofactor essential for maintaining normal biological and physical functions in human beings. High copper levels have been found in variety of tumor tissues and are involved in tumor angiogenesis processes. The ubiquitin-proteasome system plays an important role in cell growth and apoptosis and has been shown as a novel target for cancer therapy. We previously reported that some organic copper complexes can inhibit the proteasomal chymotrypsin-like activity and induce apoptosis in human cancer cells and xenograft models. In the current study, we investigated the effect of oxidation status of copper, Cu(I) or Cu(II), on inhibition of proteasome activity, induction of apoptosis, and induction of reactive oxygen species (ROS) in human cancer cells. We report four major findings here: i) both Cu(I) and Cu(II) could inhibit the chymotrypsin-like activity of purified 20S proteasome, but Cu(I) was more potent than Cu(II), ii) purified 20S proteasome protein was able to reduce Cu(II) to Cu(I), suggesting that Cu(I) is the oxidation status of copper that directly reacts with the proteasome, iii) when complexed with the copper ligand neocuproine, Cu(I) showed higher ability to induce ROS production in cancer cells, compared with Cu(II), iv) addition of a ROS scavenger in the cancer cell culture-blocked copper-induced ROS generation, but did not overcome copper-mediated proteasome-inhibitory and cell death-inducing events, demonstrating the ROS-independent proteasome-inhibitory property of copper complexes.

We have previously reported on a gold(III) complex, namely [AuBr(2)(DMDT)] (N,N-dimethyldithiocarbamate) showing potent in vitro and in vivo growth inhibitory activities toward human cancer cells and identifying the cellular proteasome as one of the major targets. However, the importance of the oxidation state of the gold center and the involved mechanism of action has yet to be established. Here we show that both gold(III)- and gold(I)-dithiocarbamato species, namely [AuBr(2)(ESDT)] (AUL12) and [Au(ESDT)](2) (AUL15), could inhibit the chymotrypsin-like activity of purified 20S proteasome and 26S proteasome in human breast cancer MDA-MB-231 cells, resulting in accumulation of ubiquitinated proteins and proteasome target proteins, and induction of cell death, but at significantly different levels. Gold(I)- and gold(III)-compound-mediated proteasome inhibition and cell death induction were completely reversed by the addition of a reducing agent, dithiothreitol or N-acetyl-L-cysteine, suggesting the involvement of redox processes. Furthermore, treatment of MDA-MB-231 cells with gold(III) compound (AUL12), but not the gold(I) analog (AUL15), resulted in the production of significant levels of reactive oxygen species. Our study provides strong evidence that the cellular proteasome is an important target of both gold(I) and gold(III)-dithiocarbamates, but distinct cellular mechanisms of action are responsible for their different overall effect.

Background: Idiopathic hypertrophic cranial pachymeningitis (IHCP) is a very infrequent disorder that causes a localized or diffuse thickening of the dura mater. The main clinical features of IHCP at presentation are headache, cranial nerve involvement, ataxia, and seizures. Transient ischemic attacks (TIAs) have not previously been reported as a main clinical manifestation. We present a case with TIA as the main clinical manifestation and investigated the treatment of the case., Case Report: A 33-year-old male complaining of recurrent left hemiparesis for 22 days was admitted into our hospital. The clinical characteristics and CT, MRI, and pathological data were investigated carefully. IHCP was diagnosed and pulse corticosteroid therapy was used to treat this case. Headache, neck pain and recurrent episodes of weakness and numbness in the left limbs were the main clinical manifestations. CT and MRI revealed thickening of the dura along the falx and tentorium. Meningeal biopsy showed diffused thickening of the dura, consisting of collagen in concentric form with inflammatory cell infiltrating and fibrinoid necrosis, confirmed to be dura mater by histopathological examination. Treatment with an antiplatelet drug, low molecular heparin and herbs did not prevent the attacks. Pulse corticosteroid therapy was used and good efficiency was achieved., Conclusions: Recurrent episodes of TIAs can be the main clinical manifestations of IHCP, and pulse corticosteroid therapy was effective.

Schiff bases have been intensively investigated due to their antibacterial and antitumor properties. Copper is a cofactor essential for the tumor angiogenesis processes, whereas other transition metals are not. Consistently, high serum or tissue levels of copper were found in many types of human cancer including breast, prostate, colon, lung, and brain, supporting the idea that copper could be used as a novel selective target for cancer therapies. In the current study we hypothesize that a synthetic taurine Schiff base copper complex (Compound 1) could suppress tumor cell growth via the direct inhibition of proteasomal activity. Compound 1 potently inhibits the activity of purified 20S and 26S proteasome in human breast cancer MDA-MB-231 and leukemia Jurkat T cells. Inhibition of tumor cellular proteasomal activity by Compound 1 results in the accumulation of ubiquitinated protein and the proteasome target proteins p27 and Bax, followed by the induction of apoptosis. Our results strongly suggest that taurine Schiff base copper complexes, as potent proteasome inhibitors, have great potential to be developed into novel anticancer drugs.

Interest in the use of metallic compounds for cancer treatment has been increasing since the discovery of cisplatin. Clinical studies suggest the use of proteasome inhibitors as potential novel anticancer agents. L-glutamine is the most abundant free amino acid in the body, and has been shown to play a regulatory role in several cellular processes, including metabolism, degradation, redox potential and cellular integrity. Although glutamine is reported to play a role in the regulation of apoptosis, the effect of glutamine copper complex on tumor cells and the involved molecular mechanism have not been investigated. Here, for the first time, we report that a newly synthesized L-glutamine-containing copper complex has proteasome-inhibitory activity in human breast cancer and leukemia cells. The inhibition of the tumor proteasomal activity results in the accumulation of ubiquitinated proteins and ubiquitinated form of IkappaB-alpha, a natural proteasome substrate, followed by induction of apoptosis. Furthermore, this glutamine Schiff base copper complex selectively inhibits the proteasomal activity and induces cell death in cultured breast cancer cells, but not normal, immortalized breast cells. Our data suggest that glutamine Schiff base copper complexes have a potential use for to be used in cancer treatment and prevention.

Background: To evaluate the clinical effect and toxicity of NVB and DDP combination chemotherapy in the treatment of advanced non-small cell lung cancer., Methods: All 52 patients were treated with NP regimen: NVB 25 mg/m² iv, D1, D8; DDP 80 mg/m² iv, D1. The regimen was repeated every 3 weeks, tumor assessment was done after 2 cycles., Results: There were 2 complete responses (CR) and 26 partial responses (PR). The overall responses rate (CR+PR) was 53.8%, and the main toxicity was leucopenia, nause, vomiting and phlebitis., Conclusions: The NP regimen is effective in the treatment of advanced non-small cell lung cancer, the toxicity is well tolerated. Hence the regimen can be regarded as first-line regimen of advanced non-small cell lung cancer.

Background: To evaluate the response, adverse effects and survival of MVP regimen and TVP regimen., Methods: Sixty six patients with advanced non-small cell lung cancer were randomized into two groups:MVP arm (32 patients, mitomycin C 6-8 mg/m² d1, vindesine 2-3 mg/m² d1 and d8, cisplatin 70-80 mg/m² d1) and TVP arm (34 patients, pirarubicin 40-50 mg/m² d1, vindesine and cisplatin were the same as arm MVP). Characteristics of the patients were similar in two arms. All patients received two to four cycles of chemotherapy., Results: The overall responses were 34% (11/32) in the MVP arm and 56% (19/34) in the TVP arm. There were 1 complete response, 10 partial responses in the MVP arm and 1 complete response, 18 partial responses in the TVP arm. TVP regimen appeared to have a higher objective response, but no statistically significant difference in the response was observed between two regimens (Chi-square=2.269, P=0.132). Main side effects were hematological toxicities. Grade III+IV hematological toxicities were significantly higher in the patients of arm TVP than arm MVP, especially neutropenia (79% vs 44%, Chi-square=7.458, P=0.006). Median survival time was 12 months vs 8 months, and 1-, 2-, 3-year survival rates were 53% vs 24% (Chi-square=4.943, P=0.026), 17% vs 6%, 6% vs 0, for arm TVP and arm MVP, respectively.., Conclusions: MVP regimen has a lower response rate and longer survival time but less hematological toxicities than TVP regimen. The results suggest MVP regimen is a safe and active regimen for advanced non-small cell lung cancer.