KI-Catalyzed Oxidative Cyclization of Enamines and tBuONO to Access Functional Imidazole-4-Carboxylic Derivatives.

A simple protocol for the noble-metal-free oxidative cyclization of enamines and tBuONO has been developed. This KI-mediated formal [4 + 1] cycloamination reaction provides a practical strategy for the synthesis of imidazole-4-carboxylic derivatives using tBuONO both as an aminating reagent and oxidant. The reaction features wide substrate scope and good functional tolerance for enamine compounds, even the unactivated ones.

Dithiocarbamates combined with copper for revitalizing meropenem efficacy against NDM-1-producing Carbapenem-resistant Enterobacteriaceae.

The worldwide prevalence of NDM-1-producing Gram-negative pathogens has drastically undermined the clinical efficacy of carbapenems, prompting a need to devise an effective strategy to preserve their clinical value. Here we constructed a focused compound library of dithiocarbamates and systematically evaluated their potential synergistic antibacterial activities combined with copper. SA09-Cu exhibited excellent inhibition against a series of clinical NDM-1-producing carbapenem-resistant Enterobacteriaceae (CRE) in restoring meropenem effect, and slowed down the development of carbapenem resistance. Enzymatic kinetic and isothermal titration calorimetry studies demonstrated that SA09-Cu was a noncompetitive NDM-1 inhibitor. The electron paramagnetic resonance (EPR) and X-ray photoelectron spectroscopy (XPS) revealed a novel inhibition mechanism, which is that SA09-Cu could convert NDM-1 into an inactive state by oxidizing the Zn(II)-thiolate site of the enzyme. Importantly, SA09-Cu showed a unique redox tuning ability, and avoided to be reduced by intracellular thiols of bacteria. In vivo experiments indicated that SA09 combined with CuGlu could effectively potentiate MER's effect against NDM-1-producing E. coli (EC23) in the murine infection model. This study provides a highly promising scaffold in developing novel inhibitors to combat NDM-1-producing CREs.

Aromatic Schiff bases confer inhibitory efficacy against New Delhi metallo-ß-lactamase-1 (NDM-1).

The irregular use of antibiotics has created a natural selection pressure for bacteria to adapt resistance. Bacterial resistance caused by metallo-ß-lactamases (MßLs) has been the most prevalent in terms of posing a threat to human health. The New Delhi metallo-ß-lactamase-1 (NDM-1) has been shown to be capable of hydrolyzing almost all ß-lactams. In this work, eight aromatic Schiff bases 1-8 were prepared and identified by enzyme kinetic assays to be the potent inhibitors of NDM-1 (except 4). These molecules exhibited a more than 95 % inhibition, and an IC50 value in the range of 0.13-19 µM on the target enzyme, and 3 was found to be the most effective inhibitor (IC50 = 130 nM). Analysis of structure-activity relationship revealed that the o-hydroxy phenyl improved the inhibitory activity of Schiff bases on NDM-1. The inhibition mode assays including isothermal titration calorimetry (ITC) disclosed that both compounds 3 and 5 exhibited a reversibly mixed inhibition on NDM-1, with a Ki value of 1.9 and 10.8 µM, respectively. Antibacterial activity tests indicated that a dose of 64 µg·mL-1 Schiff bases resulted in 2-128-fold reduction in MICs of cefazolin on E. coli producing NDM-1 (except 4). Cytotoxicity assays showed that both Schiff bases 3 and 5 have low cytotoxicity on the mouse fibroblast (L929) cells at a concentration of up to 400 µM. Docking studies suggested that the hydroxyl group interacts with Gln123 and Glu152 of NDM-1, and the amino groups interact with the backbone amide groups of Glu152 and Asp223. This study provided a novel scaffold for the development of NDM-1 inhibitors.

Dihydroxyphenyl-substituted thiosemicarbazone: A potent scaffold for the development of metallo-ß-lactamases inhibitors and antimicrobial.

The superbug infection mediated by metallo-ß-lactamases (MßLs) has grown into anemergent health threat, and development of MßL inhibitors is an ideal strategy to combat the infection. In this work, twenty-five thiosemicarbazones 1a-e, 2a-e, 3a-e, 4a-d, 5a-d and 6a-b were synthesized and assayed against MßLs ImiS, NDM-1 and L1. The gained molecules specifically inhibited NDM-1 and ImiS, exhibiting an IC50 value in the range of 0.37-21.35 and 0.45-8.76 µM, and 2a was found to be the best inhibitor, with an IC50 of 0.37 and 0.45 µM, respectively, using meropenem (MER) as substrate. Enzyme kinetics and dialysis tests revealed and confirmed by ITC that 2a is a time-and dose-dependent inhibitor of ImiS and NDM-1, it competitively and reversibly inhibited ImiS with a Ki value of 0.29 µM, but irreversibly inhibited NDM-1. Structure-activity relationship disclosed that the substitute dihydroxylbenzene significantly enhanced inhibitory activity of thiosemicarbazones on ImiS and NDM-1. Most importantly, 1a-e, 2a-e and 3a-b alone more strongly sterilized E. coli-ImiS and E. coli-NDM-1 than the MER, displaying a MIC value in the range of 8-128 µg/mL, and 2a was found to be the best reagent with a MIC of 8 and 32 µg/mL. Also, 2a alone strongly sterilized the clinical isolates EC01, EC06-EC08, EC24 and K. pneumonia-KPC-NDM, showing a MIC value in the range of 16-128 µg/mL, and exhibited synergistic inhibition with MER on these bacteria tested, resulting in 8-32-fold reduction in MIC of MER. SEM images shown that the bacteria E. coli-ImiS, E. coli-NDM-1, EC24, K. pneumonia-KPC and K. pneumonia-KPC-NDM treated with 2a (64 µg/mL) suffered from distortion, emerging adhesion between individual cells and crumpled membranes. Mice tests shown that monotherapy of 2a evidently limited growth of EC24 cells, and in combination with MER, it significantly reduced the bacterial load in liver and spleen. Docking studies suggest that the 2,4-dihydroxylbenzene of 2a acts as zinc-binding group with the Zn(II) and the residual amino acids in CphA active center, tightly anchoring the inhibitor at active site. This work offered a promising scaffold for the development of MßLs inhibitors, specifically the antimicrobial for clinically drug-resistant isolates.

A Modified Vancomycin Molecule Confers Potent Inhibitory Efficacy against Resistant Bacteria Mediated by Metallo-ß-Lactamases.

Multidrug-resistant bacterial infections mediated by metallo-ß-lactamases (MßLs) have grown into an emergent health threat, and development of novel antimicrobials is an ideal strategy to combat the infections. Herein, a novel vancomycin derivative Vb was constructed by conjugation of triazolylthioacetamide and vancomycin molecules, characterized by reverse-phase high performance liquid chromatography (HPLC) and confirmed by matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS). The biological assays revealed that Vb effectively inhibited S. aureus and methicillin-resistant S. aureus (MRSA), gradually increased the antimicrobial effect of ß-lactam antibiotics (cefazolin, meropenem and penicillin G) and exhibited a dose-dependent synergistic antibacterial effect against eight resistant strains tested, which was confirmed by the time-kill curves determination. Most importantly, Vb increased the antimicrobial effect of meropenem against the clinical isolates EC08 and EC10 and E. coli producing ImiS and CcrA, resulting in a 4- and 8-fold reduction in MIC values, respectively, at a dose up to 32 µg/mL. This work offers a promising scaffold for the development of MßLs inhibitors, specifically antimicrobials for clinically drug-resistant isolates.

Dipyridyl-substituted thiosemicarbazone as a potent broad-spectrum inhibitor of metallo-ß-lactamases.

To combat the superbug infection caused by metallo-ß-lactamases (MßLs), a dipyridyl-substituted thiosemicarbazone (DpC), was identified to be the broad-spectrum inhibitor of MßLs (NDM-1, VIM-2, IMP-1, ImiS, L1), with an IC50 value in the range of 0.021-1.08 µM. It reversibly and competitively inhibited NDM-1 with a Ki value of 10.2 nM. DpC showed broad-spectrum antibacterial effect on clinical isolate K. pneumonia, CRE, VRE, CRPA and MRSA, with MIC value ranged from 16 to 32 µg/mL, and exhibited synergistic antibacterial effect with meropenem on MßLs-producing bacteria, resulting in a 2-16-, 2-8-, and 8-fold reduction in MIC of meropenem against EC-MßLs, EC01-EC24, K. pneumonia, respectively. Moreover, mice experiments showed that DpC also had synergistic antibacterial action with meropenem. In this work, DpC was identified to be a potent scaffold for the development of broad-spectrum inhibitors of MßLs.

N-acylhydrazones confer inhibitory efficacy against New Delhi metallo-ß-lactamase-1.

The expression of ß-lactamases, especially metallo-ß-lactamases (MßLs) in bacteria is one of the main causes of drug resistance. In this work, an effective N-acylhydrazone scaffold as MßL inhibitor was constructed and characterized. The biological activity assays indicated that the synthesized N-acylhydrazones 1-11 preferentially inhibited MßL NDM-1, and 1 was found to be the most effective inhibitor with an IC50 of 1.2 µM. Analysis of IC50 data revealed a structure-activity relationship, which is that the pyridine and hydroxylbenzene substituents at 2-position improved inhibition of the compounds on NDM-1. ITC and enzyme kinetics assays suggested that it reversibly and competitively inhibited NDM-1 (Ki = 0.29 ± 0.05 µM). The synthesized N-acylhydrazones showed synergistic antibacterial activities with meropenem, reduced 4-16-fold MIC of meropenem on NDM-1- producing E. coli BL21 (DE3), while 1 restored 4-fold activity of meropenem on K. pneumonia expressing NDM-1 (NDM-K. pneumoniae). The mice experiments suggested that 1 combined meropenem to fight against NDM-K. pneumoniae infection in the spleen and liver. Cytotoxicity assays showed that 1 and 2 have low cytotoxicity. This study offered a new framework for the development of NDM-1 inhibitors.

Ebsulfur and Ebselen as highly potent scaffolds for the development of potential SARS-CoV-2 antivirals.

The emerging COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has raised a global catastrophe. To date, there is no specific antiviral drug available to combat this virus, except the vaccine. In this study, the main protease (Mpro) required for SARS-CoV-2 viral replication was expressed and purified. Thirty-six compounds were tested as inhibitors of SARS-CoV-2 Mpro by fluorescence resonance energy transfer (FRET) technique. The half-maximal inhibitory concentration (IC50) values of Ebselen and Ebsulfur analogs were obtained to be in the range of 0.074-0.91 µM. Notably, the molecules containing furane substituent displayed higher inhibition against Mpro, followed by Ebselen 1i (IC50 = 0.074 µM) and Ebsulfur 2k (IC50 = 0.11 µM). The action mechanism of 1i and 2k were characterized by enzyme kinetics, pre-incubation and jump dilution assays, as well as fluorescent labeling experiments, which suggested that both compounds covalently and irreversibly bind to Mpro, while molecular docking suggested that 2k formed an SS bond with the Cys145 at the enzymatic active site. This study provides two very potent scaffolds Ebsulfur and Ebselen for the development of covalent inhibitors of Mpro to combat COVID-19.

N-heterocyclic dicarboxylic acids: broad-spectrum inhibitors of metallo-ß-lactamases with co-antibacterial effect against antibiotic-resistant bacteria.

In an effort to identify novel, broad-spectrum inhibitors against the metallo-ß-lactamases (MßLs), several N-heterocyclic derivatives were tested as inhibitors of MßLs CcrA, ImiS, and L1, which are representative enzymes from the distinct MßL subclasses. Three N-heterocyclic dicarboxylic acid derivatives were competitive inhibitors of CcrA and L1, exhibiting K(i) values ≤2 µM, while only 2,4-thiazolidinedicarboxylic acid (1b) was a competitive inhibitor of ImiS. Two 2-mercapto-1,3,4-thiadiazole derivatives were noncompetitive inhibitors of CcrA and ImiS, exhibiting K(i) values <7 µM; however, these same compounds did not inhibit L1. Two 2-mercapto-1,3,4-triazole derivatives were shown not to inhibit any of the tested MßLs. The N-heterocyclic derivatives were tested for antibacterial activity by examining the MIC values for existing antibiotics in the presence/absence of these derivatives. Consistent with the steady-state inhibition data, the inclusion of three N-heterocyclic dicarboxylic acid derivatives resulted in lower MIC values when using Escherichia coli BL21(DE3) cells containing the CcrA or L1 plasmids or Klebsiella pneumoniae (ATCC 700603), while 1b was the only dicarboxylic acid derivative to lower the MIC value of E. coli cells containing the ImiS plasmid. Inclusion of the 2-mercapto-1,3,4-thiadiazole derivatives resulted in lower MIC values for E. coli cells containing ImiS or L1 plasmids; however, these derivatives did not alter the MIC values for K. pneumoniae or E. coli cells containing the L1 plasmid. None of the N-heterocyclic derivatives affected the MIC of two methicillin resistant Staphylococcus aureus (MRSA) strains. Taken together, these studies demonstrate that N-heterocyclic dicarboxylic acids 1a-c and pyridylmercaptothiadiazoles 2a,b are good scaffolds for future broad-spectrum inhibitors of the MßLs.

Structure-based analysis and evolution of a monomerized red-colored chromoprotein from the Olindias formosa jellyfish.

GFP-like chromoproteins (CPs) with non-fluorescence ability have been used as bioimaging probes. Existing CPs have voids in the optical absorption window which limits their extensibility. The development of new CP color is therefore ongoing. Here, we cloned CPs from the jellyfish, Olindias formosa, and developed a completely non-fluorescent monomeric red CP, R-Velour, with an absorption peak at 528 nm. To analyze the photophysical properties from a structural aspect, we determined the crystal structure of R-Velour at a 2.1 Å resolution. R-Velour has a trans-chromophore similar to the green fluorescence protein, Gamillus, derived from the same jellyfish. However, in contrast to the two coplanar chromophoric rings in Gamillus, R-Velour has a large torsion inducing non-fluorescence property. Through site-directed mutagenesis, we surveyed residues surrounding the chromophore and found a key residue, Ser155, which contributes to the generation of four-color variants with the bathochromic and hypsochromic shift of the absorption peak, ranging from 506 to 554 nm. The recently proposed spectrum shift theory, based on the Marcus-Hush model, supports the spectrum shift of these mutants. These findings may support further development of R-Velour variants with useful absorption characteristics for bioimaging, including fluorescence lifetime imaging and photoacoustic imaging.

Synthesis and activity study of phosphonamidate dipeptides as potential inhibitors of VanX.

In an effort to develop inhibitors of VanX, the phosphonamidate analogs of D-Ala-D-Ala dipeptides, N-[(1-aminoethyl) hydroxyphosphinyl]-glycine (1a), -alanine (1b), -valine (1c), -leucine (1d) and -phenylalanine (1e) were synthesized, characterized and evaluated using recombinant VanX. The crystal structure of the intermediate 6d was obtained (Deposition number: CCDC 839134), and structural analysis revealed that it is orthorhombic with a space group P2(1)2(1)2(1), the bond length of P-N is 1.62Å and angle of C-N-P is 123.6°. Phosphonamidate 1(a-e) showed to be inhibitors of VanX with IC(50) values of 0.39, 0.70, 1.12, 2.82, and 4.13mM, respectively, which revealed that the inhibition activities of the phosphonamidates were dependent on the size of R-substituent of them, with the best inhibitor 1a having the smallest substituent. Also, 1a showed antibacterial activity against Staphylococcus aureus (ATCC 25923) with a MIC value of 0.25 µg/ml.

[Endovascular management of symptomatic carotid stenosis combined with kinking].

OBJECTIVE: To study the necessity, feasibility, security of carotid angioplasty and stenting (CAS) for symptomatic carotid stenosis combined with kinking. METHODS: Twelve patients with symptomatic carotid stenosis and kinking demonstrated by digital subtraction angiography (DSA) received CAS from December 2003 to December 2009. There were 9 male and 3 female patients, age ranged from 59 to 77 years (mean 69.3 years). All the patients' clinical, imaging, intervention and follow up data were collected and analyzed. RESULTS: All CAS procedures were successfully performed with 14 self-expandable stents placed. The mean degree of stenosis was reduced from 85.6% before stenting to 11.2% after stenting, the angle of kinking, according to Metz' category, were improved from less than 90° to more than 120° in each case. No perioperative procedure related stroke and transient ischemic attack (TIA) occurred. The clinical symptoms and signs of cerebral ischemia were improved or disappeared for all patients. During follow-up of these 12 patients for 6 to 72 months, one patient experienced ipsilateral carotid territory TIA and another patient experienced contralateral carotid territory TIA. DSA follow up of 5 patients demonstrated 1 case with in-stent restenosis and arterial kinking remote to the stent of internal carotid artery. CAS were performed again and CT angiography follow up demonstrated no kinking and restenosis 2 years after the intervention. Duplex scan of the other 7 patients demonstrated neither kinking nor restenosis. CONCLUSIONS: CAS seems to be feasible and safe for the patients with symptomatic kinking and stenosis, and maybe helpful to lower the risk of cerebral ischemia, but further study is needed.

Thiosemicarbazones exhibit inhibitory efficacy against New Delhi metallo-ß-lactamase-1 (NDM-1).

The superbug infection caused by metallo-ß-lactamases (MßLs) carrying drug-resistant bacteria, specifically, New Delhi metallo-ß-lactamase (NDM-1) has become an emerging threat. In an effort to develop novel inhibitors of NDM-1, thirteen thiosemicarbazones (1a-1m) were synthesized and assayed. The obtained molecules specifically inhibited NDM-1, with an IC50 in the range of 0.88-20.2 µM, and 1a and 1f were found to be the potent inhibitors (IC50 = 1.79 and 0.88 µM) using cefazolin as substrate. ITC and kinetic assays indicated that 1a irreversibly and non-competitively inhibited NDM-1 in vitro. Importantly, MIC assays revealed that these molecules by themselves can sterilize NDM-producing clinical isolates EC01 and EC08, exhibited 78-312-fold stronger activities than the cefazolin. MIC assays suggest that 1a (16 µg ml-1) has synergistic antimicrobial effect with ampicillin, cefazolin and meropenem on E. coli producing NDM-1, resulting in MICs of 4-32-, 4-32-, and 4-8-fold decrease, respectively. These studies indicate that the thiosemicarbazide is a valuable scaffold for the development of inhibitors of NDM-1 and NDM-1 carrying drug-resistant bacteria.

[Endovascular treatment of ruptured and unruptured intracranial very small aneurysms].

OBJECTIVE: To evaluate the feasibility and safety of endovascular treatment of ruptured and unruptured intracranial very small aneurysms (< or = 3 mm in maximal diameter). METHODS: Forty-eight intracranial very small aneurysms in 44 patients treated with endovascular therapy from June 2001 to August 2009 were reviewed retrospectively in clinical, imaging, interventional and follow-up data. Among 44 patients, there were 20 males and 24 females with a mean age of 57.8 years old. The Hunt-Kosnik grade was as follows: Grade 0 (n = 11); Grades I & II (n = 23); Grades III & IV (n = 9); and ungraded (n = 1). The sizes of 48 aneurysms were not more than 3 mm in maximal diameter. The locations of aneurysms were as follows: ACoA (n = 11), MCA (n = 8), PCoA (n = 14), ICA (n = 12), pericallosal artery (n = 1), VA (n = 1) and PICA (n = 1). Thirty-nine aneurysms were embolized with coil, of which 13 with stent assistance and 6 by balloon remodeling technique. The other 9 aneurysms underwent sole stent placement in parent artery. RESULTS: Among 39 coiling aneurysms, 100% occlusion was achieved in 9 aneurysms, 90% in 20, 80% in 9 and less than 80% in 1 respectively. Only one aneurysm ruptured during coiling. Two patients had transient hemiparesis and one patient had ataxia caused by bilateral cerebellar infarction postoperatively. All patients were clinically followed up for 4-90 months and no recurrent hemorrhage occurred. Thirteen patients received repeat angiography at 4-72 months post-treatment. And no radiological re-growth was detected. CONCLUSION: Endovascular treatment of ruptured and unruptured intracranial very small aneurysms seems to be technically feasible, relatively safe and practically effective.

[Endovascular treatment of micro-intracranial aneurysms: adverse factors of micro-catheterization and its relevant managements].

OBJECTIVES: To investigate adverse factors that may hinder successful placement and stabilization of the microcatheter during endovascular therapy of micro-intracranial aneurysms (≤ 3 mm in maximum diameter), and to explore the relevant managements. METHODS: Forty-six patients with fifty-one micro-intracranial aneurysms treated by endovascular therapy from June 2001 to October 2009 were retrospectively analyzed for their intervention data. RESULTS: Adverse factors of optimal micro-catheterization mainly included, tortuosity of the proximal vessels (PVs) and the parent artery (PA), relative large gap in diameter among the PVs, the PA and the microcatheter, relative large divergence in direction among the PVs, the PA and the aneurysm dome, and stent deployed in the PA. CONCLUSIONS: Carefully considering the direction of the PVs and the PA, the aneurysm's location and dome orientation, choosing the microcatheter and microwire after balancing among their physical properties, as well as utilizing balloon and/or stent assistance, can facilitate micro-catheterization during endovascular treatment of micro-intracranial aneurysms.

[Changes of nitric oxide and endothelin serum level after carotid balloon denudation or stent assisted angioplasty: an experimental and clinical observation].

OBJECTIVE: To observe the changes of nitric oxide (NO) and endothelin (ET) serum level in the Guangxi BA-MA minipigs whose carotid arteries were injured by balloon denudation and in the patients with carotid stent assisted angioplasty. METHODS: Twelve Guangxi BA-MA minipigs were chosen. High fat/cholesterol feeding and endovascular balloon denudation were used to create a carotid artery atherosclerotic stenosis animal model. Blood samples were collected from peripheral veins before starting the procedure, and again, at 2 and 3 weeks after the procedure, respectively. Serum NO and ET concentrations of blood samples were tested. Nineteen patients with carotid artery stenosis who underwent stent assisted angioplasty were randomly selected, and their serum NO and ET were tested using the same methods as above. RESULTS: In the animal group, there was a significant decrease of mean NO concentration at 2 weeks after carotid injury (t-test, P < 0.05), however, no significant change of ET was observed. A very significant increase of ET was observed at 3 weeks after the procedure (t-test, P < 0.01). In the patient group, there were no significant differences among serum NO or ET concentration of peripheral vein blood before, immediately after, and 6 h after the endovascular treatment. CONCLUSIONS: In this study, a decrease of NO concentration and an increase of ET concentration of peripheral vein blood are found in BA-MA minipigs after carotid arteries are injured by balloon denudation, which might be a cue for the formation of atherosclerosis. However, no significant changes are observed in this group of patients who underwent carotid angioplasty treatment. Therefore, further studies are needed.

[Evaluation of cerebral hemodynamics in geriatric carotid stenosis pre- and post-carotid artery stenting].

OBJECTIVES: To explore influencing factors of regional cerebral blood flow (rCBF) in geriatric carotid stenosis, and to analyze changes of rCBF and clinical symptoms after carotid stenting. METHODS: During August 2005 and April 2008, 68 geriatric patients of carotid stenosis having SPECT examination in our hospital were retrospectively studied, whose diagnosis was approved by angiography. Correlated rCBF was compared separately in different stenotic degrees of carotid stenosis, in unilateral or bilateral stenosis, accompanied with vertebrobasilar stenosis (VBS) or not, with collateral circulation or not, before and after carotid stenting. RESULTS: When patients of unilateral carotid stenosis were grouped by different clinical factors, cases of patients with reduced rCBF were compared using chi(2) test: the P value was 0.046 and 0.020 when comparing group of stenotic degree 90% - 99% with group 70% - 89% and group 50% - 69%; the P value was 0.927 between group accompanied with VBS and group without; the P value was 0.222 between group with collateral circulation and group without. When comparing reduced rCBF cases between unilateral and bilateral carotid stenosis, the P value was 0.046. After carotid stenting, 76% of patients had their rCBF improved, and also the scores of presenting symptoms evaluated by modified Rankin scale were elevated from 1.4 +/- 0.7 on admission to 0.4 +/- 0.3 postoperatively (P < 0.001). CONCLUSIONS: The research indicates that higher stenotic degree and bilateral carotid stenosis may cause rCBF decrease in geriatric carotid stenosis. Carotid stenting may improve rCBF and change clinical symptoms significantly.

Cyanate ester resin based composites with high toughness and thermal conductivity.

A new cyanate ester resin-based composite with higher toughness and thermal conductivity was developed. First, a poly(n-butyl acrylate)/poly(methyl methacrylate-co-acrylamide) (PBMAM) core-shell structured latex was prepared by seeded emulsion polymerization. Second, hexagonal boron nitride (h-BN) particles were modified by a surface coupling agent, 3-(2-amino ethyl amino)propyl trioxysilane, to improve the dispersion in cyanate ester resin (BADCy). Third, PBMAM and the modified boron nitride were mixed with BADCy resin to increase mechanical properties and thermal conductivity. The monomer conversion in the emulsion polymerization process of the PBMAM was monitored by determining the solid content. Its particle size was characterized by dynamic laser scattering, and the morphology of the particles was characterized using scanning and transmission electron microscopes. The modified boron nitride (ABN) was verified by FTIR and TGA measurements. The mechanical properties and thermal conductivity of the BADCy/PBMAM/ABN composites were determined at various BN contents. Results showed that the unnotched impact strength of the composite increased by 151% and the thermal conductivity increased by 85% at a PBMAM content of 5 wt% and ABN content of 6 wt%. With the enhanced properties and ease of fabrication, the developed composites have good potential for application in high-end industries such as microelectronic packaging.

[Clinical study and numerical simulation of hemodynamics in the tortuosity of internal carotid artery].

OBJECTIVES: To establish a theoretical model for the tortuosity of internal carotid artery and summarize the hemodynamic rule of blood flow in a tortuous artery. To explore the relationship of cerebral ischemia and tortuous internal carotid artery. METHODS: Taking the internal carotid artery as a prototype, a geometric model of a tortuous artery was constructed according to the normal physiological and anatomical parameters of internal carotid artery. The boundary conditions and calculation conditions of blood flow are proposed. The numerical simulation of the blood flow in the tortuous artery is carried out with finite element method. Hemodynamic parameters of internal carotid artery were measured in 15 cases with the tortuosity of internal carotid artery and in 15 cases of normal control group. Blood pressure was measured by microcatheter connecting a pressure transducer at internal carotid artery, pre-tortuous and post-tortuous artery. The diameter and length of the above artery were measured and calculated by DSA machine. RESULTS: Numerical simulation results indicated pressure drop of blood flow and elongated length of artery is increased with diminution of the angle of tortuous artery. Clinical measurement data disclosed the same trend in the same curve as numerical simulation. CONCLUSION: The elongation and tortuosity of internal carotid artery results in decrease of blood pressure in the distal segment of tortuous internal carotid artery, kinking of internal carotid artery may be one of factors related to attack of cerebral ischemia on certain conditions.

[Management of elderly patients with symptomatic vertebrobasilar insufficiency].

OBJECTIVE: To evaluate the feasibility, safety and short-term efficacy of stent-assisted angioplasty and/or drug therapy for elderly patients with symptomatic vertebrobasilar insufficiency. METHODS: Elderly patients (> or = 60 years old) with symptomatic vertebrobasilar stenosis (> or = 50%) demonstrated by cerebral angiography were treated with drug therapy and some with endovascular stenting further from April 2001 to June 2006. The clinical, imaging, intervention and follow-up data were collected and analyzed. RESULTS: Eighty-one elderly patients were chosen for study, including 68 males and 13 females. The mean age is 70 years (60 - 87 years); stroke rate of 4.9% (4/81) and stroke-related mortality rate of 2.5% (2/81) were found in this group during hospitalization and follow-up (mean 28.1 months), and symptoms resolved or improved clinically in 66 (81.5%). Fifty-two balloon expandable stents were placed in 48 (59.3%) patients of this group with a technical success rate of 98.1% and the mean degree of stenosis was reduced from (82.4 +/- 13.1)% to (6.4 +/- 3.2)% (t = 22.4, P = 0.00). CONCLUSIONS: Appropriate management including endovascular stenting and/or drug therapy may improve short-term outcomes of elderly patients with symptomatic vertebrobasilar insufficiency; meanwhile, stent-assisted angioplasty is technically feasible and relatively safe.