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open access article Impaired endogenous fibrinolysis is an adverse prognostic biomarker in acute coronary syndrome (ACS). Abnormally dense in vitro fibrin thrombi have been demonstrated in ACS patients and related to hypofibrinolysis using cumbersome, laboratory-based methods. We aimed to assess endogenous fibrinolysis using a point-of-care technique and relate this to clot architecture. From patients with ST-segment elevation myocardial infarction (STEMI), venous blood was drawn immediately on arrival to assess thrombotic status. Blood was assessed using the point-of-care Global Thrombosis Test which measures occlusive thrombus formation under high shear and subsequently endogenous fibrinolysis (lysis time, LT). Two samples per patient were run in parallel. In one channel, the measurement was allowed to proceed as normal. In the other, after occlusion, thrombus was extracted, washed, fixed in glutaraldehyde, dried, sputter-coated, and assessed using scanning electron microscope. Endogenous fibrinolysis was strongly associated fibrin fibre thickness (p = 0.0001). As LT increased (less efficient fibrinolysis), the fibrin network of the thrombus was significantly more compact and dense, with thinner fibrin fibres and smaller gaps. Fibrin fibre thickness correlated inversely with LT (r = − 0.89, p = 0.001). Adverse clot architecture in vitro is directly related to impaired endogenous fibrinolysis using a relatively new point-of-care technique in patients with STEMI. This may transform the relevance of fibrin clot architecture from an off-line laboratory association to being directly relevant to endogenous fibrinolysis at the patient bedside, which could be used as a near-patient test to guide prognosis and assess the effect of treatment.

Asian patients with nonvalvular atrial fibrillation (NVAF) have a higher risk of stroke and systemic embolism than non-Asians, but experience more frequent major bleeding on oral anticoagulation (OAC), including intracranial hemorrhage. Although Asians constituted only a minority of patients in

Although used routinely to reduce thrombotic events in patients with coronary disease, the effects of P2Y

The photosynthetic performance of variegated leaves can be very important in the cultivation and management of variegated plants. Actinidia kolomikta (Rupr. & Maxim.) Maxim. leaves have striking color variation. To clarify the variegated leaf type and photosynthetic cost, we measured leaf structure and ultrastructure, spectral properties, chlorophyll fluorescence and net photosynthetic rate (Pn). The study was conducted in Jilin during spring, summer, and fall in 2013. Leaf anatomy and ultrastructure were observed with light and electron microscopy. Leaf reflectance and pigment content were measured with a Unispec spectrometer and high performance liquid chromatography. Photosynthetic characterization was performed with a photosynthesis system and plant efficiency analyzer. In the palisade tissue of variegated areas, intercellular spaces were found, and cells contained fewer and abnormally developed chloroplasts. Normal chloroplasts were distributed mostly in spongy tissue. The reflectance of the adaxial surface was higher in variegated leaves than in green leaves. The Pn of variegated leaves was 80 to 94% of green leaves, the maximum photosystem II efficiency of the adaxial and abaxial surfaces in variegated leaves was similar to green leaves, and the quantum use efficiency of the abaxial surface was higher than the adaxial surface in variegated leaves. These results show that the photosynthetic performance of variegated leaves was retained well. Thus, variegated leaves are not a limiting factor for cultivation and application in A. kolomikta, and do not need to be removed as parasitic leaves during cultivation and management.

Introduction ST-segment elevation myocardial infarction (STEMI) is attributable to an occluded coronary artery in almost 90% of patients. Accordingly, restoration of coronary perfusion as early as possible, preferably with primary percutaneous coronary intervention, is the recommended treatment by the European Society of Cardiology, to maximise myocardial salvage. However, not all cases of STEMI are because of coronary artery occlusion. ST-segment elevation myocardial infarction that occurs in the absence of obstructive coronary artery disease on angiography has been termed myocardial infarction with non-obstructive coronary arteries (MINOCA). Case presentation A 44-year-old man was admitted with retrosternal chest pain radiating to the left arm and jaw, and electrocardiography showed extensive anterior ST-segment elevation. Emergency coronary angiography showed all three coronary arteries were patent with Thrombolysis in Myocardial Infarction-3 flow and no evidence of dissection or thrombus. The ST-elevation and pain resolved spontaneously. Troponin-T level rose from

76-year-old female presented following an episode of collapse. She was hypotensive with the paramedics and remained refractory despite fluid resuscitation. Her initial baseline tests revealed an elevated troponin; she subsequently underwent a coronary angiogram that showed mild coronary artery disease. Left ventriculogram was performed, which showed abnormal mid-wall ballooning and severely impaired systolic function, characteristic of Takotsubo syndrome. Echocardiogram confirmed the presence of diagnosis and presence of left ventricular outflow tract obstruction with high gradient. She was initiated on medical heart failure therapy and improved. Follow-up investigations after 2 months showed complete resolution of systolic dysfunction and symptoms. Learning points: Takotsubo syndrome can present similarly to ACS. Early use of echocardiography in the acute setting can provide vital information. Takotsubo syndrome can result in hemodynamic instability requiring urgent interventions. Other investigative modalities can be used in conjunction with echocardiography to confirm the diagnosis of Takotsubo syndrome. Prognosis is generally good in patients with Takotsubo syndrome.

Objectives There are multifaceted views on the use of ketamine, a potentially addictive substance, to treat mental health problems. The past 15 years have seen growing media coverage of ketamine for medical and other purposes. This study examined the print news media coverage of medical and other uses of ketamine in North America to determine orientations and trends over time. Methods Print newspaper coverage of ketamine from 2000 to 2015 was reviewed, resulting in 43 print news articles from 28 North American newspapers. A 55-item structured coding instrument was applied to assess news reports of ketamine. Items captured negative and positive aspects, therapeutic use of ketamine, and adverse side effects. Chi-squares tested for changes in trends over time. Results In the 15-year reviewed period, the three most frequent themes related to ketamine were: abuse (68.2%), legal status (34.1%), and clinical use in anesthesia (31.8%). There was significant change in trends during two periods (2000–2007 and 2008–2015). In 2008–2015, print news media articles were significantly more likely to encourage clinical use of ketamine to treat depression (p = 0.002), to treat treatment resistant depression (p = 0.043), and to claim that ketamine is more effective than conventional antidepressants (p = 0.043). Conclusions Our review found consistent positive changes in the portrayals of ketamine by the print news media as a therapeutic antidepressant that mirror the recent scientific publications. These changes in news media reporting might influence the popularity of ketamine use to treat clinical depression. Guidance is required for journalists on objective reporting of medical research findings, including limitations of current research evidence and potential risks of ketamine.

This paper presents an interactive visual analysis tool created for studying collections of video data. Our driving application is cellular behavior studies that use microscopy imaging methods. The studies routinely generate large amounts of videos with various experimental conditions. It is very time-consuming for the scientists to watch each video and manually extract features-of-interest for further comparative and quantitative studies. We show that with our visualization tool, scientists are now able to conveniently observe, select and isolate, and compare and analyze the cellular behaviors from different perspectives within one framework. The tremendous time and effort saved allow scientist to focus on deriving the actual meaning behind certain observed behaviors.

Background— Genome-wide association studies have identified multiple variants associating with coronary artery disease (CAD) and myocardial infarction (MI). Whether a combined genetic risk score (GRS) is associated with prevalent and incident MI in high-risk subjects remains to be established. Methods and Results— In subjects undergoing cardiac catheterization (n=2597), we identified cases with a history of MI onset at age P P value of P =0.11). Finally, during a median 2.5-year follow-up, only a nonsignificant trend was noted between the GRS and incident events, which was also not significant in the replication cohort. Conclusions— A GRS of 11 CAD/MI variants is associated with prevalent MI but not near-term incident adverse events in 2 independent angiographic cohorts. These findings have implications for understanding the clinical use of genetic risk scores for secondary as opposed to primary risk prediction.

Li-Yong Jie,1 Li-Li Cai,2 Le-Jian Wang,2 Xiao-Ying Ying,2 Ri-Sheng Yu,1 Min-Ming Zhang,1 Yong-Zhong Du21Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, 2College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of ChinaBackground: Magnetic resonance imaging (MRI) is widely used in modern clinical medicine as a diagnostic tool, and provides noninvasive and three-dimensional visualization of biological phenomena in living organisms with high spatial and temporal resolution. Therefore, considerable attention has been paid to magnetic nanoparticles as MRI contrast agents with efficient targeting ability and cellular internalization ability, which make it possible to offer higher contrast and information-rich images for detection of disease.Methods: LTVSPWY peptide-modified PEGylated chitosan (LTVSPWY-PEG-CS) was synthesized by chemical reaction, and the chemical structure was confirmed by 1H-NMR. LTVSPWY-PEG-CS-modified magnetic nanoparticles were prepared successfully using the solvent diffusion method. Their particle size, size distribution, and zeta potential were measured by dynamic light scattering and electrophoretic mobility, and their surface morphology was investigated by transmission electron microscopy. To investigate their selective targeting ability, the cellular uptake of the LTVSPWY-PEG-CS-modified magnetic nanoparticles was observed in a cocultured system of SKOV-3 cells which overexpress HER2 and A549 cells which are HER2-negative. The in vitro cytotoxicity of these nanoparticles in SKOV-3 and A549 cells was measured using the MTT method. The SKOV-3-bearing nude mouse model was used to investigate the tumor targeting ability of the magnetic nanoparticles in vivo.Results: The average diameter and zeta potential of the LTVSPWY-PEG-CS-modified magnetic nanoparticles was 267.3 ± 23.4 nm and 30.5 ± 7.0 mV, respectively, with a narrow size distribution and spherical morphology. In vitro cytotoxicity tests demonstrated that these magnetic nanoparticles were carriers suitable for use in cancer diagnostics with low toxicity. With modification of the LTVSPWY homing peptide, magnetic nanoparticles could be selectively taken up by SKOV-3 cells overexpressing HER2 when cocultured with HER2-negative A549 cells. In vivo biodistribution results suggest that treatment with LTVSPWY-PEG-CS-modified magnetic nanoparticles/DiR enabled tumors to be identified and diagnosed more rapidly and efficiently in vivo.Conclusion: LTVSPWY-PEG-CS-modified magnetic nanoparticles are a promising contrast agent for early detection of tumors overexpressing HER2 and further diagnostic application.Keywords: LTVSPWY peptide, HER2, poly(ethylene glycol), chitosan, magnetic nanoparticles, tumor targeting

Ying Men*, Xiao-Xing Wang*, Ruo-Jing Li, Yan Zhang, Wei Tian, Hong-Juan Yao, Rui-Jun Ju, Xue Ying, Jia Zhou, Nan Li, Liang Zhang, Yang Yu, Wan-Liang LuState Key Laboratory of Natural and Biomimetic Drugs, and School of Pharmaceutical Sciences, Peking University, Beijing, People's Republic of China*These authors contributed equally to this manuscriptBackground: Multidrug resistance (MDR) of cancers can be circumvented by inducing programmed cell death, which is known as apoptosis. Mitochondria play a crucial role in apoptosis. Mitochondria-specific therapy would provide an efficient strategy for treating resistant cancers.Design and methods: A strategy was proposed here to overcome MDR by designing cancer mitochondria-specific drug-loaded liposomes, namely, antiresistant epirubicin mitosomes, aimed at treating resistant leukemia by targeting mitochondria. Evaluations were performed on human chronic leukemia K562, MDR K562/ADR cells, and female BALB/c nude mice xenografted with MDR K562/ADR cells. The liposomes were characterized through assays of cytotoxicity, mitochondrial targeting, caspase-9 and caspase-3, antitumor activities, and TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) analysis.Results: The average size of antiresistant epirubicin mitosomes was in the range of 105–115 nm. Antiresistant epirubicin mitosomes were effective in inhibiting proliferation of MDR K562/ADR cells in vitro and selectively accumulated into the mitochondria. Caspase-9 and caspase-3 activity was increased after applying antiresistant epirubicin mitosomes. In xenografted resistant MDR K562/ADR tumor in nude mice, antiresistant tumor effect of antiresistant epirubicin mitosomes was evidently observed. Apoptotic inducing effects by antiresistant epirubicin mitosomes were noticeably evidenced via mitochondrial pathway.Conclusions: Antiresistant epirubicin mitosomes had significant inhibitory effect against resistant leukemia in vitro and in vivo, hence providing a promising strategy for improving therapeutic efficacy in resistant human leukemia.Keywords: mitosomes, mitochondria signaling pathway, nude mice

Our previous studies have shown that local perfusion of morphine causes an increase of extracellular ascorbic acid (AA) levels in nucleus accumbens (NAc) of freely moving rats. Lines of evidence showed that glutamatergic and GABAergic were associated with morphine-induced effects on the neurotransmission of the brain, especially on the release of AA. In the present study, the effects of morphine on the release of extracellular AA, γ-aminobutyric acid (GABA) and glutamate (Glu) in the NAc following bilateral NAc lesions induced by kainic acid (KA) were studied by using the microdialysis technique, coupled to high performance liquid chromatography with electrochemical detection (HPLC-ECD) and fluorescent detection (HPLC-FD). The results showed that local perfusion of morphine (100 µM, 1 mM) in NAc dose-dependently increased AA and GABA release, while attenuated Glu release in the NAc. Naloxone (0.4 mM) pretreated by local perfusion to the NAc, significantly blocked the effects of morphine. After NAc lesion by KA (1 µg), morphine-induced increase in AA and GABA were markedly eliminated, while decrease in Glu was not affected. The loss effect of morphine on AA and GABA release after KA lesion could be recovered by GABA agonist, musimol. These results indicate that morphine-induced AA release may be mediated at least by µ-opioid receptor. Moreover, this effect of morphine possibly depend less on the glutamatergic afferents, but more on the GABAergic circuits within this nucleus. Finally, AA release induced by local perfusion of morphine may be GABA-receptor mediated and synaptically localized in the NAc.

Although it has been demonstrated that carbon nanotubes (CNTs) may have potentials for tissue engineering applications because of their unparalleled physical properties, little has been known on the cell adhesion mechanisms on model CNT monolayer pertaining to the design of novel cell therapeutics device. In this study, the adhesion dynamics of primary porcine esophageal fibroblasts (PEFs) on CNT monolayer were elucidated with confocal reflectance interference contrast microscopy (C-RICM) integrating with phase contrast microscopy. Moreover, CNT monolayer (CNT-ML) was functionalized with two typical extracellular matrix (ECM) proteins including collagen type I (COL) and fibronectin (FN) in order to promote its biocompatibility. First, it is shown by atomic force microscopy that the topographical features of CNT-ML were dependent on the types of immobilized ECM protein. Second, significant time lag in adhesion contact evolution (around 10 min) for PEFs was found on both CNT-ML and CNT-COL compared to the negligible time lag on CNT-FN. It was found that adhesion energy of PEFs on the CNT-COL and CNT-FN surfaces reached steady state at 60 and 30 min after cell seeding compared to 70 min on CNT-ML surface. At steady state, the adhesion energy of PEFs on the CNT-COL and CNT-FN surfaces was about twice as much than that on the CNT-ML surface. Moreover, immobilization of collagen or fibronectin on CNT monolayer led to an increase in seeding efficiency and proliferation rate of PEFs. Scanning electron microscopy and immunostaining together demonstrated that PEFs displayed an elongated morphology and highly polarized actin network on both CNT-COL and CNT-FN surfaces, whereas PEFs displayed nonuniform cell morphology and actin organization on the CNT-ML surface. Overall, our results demonstrated that the biophysical responses and biological behavior of PEFs on unmodified or functionalized CNT monolayer were different. Functionalization of CNT through extracellular matrix protein immobilization effectively promotes cell adhesion and proliferation, which may provide information for designing CNT-based biomaterials or novel cell therapeutics devices in biomedical engineering.

Scanning tunneling microscopy (STM) is known to provide the highest spatial resolution in real space imaging of materials, and its applications are most common among conductive and semiconductive systems. The high tunneling barrier of insulators diminishes the tunneling probability and thus compromises STM's resolution. This work introduces a simple method to approach this problem, by using STM for high-resolution imaging of insulating materials such as the fourth and fifth generations of poly(amidoamine) hydroxyl-terminated dendrimers. The tunneling barrier is lowered by precoordination with Cu(II) or Pt(II) ions, enabling intramolecular hyperfine features be resolved with 0.2 nm resolution. The spatial distribution, size, and overall number of hyperfine features are consistent with the location of dendrimer termini. The immobilization process deforms dendrimers from the spherical geometry in solution phase to asymmetrical domes in ambient. The ultrahigh vacuum (UHV) environment leads to a higher degree of deformation with reduction of volume. The high-resolution images enable the determination of fundamental parameters of individual dendrimers, including axis, height, asymmetry, and volume. From STM spectroscopy and prior knowledge of dendritic systems, the STM imaging mechanism under UHV is consistent with metal(0) nanoparticles encapsulated by dendrimers, while ambient imaging is most likely via metal-ion-facilitated charge transport. The results from this investigation bring us one step closer toward structural characterization at atomistic level and should enable direct comparison of dendrimer structures with simulations, and deepen our understanding of charge transport in dendrimer systems.