Cholinergic Stimulation by Pyridostigmine Bromide Before Myocardial Infarction Prevent Cardiac and Autonomic Dysfunction.

Inflammatory processes and cardiovascular autonomic imbalance are very relevant characteristic of the enormous dynamic process that is a myocardial infarction (MI). In this sense, some studies are investigating pharmacological therapies using acetylcholinesterase inhibitors, such as pyridostigmine bromide (PYR), aiming to increase parasympathetic tone after MI. Here we hypothesized that the use of PYR before the MI might bring an additional positive effect to the autonomic function, and consequently, in the inflammatory response and cardiac function. The present study aimed to evaluate left ventricular function, baroreflex sensitivity, autonomic modulation, and inflammatory profile in PYR-treated rats previously to MI. METHODS: Male Wistar rats (250-300 g) were treated for 60 days with PYR. After treatment, they were submitted to the MI. After the MI, the autonomic and ventricular function were evaluated, as well as the systemic, left ventricle, and adipose tissue inflammatory profile. RESULTS: PYR, performed before MI, prevented HR increase, systolic function impairment, baroreflex sensitivity drop, as well as pulse interval variance, RMSSD, blood pressure and parasympathetic modulation reduction in treated rats compared to untreated rats. Also, this positive functional changes may have been a result of the reduced inflammatory parameters in the left ventricle (IFN-γ, IL-6, and IL-1ß), as well as increased IL-10 expression and IL-10/TNF-α ratio in treated animals before MI. CONCLUSION: Prior treatment with PYR prevents impairment of the autonomic nervous system after MI, which may be associated with the attenuated expression of inflammatory factors and heart dysfunction.

Temporal pattern recognition with delayed feedback spin-torque nano-oscillators.

The recent demonstration of neuromorphic computing with spin-torque nano-oscillators has opened a path to energy efficient data processing. The success of this demonstration hinged on the intrinsic short-term memory of the oscillators. In this study, we extend the memory of the spin-torque nano-oscillators through time-delayed feedback. We leverage this extrinsic memory to increase the efficiency of solving pattern recognition tasks that require memory to discriminate different inputs. The large tunability of these non-linear oscillators allows us to control and optimize the delayed feedback memory using different operating conditions of applied current and magnetic field.

Mutual synchronization of spin torque nano-oscillators through a long-range and tunable electrical coupling scheme.

The concept of spin-torque-driven high-frequency magnetization dynamics, allows the potential construction of complex networks of non-linear dynamical nanoscale systems, combining the field of spintronics and the study of non-linear systems. In the few previous demonstrations of synchronization of several spin-torque oscillators, the short-range nature of the magnetic coupling that was used has largely hampered a complete control of the synchronization process. Here we demonstrate the successful mutual synchronization of two spin-torque oscillators with a large separation distance through their long range self-emitted microwave currents. This leads to a strong improvement of both the emitted power and the linewidth. The full control of the synchronized state is achieved at the nanoscale through two active spin transfer torques, but also externally through an electrical delay line. These additional levels of control of the synchronization capability provide a new approach to develop spin-torque oscillator-based nanoscale microwave-devices going from microwave-sources to bio-inspired networks.

Neuromorphic Computing through Time-Multiplexing with a Spin-Torque Nano-Oscillator.

Fabricating powerful neuromorphic chips the size of a thumb requires miniaturizing their basic units: synapses and neurons. The challenge for neurons is to scale them down to submicrometer diameters while maintaining the properties that allow for reliable information processing: high signal to noise ratio, endurance, stability, reproducibility. In this work, we show that compact spin-torque nano-oscillators can naturally implement such neurons, and quantify their ability to realize an actual cognitive task. In particular, we show that they can naturally implement reservoir computing with high performance and detail the recipes for this capability.

Coherent microwave generation by spintronic feedback oscillator.

The transfer of spin angular momentum to a nanomagnet from a spin polarized current provides an efficient means of controlling the magnetization direction in nanomagnets. A unique consequence of this spin torque is that the spontaneous oscillations of the magnetization can be induced by applying a combination of a dc bias current and a magnetic field. Here we experimentally demonstrate a different effect, which can drive a nanomagnet into spontaneous oscillations without any need of spin torque. For the demonstration of this effect, we use a nano-pillar of magnetic tunnel junction (MTJ) powered by a dc current and connected to a coplanar waveguide (CPW) lying above the free layer of the MTJ. Any fluctuation of the free layer magnetization is converted into oscillating voltage via the tunneling magneto-resistance effect and is fed back into the MTJ by the CPW through inductive coupling. As a result of this feedback, the magnetization of the free layer can be driven into a continual precession. The combination of MTJ and CPW behaves similar to a laser system and outputs a stable rf power with quality factor exceeding 10,000.

Spin-torque resonant expulsion of the vortex core for an efficient radiofrequency detection scheme.

It has been proposed that high-frequency detectors based on the so-called spin-torque diode effect in spin transfer oscillators could eventually replace conventional Schottky diodes due to their nanoscale size, frequency tunability and large output sensitivity. Although a promising candidate for information and communications technology applications, the output voltage generated from this effect has still to be improved and, more pertinently, reduces drastically with decreasing radiofrequency (RF) current. Here we present a scheme for a new type of spintronics-based high-frequency detector based on the expulsion of the vortex core in a magnetic tunnel junction (MTJ). The resonant expulsion of the core leads to a large and sharp change in resistance associated with the difference in magnetoresistance between the vortex ground state and the final C-state configuration. Interestingly, this reversible effect is independent of the incoming RF current amplitude, offering a fast real-time RF threshold detector.

Understanding of Phase Noise Squeezing Under Fractional Synchronization of a Nonlinear Spin Transfer Vortex Oscillator.

We investigate experimentally the synchronization of vortex based spin transfer nano-oscillators to an external rf current whose frequency is at multiple integers, as well as at an integer fraction, of the oscillator frequency. Through a theoretical study of the locking mechanism, we highlight the crucial role of both the symmetries of the spin torques and the nonlinear properties of the oscillator in understanding the phase locking mechanism. In the locking regime, we report a phase noise reduction down to -90 dBc/Hz at 1 kHz offset frequency. Our demonstration that the phase noise of these nanoscale nonlinear oscillators can be tuned and eventually lessened, represents a key achievement for targeted radio frequency applications using spin torque devices.

Effect of laser suture lysis on filtration openings: a prospective three-dimensional anterior segment optical coherence tomography study.

PURPOSE: To investigate the effects of laser suture lysis (LSL) on filtration openings after trabeculectomy. METHODS: Prospective study analyzing the changes in the location and width of filtration openings, fluid cavity height, total bleb height, bleb wall thickness, and bleb wall intensity before and after LSL using three-dimensional anterior segment optical coherence tomography (3D AS-OCT). RESULTS: Fourteen patients had clear scleral flap image analysis. As five patients underwent LSL twice and two patients underwent LSL thrice, 23 comparison studies were possible. After LSL the intraocular pressure (IOP) decreased (P = 0.0015) from 20.5 ± 5.3 to 14.9 ± 6.4 mm Hg, and the fluid cavity height increased significantly from 0.2 ± 0.2 mm to 0.3 ± 0.1 mm (P = 0.0094). Other bleb parameters were not significantly different when comparing before and after LSL. When the IOP reduction ratio was > 25% following LSL, the width of the filtration openings on the LSL side, the total bleb height, and the fluid cavity height increased (P = 0.0273, 0.0342, and 0.0024, respectively). In multiple regression analysis the changes in fluid cavity height, the wall thickness, the wall intensity, and the width of the filtration opening were positively associated with the IOP reduction rate (P = 0.0428, 0.0226, 0.0420, and 0.0356, respectively). CONCLUSIONS: 3D AS-OCT allowed a detailed examination of the internal morphology of filtration blebs and openings before and after LSL. The changes in the internal morphology were closely associated with the success of LSL to decrease IOP.

Microbiologically induced corrosive properties of the titanium surface.

Corrosion of titanium is the major concern when it is used for dental treatment. This study aimed to investigate the mechanism of the microbiologically induced corrosive properties of titanium. An experimental well was made of polymethyl methacrylate with pure titanium at the bottom. Viable or killed cells of Streptococcus mutans were packed into the well, and pH at the bacteria-titanium interface was monitored with and without glucose. Before and after 90-minute incubation, the electrochemical behavior on the titanium surface was measured by means of a potentiostat. The oxygen concentration under bacterial cells was monitored with oxygen-sensitive fluorescent film. The amount of titanium eluted was measured by inductively coupled plasma-mass spectrometry. The corrosion current and passive current under killed cells were low and stable during 90 min, while those under viable cells increased, regardless of the glucose-induced pH fall. The polarization resistance and oxygen concentration under killed cells were high and stable, while those under viable cells decreased. No elution of titanium was detected. Viable bacterial cells may form 'oxygen concentration cells' through metabolism-coupled oxygen consumption and subsequently induce corrosive properties of the titanium surface.

Highly sensitive nanoscale spin-torque diode.

Highly sensitive microwave devices that are operational at room temperature are important for high-speed multiplex telecommunications. Quantum devices such as superconducting bolometers possess high performance but work only at low temperature. On the other hand, semiconductor devices, although enabling high-speed operation at room temperature, have poor signal-to-noise ratios. In this regard, the demonstration of a diode based on spin-torque-induced ferromagnetic resonance between nanomagnets represented a promising development, even though the rectification output was too small for applications (1.4 mV mW(-1)). Here we show that by applying d.c. bias currents to nanomagnets while precisely controlling their magnetization-potential profiles, a much greater radiofrequency detection sensitivity of 12,000 mV mW(-1) is achievable at room temperature, exceeding that of semiconductor diode detectors (3,800 mV mW(-1)). Theoretical analysis reveals essential roles for nonlinear ferromagnetic resonance, which enhances the signal-to-noise ratio even at room temperature as the size of the magnets decreases.

Optimization of cell-wall skeleton derived from Mycobacterium bovis BCG Tokyo 172 (SMP-105) emulsion in delayed-type hypersensitivity and antitumor models.

Cell-wall skeleton prepared from Mycobacterium bovis BCG (BCG-CWS) is known as a potent adjuvant and has been shown to possess antitumor activity in many non-clinical and clinical studies. As there are no approved BCG-CWS formulations for cancer therapy, we investigated the potential for cancer immunotherapy of SMP-105, our originally produced BCG-CWS. For optimizing SMP-105 emulsion, we compared the effects of drakeoland squalane-based SMP-105 emulsions on IFN-γ production in rats and evaluated their ability to induce skin reaction in guinea pigs. Both emulsions had the same activity in both experiments. We selected squalane as base material and produced two types of squalane-based formulations (vialed emulsion and pumped emulsion) that can easily be prepared as oil-in-water emulsions. Although the vialed emulsion showed the same pattern of distribution as a usual homogenized emulsion, the pumped emulsion showed more uniform distribution than the other two emulsions. Whereas both emulsions enhanced strong delayed type hypersensitivity (DTH) reaction in a mouse model, the pumped emulsion induced slightly smaller edema. Data on oil droplet size distribution suggest that few micrometer oil droplet size might be appropriate for oil-in-water microemulsion of SMP-105. The antitumor potency of SMP-105 emulsion was stronger than that of some of the launched toll-like receptor (TLR) agonists (Aldara cream, Picibanil, and Immunobladder). Aldara and Picibanil showed limited antitumor effectiveness, while Immunobladder had almost the same effect as SMP-105 at the highest dose, but needed about 10 times the amount of SMP-105. These findings first indicate that SMP-105 has great potential in cancer immunotherapy.

Comparison of sensitivity of lung nodule detection between radiologists and technologists on low-dose CT lung cancer screening images.

OBJECTIVES: The objective of this study was to compare the sensitivity of detection of lung nodules on low-dose screening CT images between radiologists and technologists. METHODS: 11 radiologists and 10 technologists read the low-dose screening CT images of 78 subjects. On images with a slice thickness of 5 mm, there were 60 lung nodules that were ≥5 mm in diameter: 26 nodules with pure ground-glass opacity (GGO), 7 nodules with mixed ground-glass opacity (GGO with a solid component) and 27 solid nodules. On images with a slice thickness of 2 mm, 69 lung nodules were ≥5 mm in diameter: 35 pure GGOs, 7 mixed GGOs and 27 solid nodules. The 21 observers read screening CT images of 5-mm slice thickness at first; then, 6 months later, they read screening CT images of 2-mm slice thickness from the 78 subjects. RESULTS: The differences in the mean sensitivities of detection of the pure GGOs, mixed GGOs and solid nodules between radiologists and technologists were not statistically significant, except for the case of solid nodules; the p-values of the differences for pure GGOs, mixed GGOs and solid nodules on the CT images with 5-mm slice thickness were 0.095, 0.461 and 0.005, respectively, and the corresponding p-values on CT images of 2-mm slice thickness were 0.971, 0.722 and 0.0037, respectively. CONCLUSION: Well-trained technologists may contribute to the detection of pure and mixed GGOs ≥5 mm in diameter on low-dose screening CT images.

Large microwave generation from current-driven magnetic vortex oscillators in magnetic tunnel junctions.

Spin-polarized current can excite the magnetization of a ferromagnet through the transfer of spin angular momentum to the local spin system. This pure spin-related transport phenomenon leads to alluring possibilities for the achievement of a nanometer scale, complementary metal oxide semiconductor-compatible, tunable microwave generator that operates at low bias for future wireless communication applications. Microwave emission generated by the persistent motion of magnetic vortices induced by a spin-transfer effect seems to be a unique manner to reach appropriate spectral linewidth. However, in metallic systems, in which such vortex oscillations have been observed, the resulting microwave power is much too small. In this study, we present experimental evidence of spin-transfer-induced vortex precession in MgO-based magnetic tunnel junctions, with an emitted power that is at least one order of magnitude stronger and with similar spectral quality. More importantly and in contrast to other spin-transfer excitations, the thorough comparison between experimental results and analytical predictions provides a clear textbook illustration of the mechanism of spin-transfer-induced vortex precession.

Evaluation of histamine-induced conjunctival oedema in guinea pigs by means of image analysis.

BACKGROUND: Conjunctival oedema is commonly observed in patients with allergic conjunctivitis and can be induced by histamine. In animal models of allergic conjunctivitis, conjunctival oedema is generally evaluated by measuring the extravasation of Evans blue dye into the conjunctiva. A limitation of this method is that it only allows evaluation at a single time point. The aim of the present study was to investigate kinetic changes in histamine-induced bulbar oedema. METHODS: Evans blue dye was injected intravenously into male guinea pigs. Histamine eye-drops were administered 30 min later. One group of animals received levocabastine (an antihistamine) eye-drops 10 min before histamine challenge. A digital camera was used to obtain images of the bulbar conjunctiva at 1 min intervals until 30 min after histamine challenge. The conjunctivas were then harvested, and the concentration of Evans blue was measured. The ImageJ software was used to analyse the images by counting the number of absolute pixel values. RESULTS: The degree of conjunctival oedema increased progressively until 20 min after histamine challenge and then stabilised. Correspondingly, the number of absolute pixel values increased significantly until 5 min after histamine challenge, then increased gradually until the 20 min time point and finally plateaued. Pixel values were significantly lower in animals treated with levocabastine than in control animals. A significant correlation was observed between the pixel values of the conjunctival images and the concentration of Evans blue in the conjunctiva. CONCLUSIONS: This is the first study to have quantitatively evaluated kinetic changes in histamine-induced bulbar oedema by means of image analysis.

Systemic overexpression of IFN-gamma and IL-5 exacerbates early phase reaction and conjunctival eosinophilia, respectively, in experimental allergic conjunctivitis.

AIMS/BACKGROUND: To investigate how systemic overexpression of IL-4, IL-5 and IFN-gamma affects the severity of experimental conjunctivitis (EC) in mice. METHODS: The tibialis anterior muscle of naive BALB/c mice was electroporated with IL-4, IL-5, IFN-gamma or a control gene, and then the mice blood and conjunctivas were harvested to measure the eosinophil content in these tissues. To evaluate the effects of cytokine gene electroporation on the early-phase reaction (EPR), cytokine gene-electroporated ragweed (RW)-immunised mice were intravenously injected with Evans Blue (EB) and then challenged with RW in eye-drops. Thirty minutes later, their conjunctivas were harvested to extract EB and evaluate the EPR. Additionally, 24 h after RW challenge, conjunctivas were harvested from cytokine gene-electroporated RW-immunised mice, which had not received intravenous injection of EB, to measure conjunctival eosinophilia. RESULTS: Significantly more eosinophils were detected in the blood and conjunctivas of IL-5-electroporated mice in which EC was not induced. The intensity of the EPR was significantly greater in IFN-gamma-electroporated mice. Significantly greater eosinophil infiltration was seen in the conjunctivas of IL-5-electroporated EC-developing mice. CONCLUSIONS: It appears that systemic IL-5 and IFN-gamma play different roles in the development of EC.

PTHrP induces Notch signaling in periodontal ligament cells.

Periodontal ligament (PDL) cells are known to play important roles in tooth eruption and alveolar bone metabolism. We previously reported that PTHrP increases RANKL expression in human PDL cells, suggesting that it promotes odontoclastic root resorption during tooth eruption. While it is known that Notch-related genes play a key role during bone development, the role of the Notch signaling pathway in PDL cells during tooth and bone resorption is less clear. We hypothesized that PTHrP induces a Notch ligand in PDL cells and thereby regulates osteo- and odontoclastogenesis. We found that PTHrP increased Notch1 ligand Jagged1 expression in human PDL cells in a dose- and time-dependent manner. PTHrP-induced Jagged1 up-regulation was mediated by PKA activation, but not by PKC. Jagged1 also promoted RANKL-induced osteoclastogenesis. These results demonstrate that PTHrP induces Jagged1 expression in PDL cells, leading to osteo- and odontoclastogenesis, and thus likely promoting tooth and alveolar bone resorption.

Detectability of peripheral lung cancer on chest radiographs: effect of the size, location and extent of ground-glass opacity.

The purpose of this study was to evaluate the effect of the size and location of lung tumour and the extent of ground-glass opacity (GGO) on thin-section CT for the detection of peripheral lung cancer on chest radiographs. 100 posteroanterior chest radiographs of peripheral lung cancer 20 mm in diameter or smaller were reviewed retrospectively by two chest radiologists individually. Lung cancer was detectable on chest radiographs in 51 (51%) cases. However, in six cases, the tumour was recognized not as a nodular opacity but as a subpleural linear or localized hazy opacity. The median size of detectable lung cancer (17 mm) was larger than that of undetectable lung cancer (14 mm; p<0.001). The frequency of tumours with extent of GGO less than 70% was 94% in detectable cases and 59% in undetectable cases (p<0.001). The frequency of tumours located in unobscured lung was 94% in detectable cases and 59% in undetectable cases (p<0.001). The detectability of peripheral lung cancer on chest radiographs is influenced by tumour size, location and extent of GGO seen on thin-section CT. It should also be noted that some tumours may not be recognized as a nodular opacity even if they are detectable.

Activation of tumour-necrosis factor-related apoptosis-inducing ligand receptor enhances the severity of murine allergic conjunctivitis.

BACKGROUND/AIMS: Tumour-necrosis-factor-related apoptosis-inducing ligand (TRAIL) plays a role in the development of allergic asthma. The study aimed to determine whether TRAIL also participates in the development of experimental allergic conjunctivitis (EC), another allergic disease model. METHODS: EC was induced in BALB/c mice by active immunisation with ragweed (RW) followed by RW challenge. To investigate whether TRAIL in the conjunctiva plays a role in the development of EC, conjunctival TRAIL expression in EC-developing mice was evaluated by immunohistochemistry. Additionally, the effect of subconjunctival injection of recombinant TRAIL on conjunctival inflammation was examined. To investigate whether TRAIL expressed in systemic immunocompetent cells plays a role in the development of EC, anti-TRAIL blocking Ab or anti-TRAIL receptor agonistic Ab was intraperitoneally injected into EC-developing mice, and conjunctival eosinophil infiltration was evaluated. RESULTS: Conjunctival TRAIL expression was not increased by EC induction. Moreover, subconjunctival injection of TRAIL protein in naive mice did not induce conjunctival inflammation. Thus, TRAIL in the conjunctiva is less likely to participate in the development of EC. Systemic treatment with anti-TRAIL blocking Ab in EC-developing mice did not affect the severity of EC. However, systemic treatment during the induction phase of EC with an agonistic Ab for the TRAIL receptor significantly augmented the severity of EC and increased Ag-recall splenocyte IFN-gamma production in vitro. CONCLUSIONS: These results indicate that TRAIL receptor-expressing cells in lymphoid organ participate in the development of EC.

Immune response against cell-wall skeleton of Mycobacterium bovis BCG at the inoculation site and peripheral lymphoid organs.

We reported in the previous paper that highly purified cell-wall skeleton of M. bovis BCG (SMP-105) eliminated lymph node metastases and primary implanted tumor, presumably by generating tumor immunity, employing guinea pigs. In this paper, we investigated the immune reactions to elucidate the mechanisms of antitumor activity. Twenty-four hours after intradermal injection, inflammatory cells were seen migrating to the inoculation site. Massive infiltrations of lymphocytes were observed on day 7, when a large amount of SMP-105 was still observed in the dermis. Several chemokines attracting neutrophils and monocytes, detected by TaqMan RT-PCR, were induced rapidly and declined 72 h post-injection, but most increased again on day 7, consistent with the pathological findings of lymphocyte infiltration. Activation of lymph node cells was investigated using mice. Upon stimulation by SMP-105 in vitro, the draining lymph node cells collected from mice treated with SMP-105 produced interferon-γ (IFN-γ), whereas, lymph node cells did not release IFN-γ when prepared from mice treated with OK-432. This evidence prompted us to assume that SMP-105 functioned as T cell antigens. Intracellular cytokine analysis demonstrated that IFN-γ was mainly attributable to CD4-CD8+αßT and CD4-CD8-αßT cells. In conclusion, oil-in-water emulsion of SMP-105 resided for a long time at the inoculation site and activated T cells, probably recognizing SMP-105 itself. The strong tumor eliminating activity of SMP-105 may be explained by the boost of generating tumor immunity via positive feed-back from T cells reacting to it, and CD4-CD8+αßT and CD4-CD8-αßT cells may distinguish SMP-105 from other synthetic adjuvants.