221 K Local Photothermal Heating in a Si Plasmonic Waveguide Loaded with a Co Thin Film.

Photothermal heaters are important devices for optical switches and memories based on the thermo-optic/magneto-optic effect and phase change materials. We demonstrated photothermal heating in Si plasmonic waveguides loaded with Co thin films by measuring the resistance change upon inputting transverse-magnetic (TM) mode light. Temperature rise is proportional to the light intensity with clear polarization dependence. The photothermal conversion efficiency was estimated at 36 K/mW and maximum temperature rise was estimated at 221 K at steady state upon the inputting 6.3 mW TM mode light for the 400 nm-wide, 8 µm-long and 189 nm-thick Co film deposited on the Si wire waveguide with 129 nm-thick SiO2 buffer layer. The method to increase the efficiency is discussed based on the experimental and simulation results considering the thickness of the SiO2 buffer layer, Co layer and Si core layer, waveguide width, and wavelength. Local photothermal heaters in this study can be applied to a variety of fields including optical switches/memories without electrical control signals in photonic integrated circuits, on-chip optical sensors, and a lab-on-a-chip in biology, chemistry, and medicine.

Nonreciprocal dielectric-loaded plasmonic waveguides using magneto-optical effect of Fe.

We have implemented the nonreciprocal propagation capabilities into plasmonic waveguides and have simulated the performances. We employed dielectric-loaded surface plasmon polariton waveguide (DLSPPW) and long-range DLSPPW (LR-DLSPPW) configurations, where ferromagnetic-metal Fe is used instead of noble metals in order to obtain nonreciprocal propagations by the transverse magneto-optical (MO) effect. The nonreciprocal performances were characterized by the finite-difference frequency-domain (FDFD) method in terms of the propagation losses in return for the nonreciprocal phase shift (NRPS) and nonreciprocal propagation loss (NRL). The NRPS and NRL of the DLSPPW configuration are larger than those of the previously reported semiconductor waveguide optical isolators owing to the large MO constant of Fe and the field confinement by surface plasmons although the propagation loss for NRL of 1 dB is at least 31 dB and the propagation length is limited to less than 10 µm. To reduce such a large propagation loss, we introduced the LR-DLSPPW configuration composed of Polymethyl methacrylate (PMMA) ridge and Benzocyclobutene (BCB) buffer layer. The Fe layer thickness and width are optimized to 50 nm and 500 nm, respectively, so that sizable MO effect and low propagation loss coexist. The propagation loss for NRL of 1 dB is suppressed to ~10 dB within a waveguide length of ~56 µm. Our comprehensive investigation offers fundamental information on practical magneto-plasmonic waveguides and how much nonreciprocal performances are expected, providing an insight into the integration of magneto-plasmonics with on-chip photonics and electronics.

Enhancement of magneto-optical Kerr effect by surface plasmons in trilayer structure consisting of double-layer dielectrics and ferromagnetic metal.

Giant enhancement of the magneto-optical Kerr effect (MOKE) by surface plasmon polaritons (SPPs) is theoretically shown in a trilayer structure consisting of double-layer dielectrics and a ferromagnetic metal (Al2O3/SiO2/Fe). We calculated the resonant enhancement of the transverse MOKE (TMOKE) and polar MOKE (PMOKE) using the attenuated total reflection (ATR) configuration with the transfer matrix method using a 4 × 4 scattering matrix. At a specific film thickness of the low-index SiO2 layer, where confinement of the SPPs on the Fe surface becomes close to the cutoff condition, the incident light from the Al2O3 couples with the SPPs at the SiO2/Fe boundary most efficiently, resulting in resonant enhancement of the MOKE at an incident angle corresponding to the wave vector of the SPPs. The calculated PMOKE showed orthogonal transformation (90°-rotation) and almost full-orbed deformation (44°-ellipticity) of the polarization, and the TMOKE showed a change in reflectance of about 34 dB upon magnetization reversal.

A precise pharmacodynamic study showing the advantage of a marked reduction in cardiotoxicity in continuous infusion of doxorubicin.

We have already shown that the antileukemic activity of daunorubicin that had been reported to be dependent on the area under the concentration - time curve (AUC) was actually peak concentration (Cmax) dependent. The antitumor activity of doxorubicin (DXR) has also been reported to be dependent on AUC, whereas its cumulative cardiotoxicity has been reported to be Cmax dependent. In this study, we evaluated whether the antileukemic and cardiotoxic effects of DXR were AUC or Cmax dependent, and compared their cytotoxic effects, utilizing the computer-controlled in vitro pharmacokinetic simulation system or a conventional culture system for a leukemic cell line and measuring the intracellular ATP amount or the proportion of beating cells for the cardiotoxicity. In leukemic cells, the cytotoxic rate decreased as the simulated infusion time or exposure time increased with the same AUC value in the simulation and conventional culture system (P < 0.05 and <0.01, respectively). The intracellular ATP and proportion of beating cells also increased with prolonged DXR exposure time with the same constant concentration - time product value (P < 0.05 and <0.0001, respectively) in heart cells. These results indicated that both the antileukemic effects and the cardiotoxicity were Cmax dependent. However, a comparison of the two showed that cardiotoxicity was more Cmax dependent than the antileukemic effect. These results suggested that the continuous infusion treatment schedule of DXR may have the clinical advantage of reducing cardiotoxicity more markedly than the antileukemic effect.

Effects of long-term oral treatment with selective vasopressin V2 receptor antagonist (OPC-31260) on adriamycin-induced heart failure in rats.

BACKGROUND: In the treatment of heart failure, the effects of therapeutic agents on life prognosis remains unclear. We investigated the effects of long-term oral administration of a nonpeptide, selective, vasopressin V2 receptor antagonist, OPC-31260, on Sprague-Dawley rats that were treated with adriamycin to induce progressive water retention. METHODS: Intraperitoneal saline was administered to 14 rats as a control (Group 1). A total cumulative dose of 15 mg/kg of adriamycin was administered intraperitoneally in six equal doses over a period of 2 weeks to another 52 rats. Adriamycin-treated rats were further divided into Group 2, which received saline (p.o.), and Group 3, which received 50 mg/kg (p.o.) of V2 antagonist. Oral administration continued every day for 6 weeks. Group 1 rats also received saline (p.o.) for 6 weeks. RESULTS: The V2 antagonist decreased urine osmolality and increased diuresis of rats in Group 3. Urinary excretion of electrolytes was not increased by the V2 antagonist in Group 3. Serum osmolality was likewise unchanged by the V2 antagonist in Group 3. Plasma concentrations of vasopressin were significantly higher in Group 3 than in the other groups (Group 1, 4.0+/-1.1 pg/ml; Group 2, 4.2+/-1.5 pg/ml; Group 3, 8.5+/-1.0 pg/ml; p<0.05). During the experimental period, survival rate was higher in Group 3 than in Group 2 (Group 1, 100%; Group 2, 59%; Group 3, 83%). CONCLUSION: Our data show that administration of orally active V2 antagonist did not reduce the survival of adriamycin-treated rats through continuous aquaretic action, despite elevated plasma levels of vasopressin.

Pravastatin suppresses the increase in matrix metalloproteinase-2 levels after acute myocardial infarction.

BACKGROUND: Matrix metalloproteinase (MMP) may contribute to myocardial remodeling after myocardial infarction. The goal of this study was to characterize the effects of pravastatin on circulating levels of MMP and on left ventricular dilatation after acute myocardial infarction (AMI). METHODS: Thirty-four consecutive patients with successful reperfusion following AMI were assigned to either pravastatin group (group P, n=12) or non-pravastatin group (group NP, n=22). Serum MMP-2 and tissue inhibitor of MMP (TIMP)-2 were measured immediately after reperfusion, on days 2, 3, 7, 30, and at 6 months after MI. Left ventriculography was performed after reperfusion and at 4 weeks and 6 months. RESULTS: MMP-2 levels were higher in patients with MI than control on days 1, 30, and at 6 months. Left ventricular end-diastolic volume index (LVEDVI) at 6 months correlated with MMP-2 levels on day 30 (r=0.47, p<0.01) and at 6 months (r=0.56, p<0.001). MMP-2 levels at 6 months were significantly lower in group P than group NP. Further, LVEDVI at 6 months tended to be smaller and DeltaLVEDVI was significantly smaller in group P when compared with group NP. CONCLUSION: Serum MMP-2 varied in a time-dependent manner following AMI and correlated with late changes in LVEDVI. Serum MMP-2 levels were significantly lower in treatment group than in non-treatment group and DeltaLVEDVI was significantly smaller in treatment group after long-term pravastatin administration. Use of statins in AMI patients may provide beneficial effects in terms of preventing heart failure over and above its lipid-lowering effects.

Microvascular angina, adverse outcome: a case report.

We encountered a patient with microvascular angina (MVA) who was died suddenly, and observed ST-segment elevation during attack without epicardial coronary arterial vasoconstriction, suggesting the occurrence of microvascular spasm. Doppler guide wire (DGW) and N-13 ammonia positron emission tomography (PET) demonstrate severe impairment of the coronary microcirculation extending throughout the whole of the left ventricle. Conventional medical treatment was not effective in this case. We speculate that the prognosis of microvascular angina with severe coronary microcirculatory disturbance and accompanied by microvascular spasm might not always be good. Therefore, methods for treating such cases need to be established.

Different effects of calcium channel blockers on matrix metalloproteinase-2 expression in cultured rat cardiac fibroblasts.

The cardiac effects of calcium channel blockers (CCBs) related to cardiac remodeling are inconsistent. Matrix metalloproteinases (MMPs) contribute to tissue remodeling. Cardiac fibroblasts play an important role in the regulation of collagen degradation by MMPs. Using gelatin zymography, Western blotting, Griess reagent, and a calcium kit-fluo 3, we investigated the effects of nifedipine, verapamil, diltiazem, and amlodipine on MMP-2 expression and further elucidate the mechanisms in cultured rat cardiac fibroblasts. Nifedipine increased and amlodipine decreased the expression of MMP-2; however, neither verapamil nor diltiazem altered MMP-2 expression. Nifedipine also increased nitrite production, and this increase was blunted by a nitric oxide (NO) synthases inhibitor (L-NAME). Nifedipine-induced MMP-2 expression was also blunted by L-NAME. An NO donor (sodium nitroprusside) induced MMP-2 expression. Data indicated that nifedipine might increase MMP-2 expression through a possible NO-dependent pathway. Amlodipine had no influence on nitrite production. The amlodipine-induced decrease of MMP-2 expression was abolished by two protein tyrosine kinase inhibitors, genistein and herbimycin A, indicating that amlodipine might decrease MMP-2 expression through a possible protein tyrosine kinase pathway. None of the four CCBs could alter the fluoscence intensity of fluo 3, indicating that the effects of CCBs on MMP-2 expression were independent of the variation in intracellular C2+ concentration. Our findings revealed that different CCBs exerted different effects on MMP-2 expression in cardiac fibroblasts.

Effects of magnesium on matrix metalloproteinase-2 production in cultured rat cardiac fibroblasts.

The precise correlation between magnesium and cardiac disease remains to be established. Matrix metalloproteinases (MMPs) are important in cardiac disease such as heart failure. Cardiac fibroblasts are the most abundant cell type in the heart and play an important role in the regulation of collagen degradation by MMPs. To assess the association between magnesium and MMPs, we examined the effects of different extracellular magnesium concentrations (0-3.0 mmol/L) on MMP-2 production in cultured rat cardiac fibroblasts. Using gelatin zymography and western blotting, we found that magnesium reduced MMP-2 production dose-dependently, and this effect was inhibited by the tyrosine kinase inhibitors, genistein or herbimycin A. The results of this study indicated that the beneficial effect of magnesium supplementation on the cardiac disease may be due, at least in part, to the inhibitory effect of magnesium on production of MMPs in cardiac fibroblasts, which appears to be mediated by a protein tyrosine phosphorylation related signal transduction pathway.

Effects of magnesium on prostacyclin synthesis and intracellular free calcium concentration in vascular cells.

This study investigated the effects of extracellular magnesium concentration ([Mg2+]e; 0.3-3 mM) on intracellular free calcium concentration ([Ca2+]i) and prostacyclin (PGI2) production in cultured human umbilical vein endothelial cells (HUVEC) and vascular smooth muscle cells from rats (VSMC) under basal and agonist-stimulated conditions. We used histamine as agonist which increases [Ca2+]i and PGI2 production in HUVEC, norepinephrine in VSMC. [Mg2+]e dose-dependently increased basal and agonist-stimulated PGI2 production in both cells. [Mg2+]e dose-dependently reduced basal [Ca2+]i in VSMC, but did not influence in HUVEC. In both cells, increasing [Mg2+]e reduced agonist-stimulated [Ca2+]i responses. Furthermore, [Mg2+]e dose-dependently reduced agonist-stimulated [Ca2+]i in Ca(2+)-free buffer, indicating intracellular Ca2+ release. In VSMC, 10(-6) M diltiazem and 10(-7) M nifedipine, Ca2+ channel blockers, reduced agonist-stimulated [Ca2+]i as well as 3 mM Mg2+, but did not affect PGI2 production. [Mg2+]e amplified dose-dependently arachidonic acid-induced PGI2 production in both cells, suggesting the activation of cyclooxygenase and/or PGI2 synthetase. Our results suggest that [Mg2+]e influences intracellular Ca2+ mobilization of not only vascular smooth muscle cells but also endothelial cells by inhibiting both Ca2+ influx and intracellular Ca2+ release. [Mg2+]e enhances PGI2 production in both types of cells, although the mechanism is likely to be independent from Ca2+ mobilization.

Circulating matrix metalloproteinase-2 is elevated in patients with congestive heart failure.

BACKGROUND AND AIMS: It has been reported that matrix metalloproteinase (MMP) protein concentration and activity are upregulated in the failing human heart. However, there are few reports describing the role of elevated level of circulating MMPs in congestive heart failure (CHF) patients. This study examined whether circulating matrix metalloproteinases (MMPs) are also related to the pathogenesis of CHF. METHODS: We measured circulating levels of matrix metalloproteinase-2 (MMP-2) in 52 patients with CHF (left ventricular ejection fraction (LVEF) <50%). The patients were also subdivided into two groups according to NYHA functional class; mild CHF (class II, n=43) and severe CHF (class III, n=9). RESULTS: The serum level of MMP-2 and MMP-2/TIMP-2 ratio were significantly higher in CHF than in controls (P<0.01). Among patient groups, serum levels of MMP-2 were significantly higher in patients with severe CHF than in patients with mild CHF (P<0.01). Plasma levels of BNP had a significant positive correlation with circulating levels of MMP-2 (r=0.78; P<0.01) and MMP-2/TIMP-2 ratio (r=0.60; P<0.01). CONCLUSIONS: Our data showed that the circulating MMP-2 concentration was increased in CHF patients and that the levels were related to the plasma levels of BNP in CHF, suggesting that the elevated levels are related to developing heart failure syndrome.

Mitochondrials complex I activity is reduced in latent adriamycin-induced cardiomyopathy of rat.

We previously reported on the use of enzymatic analysis to impair fatty acid metabolism followed by reduced myocardial energy content, leading to severe heart failure in adriamycin (ADR)-treated rats. The aim of this study is to investigate whether impaired myocardial energy metabolism can also be detected by other methods; i.e. measuring mitochondrial complex I activity and myocardial 125I-15-(p-iodophenyl)-3-(R,S)- methylpentadecanoic acid (BMIPP) accumulation in ADR-treated rats. Eight-week-old male Sprague-Dawley rats received 6 intraperitoneal injections of ADR (total 15 mg/kg: group ADR) or saline (control group) over 2 weeks. Left ventricular (LV) ejection fraction was assessed using echocardiography at 3- and 6-weeks after ADR injection (3 weeks and 6 weeks, respectively). Myocardial fatty acid utilization was assessed at 3 weeks and 6 weeks. The myocardial counts of BMIPP were measured after intravenous BMIPP (370 kBq) injection, and 125I counts were measured to calculate the uptake ratio. The enzymatic activity of complex I was assessed by monitoring the oxidation of nicotinamide-adenine-dinucleotide-disodium-salt (NADH). In rats treated with ADR, significant decrease in LV ejection fraction was observed only at 6 weeks compared to control (72.5 vs. 84.5%, p < 0.01). LV ejection fraction at 3 weeks was identical between group ADR and control (81.8 vs. 84.4%). However, at 3 weeks, complex I activity was already reduced significantly in group ADR as compared to control group (p = 0.03), but the reduction in BMIPP accumulation was not (p = 0.15). Our data indicated that reduced complex I activity in a phenomenon occurred in early phase of ADR-induced cardiomyopathy, and it might play an important role in the progression of ADR-induced heart failure.

Cutaneous arteriolar thioredoxin expression in patients with heart failure.

Cutaneous microangiopathic lesions exist in patients with heart failure, and heart failure is associated with increased oxidative stress. Thioredoxin (TRX) is stress-inducible and has a cytoprotective effect against oxidative stress. Accordingly, to investigate whether arteriolar TRX expression was increased in the skin of patients with congestive heart failure (CHF), skin biopsies were taken at the time of cardiac catheterization, and the results were compared with those of control subjects. The diagnosis of CHF was done by cardiac catheterization with reference to elevated plasma concentrations of TRX and brain natriuretic peptide (BNP). Increased TRX expression was found in the skin biopsies of 29 of the 35 patients with CHF, but in none of the 8 control subjects; the semiquantitative grade of arteriolar TRX immunoreactivity was 2.5+/-1.0 in patients with CHF and 1.0+/-0.0 in controls, respectively (p<0.01). The severity of arteriolar TRX expression did not correlate with the New York Heart Association functional class. These results indicate that cutaneous arteriolar TRX expression in patients with CHF may reflect the excessive oxidative stress of the peripheral circulation associated with the condition.

Effects of magnesium on the production of extracellular matrix metalloproteinases in cultured rat vascular smooth muscle cells.

The precise correlation between magnesium and cardiovascular disease remains to be established. Matrix metalloproteinases (MMPs) are expressed in coronary arterial atherosclerotic lesions. MMP production in vascular smooth muscle cells (VSMCs) is stimulated by growth factors such as platelet-derived growth factor (PDGF). To assess the association between magnesium and MMPs, we examined the effects of different extracellular magnesium concentrations (0-3.0 mmol/l) on MMPs production in cultured rat VSMCs under basal and PDGF-stimulated conditions using gelatin zymography and western blotting. As magnesium is called a natural calcium antagonist, we further compared the effects of magnesium with some calcium antagonists. Magnesium reduced MMP-2 production dose-dependently at basal and PDGF-stimulated conditions in VSMCs. However, neither verapamil nor nifedipine influenced MMP-2 production under any conditions examined. The effect of magnesium on the production of MMP-2 was inhibited by two tyrosine kinase inhibitors-genistein and herbimycin A. The results of this study indicate that extracellularly added magnesium decreased MMPs secretion, which appears to be associated with protein tyrosine kinase.

Serum cytokine level during continuous venovenous hemofiltration in toxic shock-like syndrome due to group G beta Streptococcus bacteremia in a patient with idiopathic thrombocytopenic purpura.

We report a case of toxic shock-like syndrome due to a rare infection of group G Streptococcus bacteremia in a patient with idiopathic thrombocytopenic purpura and its successful treatment with continuous venovenous hemofiltration (CVVH). As the result of sepsis treatment with CVVH, in addition to administration of vasopressors and antibiotics, serum levels of interleukin-1beta, interleukin-10 and tumor necrosis factor-a fell and shock was controlled.

Reversible defect of 123I-15-(p-iodophenyl)-9-(R,S)-methylpentadecanoic acid indicates residual viability within infarct-related area.

To evaluate the relationship between the reversible defect of 123I-15-(p-iodophenyl)-9-(R,S)-methylpentadecanoic acid (9MPA) and residual viability within an infarct-related area, we performed resting single photon emission computed tomography (SPECT) with 9MPA and positron emission tomography (PET) with 18F-deoxyglucose (FDG) and 13N-ammonia (NH3) in 7 patients with prior myocardial infarction. 9MPA-SPECT was obtained 2 min (early) and 50 min (delayed) after tracer injection. Tomographic images of the left ventricle were divided into 13 segments to correlate the regional uptake of each tracer. Residual viability within an infarct-related segment was confirmed by NH3- and FDG-PET. Twenty-six infarct-related segments, confirmed by NH3-PET, showed reduced uptake of 9MPA on early images. In these 26 segments, 6 showed reversible defect of 9MPA and 20 showed fixed defect on delayed images. Residual viability was present in all segments exhibiting reversible 9MPA defect and 7 segments (35%) exhibiting fixed defect (p < 0.05). The sensitivity, specificity and accuracy of reversible 9MPA defect for the detection of myocardial viability were 46%, 100%, and 73%, respectively. Myocardial clearance of 9MPA was significantly slower in non-viable segments than in ischemic but viable segments (4.9+/-5.1% vs. 10.1+/-5.3%; p < 0.05). These data suggest that a reversible 9MPA defect indicates residual viability within the infarct-related area.

Evaluation of arteriolar hyalinosis of the skin of patients with chronic congestive heart failure.

To investigate whether microvascular lesions are present in the skin of patients with chronic congestive heart failure (CHF), skin biopsies were performed at the time of cardiac catheterization, and the results were compared with control subjects. The diagnosis of CHF was done by cardiac catheterization with reference to the elevation of plasma levels of brain natriuretic peptide (BNP). Although the severity of arteriolar hyalinosis did not correlate with the New York Heart Association functional class, increased hyalinosis was found in skin biopsies from 17 of 20 patients with CHF, but in none of the 6 control subjects. These results indicate that microangiopathic alterations in arterioles may exist in patients with CHF and therapy for peripheral vascular remodeling might be considered for such patients.