Search

Patient: Female, 71-year-old Final Diagnosis: Pacemaker related pleural effusion Symptoms: Dry cough Medication:— Clinical Procedure: — Specialty: Cardiology • General and Internal Medicine Objective: Unusual or unexpected effect of treatment Background: Post-cardiac injury syndrome, including pleural effusion as a delayed complication of permanent pacemaker implantation, has rarely been reported. To resolve pleural effusion, prolonged chest tube placement is often required. Anti-inflammatory agents combined with diuretics are also often prescribed. Saireito, a Japanese herbal medication, which is a combination of Goreisan and Shousaikoto, has both anti-inflammatory and water-modulation properties and has been used for edema (lymph edema, cerebral edema) and inflammation (chronic nephritis). Case Report: We describe a 71-year-old woman with a history of syncope and bradycardia who underwent dual permanent pacemaker implantation (placed in the right chest because of a persistent left superior vena cava) without complications. Two months later, she came to the hospital as an outpatient with a dry cough, and was diagnosed with right-sided pleural effusion. A pleural fluid analysis revealed exudative effusion, according to Light’s criteria. The fluid was negative for infectious etiology. Chest X-ray, computed tomography, and echocardiography revealed no signs of pericardial effusion or perforation of the pacemaker lead to outside the heart. The pleural effusion persisted despite use of anti-inflammatory medication for several weeks and diuretics for a short period. Saireito was administered with good response; the pleural effusion resolved completely and there was no deterioration of renal function. Conclusions: The present case highlights the clinical significance of Saireito as an effective therapeutic agent for late-onset pacemaker-related pleural effusion, without adverse effects such as renal dysfunction.

Background: Coronary artery spasms (CASs), which can cause angina attacks and sudden death, have been recently reported during catheter ablation. The aim of the present study was to report the incidence, characteristics, and prognosis of CASs related to atrial fibrillation (AF) ablation procedures. Methods and Results: The AF ablation records of 22,232 patients treated in 15 Japanese hospitals were reviewed. CASs associated with AF ablation occurred in 42 of 22,232 patients (0.19%). CASs occurred during ablation energy applications in 21 patients (50%). CASs also occurred before ablation in 9 patients (21%) and after ablation in 12 patients (29%). The initial change in the electrocardiogram was ST-segment elevation in the inferior leads in 33 patients (79%). Emergency coronary angiography revealed coronary artery stenosis and occlusions, which were relieved by nitrate administration. No air bubbles were observed. A comparison of the incidence of CASs during pulmonary vein isolation between the different ablation energy sources revealed a significantly higher incidence with cryoballoon ablation (11/3,288; 0.34%) than with radiofrequency catheter, hot balloon, or laser balloon ablation (8/18,596 [0.04%], 0/237 [0%], and 0/111 [0%], respectively; P

Currently, cardiomyocyte (CM) differentiation methods require a purification step after CM induction to ensure the high purity of the cell population. Here we show an improved human CM differentiation protocol with which high-purity ventricular-type CMs can be obtained and maintained without any CM purification process. We induced and collected a mesodermal cell population (platelet-derived growth factor receptor-α (PDGFRα)-positive cells) that can respond to CM differentiation cues, and then stimulated CM differentiation by means of Wnt inhibition. This method reproducibly generated CMs with purities above 95% in several human pluripotent stem cell lines. Furthermore, these CM populations were maintained in culture at such high purity without any further CM purification step for over 200 days. The majority of these CMs (>95%) exhibited a ventricular-like phenotype with a tendency to structural and electrophysiological maturation, including T-tubule-like structure formation and the ability to respond to QT prolongation drugs. This is a simple and valuable method to stably generate CM populations suitable for cardiac toxicology testing, disease modeling and regenerative medicine.

Summary: Here, we find that human-induced pluripotent stem cell (hiPSC)-derived cardiomyocyte (CM)-fated progenitors (CFPs) that express a tetraspanin family glycoprotein, CD82, almost exclusively differentiate into CMs both in vitro and in vivo. CD82 is transiently expressed in late-stage mesoderm cells during hiPSC differentiation. Purified CD82+ cells gave rise to CMs under nonspecific in vitro culture conditions with serum, as well as in vivo after transplantation to the subrenal space or injured hearts in mice, indicating that CD82 successfully marks CFPs. CD82 overexpression in mesoderm cells as well as in undifferentiated hiPSCs increased the secretion of exosomes containing β-catenin and reduced nuclear β-catenin protein, suggesting that CD82 is involved in fated restriction to CMs through Wnt signaling inhibition. This study may contribute to the understanding of CM differentiation mechanisms and to cardiac regeneration strategies. : Takeda et al. find that CD82+ is a cell-surface marker on cardiomyocyte-fated progenitors made from human iPSCs. Keywords: iPSCs, CD82, cardiomyocytes, progenitors, exosome, Wnt inhibition

In ultrasound-guided central venous catheterization, there is no standard technique either for the needle tip visualization or for the adequate needle angle and entry to the skin with short-axis view under out-of-plane technique. In the present study, we propose a novel technique named "stepwise flashing with triangulation", and the efficacy of this technique is assessed. Before and after a didactic session in which the technique was explained, 12 novice residents were asked to position the needle tip on or into the imitation vessels and to avoid deeper penetration by using an agar tissue phantom with ultrasound guidance. "Stepwise flashing" technique was for stepwise visualization of the needle tip, and "triangulation" technique was for adequate needle angle and entry to the skin. After the session, the success rate was increased and a deeper penetration rate was decreased. This technique will help us to facilitate vascular access and to avoid complications in clinical settings.

Objective— UVB irradiation is an established treatment for immunoinflammatory cutaneous disorders and has been shown to suppress cutaneous and systemic inflammatory diseases through modulation of the adaptive immune response. However, it remains unknown whether UVB irradiation prevents an immunoinflammatory disease of arteries such as atherosclerosis. Approach and Results— Here, we show that UVB exposure inhibits the development and progression of atherosclerosis in atherosclerosis-prone mice by expanding and enhancing the functional capacity of CD4 + forkhead box P3 + regulatory T cells and regulating proatherogenic T-cell responses. Experimental studies in Langerhans cell–depleted mice revealed that epidermal Langerhans cells play a critical role in UVB-dependent induction of CD4 + forkhead box P3 + regulatory T cells, suppression of proatherogenic T-cell responses, and prevention of atherosclerotic plaque development. Conclusions— Our findings suggest the skin immune system as a novel therapeutic target for atherosclerosis and provide a novel strategy for the treatment and prevention of atherosclerosis.

Patient: Female, 54-year-old Final Diagnosis: Takotsubo cardiomyopathy Symptoms: Chest discomfort • general malaise Medication: — Clinical Procedure: — Specialty: Cardiology Objective: Unusual clinical course Background: Takotsubo cardiomyopathy is characterized by apical ballooning and excessive constriction of the base of heart. However, reverse takotsubo cardiomyopathy, wherein ballooning from the mid-ventricle to the base of the heart occurs with excessive constriction of the apex, has also been reported. We report a case of a transition from atypical wall motion abnormality to a typical takotsubo cardiomyopathy pattern. Case Report: A 54-year-old woman was following excessive sugar and dietary restrictions because of concerns regarding her blood sugar levels while receiving treatment for diabetes at another hospital. She presented at our hospital with general malaise and chest discomfort after several days of significantly increased workload. On admission, blood tests showed elevated cardiac enzymes. Electrocardiogram showed ST elevation of V2-V3 and poor R-wave enhancement of the anterior precordial lead. Coronary angiography showed no significant stenosis; however, left ventricular (LV) angiography showed a decrease in mid-ventricular wall motion. On the basis of these findings, she was diagnosed with a reverse takotsubo cardiomyopathy. We initiated conservative treatment for her condition. During her treatment, the LV wall motion showed a typical pattern of the apical ballooning that is characteristic of takotsubo cardiomyopathy. This LV wall motion was normalized on day 22 of the onset. Conclusions: We observed a rare case of takotsubo cardiomyopathy where the pattern of LV wall motion abnormality changed over time. This case suggests that it is necessary to follow up LV abnormality over time rather than rely on single-point observations in cases with takotsubo cardiomyopathy.

Background Evaluations for the tumorigenicity of transplantation of stem cell products is mandatory for clinical application. It is of importance to establish a system to accurately quantify contaminated tumorigenic cells regardless of the format of stem cell product. In the present report, we aimed to examine the accuracy of the quantification of tumorigenic cell numbers with commonly used 2 methods, quantitative polymerase chain reaction (qPCR) and flow cytometry (FCM) using experimental models of stem cell products spiked with tumorigenic cells. Methods Human mesenchymal stem cells (hMSCs) and melanoma Mewo-Luc cells constitutively expressing luciferase were used. We stained Mewo-Luc cells with a cell linker then spiked onto hMSC suspensions and hMSC sheets. We validated the accuracy of 10-fold serial dilution technique for Mewo-Luc cell suspension using a Coulter counter. The samples spiked with Mewo-Luc cells were subjected to qPCR and FCM analyses, respectively for the quantification of Mewo-Luc cells. Results Ten-fold serial dilutions of Mewo-Luc cells were performed accurately with small deviation. In samples spiked with or less than 100 cells in hMSC suspensions, and samples spiked with or less than 1,000 cells in hMSC sheets showed significantly higher cell numbers in calculations by FCM, respectively (suspensions; qPCR vs FCM: 100 cells: 59 ± 25 vs 232 ± 35 cells, p = 0.022/10 cells: 21 ± 7 vs 114 ± 27 cells, p = 0.030, sheets; qPCR vs FCM: 1,000 cells: 1723 ± 258 vs 5810 ± 878 cells, p = 0.012/100 cells: 110 ± 18 vs 973 ± 232 cells, p = 0.012/10 cells: 20 ± 6 vs 141 ± 36 cells, p = 0.030). Conclusion Differences in accuracy between quantification methods should be considered in designing a tumorigenicity study model., Biochemistry; Cell biology; Tissue engineering; Cell culture; Stem cells research; Biomedical engineering; Regenerative medicine; Stem cell therapy; Tumorigenicity; Pre-clinical safety tests; Methodology.

Aims Type 3 iodothyronine deiodinase (D3), which converts thyroxine (T4) and 3,5,3′-triiodothyronine (T3) to 3,3′,5′-triiodothyronine (rT3) and 3,3′-diiodothyronine (T2), respectively, inactivates thyroid hormones. We investigated the expression and regulation of D3 in human cardiomyocytes which were differentiated from human induced pluripotent stem cells (hiPSCs). Main methods We characterized D3 activity using liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. D3, myosine heavy chain α and β (MHCα and β, respectively), sarcoplasmic reticulum calcium ATPase (SERCA), and phospholamban (PLB) mRNA levels were analyzed by quantitative real-time PCR (qPCR) in hiPSC-derived cardiomyocytes (hiPS-CMs). Key findings We identified enzyme activity that catalyzes the conversion of T3 to T2 in both hiPS-CMs and hiPSCs, which showed characteristics compatible with those for D3. D3 mRNA was identified in these cells using qPCR analysis. T3 and hypoxia mimetics such as CoCl2 and DFO, increased the D3 mRNA level in both hiPS-CMs and hiPSCs. Addition of iopanoic acid, a competitive inhibitor of iodothyronine deiodination, in the culture medium of hiPS-CMs, increased the mRNA levels such as MHCα and β, SERCA, and PLB induced by T3. Significants Our findings indicate that D3 is expressed in hiPS-CMs, and may decrease the intracellular T3 concentration, and may decrease the expression of cardiac genes such as MHCα and β, SERCA, and PLB in hiPS-CMs.

Left ventricular noncompaction (LVNC) is a primary cardiomyopathy with heterogeneous genetic origins. The aim of this study was to elucidate the role of sarcomere gene variants in the pathogenesis and prognosis of LVNC. We screened 82 Japanese patients (0–35 years old), with a diagnosis of LVNC, for mutations in seven genes encoding sarcomere proteins, by direct DNA sequencing. We identified variants in a significant proportion of cases (27%), which were associated with poor prognosis (p = 0.012), particularly variants in TPM1, TNNC1, and ACTC1 (p = 0.012). To elucidate the pathological role, we developed and studied human-induced pluripotent stem cells (hiPSCs) from a patient carrying a TPM1 p.Arg178His mutation, who underwent heart transplantation. These cells displayed pathological changes, with mislocalization of tropomyosin 1, causing disruption of the sarcomere structure in cardiomyocytes, and impaired calcium handling. Microarray analysis indicated that the TPM1 mutation resulted in the down-regulation of the expression of numerous genes involved in heart development, and positive regulation of cellular process, especially the calcium signaling pathway. Sarcomere genes are implicated as genetic triggers in the development of LVNC, regulating the expression of numerous genes involved in heart development, or modifying the severity of disease.

Innate and adaptive immunity has been shown to be critically involved in the pathogenesis of atherosclerosis. In particular, immune suppression mediated by regulatory T cells (Tregs) or tolerogenic dendritic cells (DCs) serves as a vital mechanism for regulating pathogenic chronic inflammation in atherogensis, suggesting that promotion of endogenous regulatory immune responses could be a possible therapeutic approach to suppress atherosclerotic disease. In this review, we discuss the possible role of Tregs and tolerogenic DCs in the prevention of atherosclerosis and the promising strategies to prevent or cure atherosclerotic disease by modulating regulatory immune responses mediated by these suppressor cells.

We propose a novel biometric sensing technique for personal authentication in which fingerprint images are captured using an optical encryption method. This method can reduce the risk of data theft or leakage of personal information captured by biometric sensing. This method, termed encrypted sensing, is implemented using digital holography with double random phase encoding. We demonstrate experimentally that a fingerprint image can be captured as an optically encrypted image and can be restored correctly only when the correct cipher key is used. Moreover, we investigate experimentally the verification accuracy of the decrypted images.

This publisher’s note corrects a value in Table 3 in [Appl. Opt.56, 4474 (2017)APOPAI0003-693510.1364/AO.56.004474].

The security of important information captured by sensors and cameras is currently a growing concern as information theft via techniques such as side-channel attacks become increasingly more prevalent. Double random phase encoding (DRPE) is an optical encryption method based on optical Fourier transform that is currently being used to implement secure coherent optical systems. In this paper, we propose a new DRPE implementation for incoherent optical systems based on integral photography that can be applied to “encrypted imaging (EI)” to optically encrypt an image before it is captured by an image sensor. Because the proposed incoherent DRPE is constituted from conventional DRPE by rewriting the optical encryption via discretization and Euler’s formula, its security level is the same as that of conventional DRPE. The results of an experiment in which we encrypted a plaintext image optically and then decrypted it numerically demonstrate that our proposed incoherent optical security system is feasible.

Although initial research shows that double-random phase encoding (DRPE) is vulnerable to known-plaintext attacks that use phase retrieval algorithms, subsequent research has shown that phase-only DRPE, in which the Fourier amplitude component of an image encrypted with classical DRPE remains constant, is resistant to attacks that apply phase retrieval algorithms. Herein, we numerically analyze the key-space of DRPE and investigate the distribution property of decryption keys for classical and phase-only DRPE. We determine the difference in the distribution property of successful decryption keys for these DRPE techniques from the numerical analysis results and then discuss the security offered by them.

We propose a generalized model for double random phase encoding (DRPE) based on linear algebra. We defined the DRPE procedure in six steps. The first three steps form an encryption procedure, while the later three steps make up a decryption procedure. We noted that the first (mapping) and second (transform) steps can be generalized. As an example of this generalization, we used 3D mapping and a transform matrix, which is a combination of a discrete cosine transform and two permutation matrices. Finally, we investigated the sensitivity of the proposed model to errors in the decryption key.

We present two patients developing intraoperative massive bleeding and showed ischemic changes in the electrocardiogram and circulatory collapse accompanied by severe anemia owing to the delay of red blood cell concentrate transfusion. One patient underwent hepatectomy and the other pancreaticoduodenectomy. Their lowest hemoglobin concentration was around 2 g x dl(-1), and they showed ischemic changes in the electrocardiogram and severe decreases in blood pressure. The former received compatible red blood cell concentrate and the latter received uncrossmatched same blood group red blood cell concentrate immediately, and their electrocardiogram and blood pressure quickly improved. To avoid life-threatening anemia, emergency red blood cell concentrate transfusion including compatible different blood group transfusion should be applied for intraoperative massive bleeding.

Objective— Eicosapentaenoic acid (EPA) has been shown to have beneficial effects on cardiovascular diseases, although the precise mechanism is unknown. We investigated the effect of EPA on the regression of atherosclerosis. Methods and Results— LDL-receptor–deficient mice were fed a high-cholesterol diet for 8 weeks to build up aortic sinus atherosclerotic lesions and then were fed a normal diet with or without 5% EPA for 4 weeks. Atherosclerotic lesions were histologically assessed, and immunologic assays were performed. EPA treatment significantly regressed atherosclerosis (−22.7%, P + T cells, and dendritic cells (DCs) in atherosclerotic lesions, though only changing the chow never induced the regression. Flow cytometric analysis revealed that EPA increased immature DCs (CD11c + CD80 − CD86 − ), increased the indoleamine 2,3-dioxygenase (IDO) in DCs, and decreased the number of CD4 + T cells. In the presence of the IDO inhibitor, the beneficial effects of EPA on regression were inhibited, suggesting that the effect of EPA was mainly mediated through IDO. Conclusion— In addition to lowering plasma cholesterol, EPA regressed atherosclerosis probably due to modulation of DC phenotype and reduction in T cell numbers. The present findings might partly explain the beneficial effects of EPA in clinics and support clinical evidence.

We have shown that the application of double random phase encoding (DRPE) to biometrics enables the use of biometrics as cipher keys for binary data encryption. However, DRPE is reported to be vulnerable to known-plaintext attacks (KPAs) using a phase recovery algorithm. In this study, we investigated the vulnerability of DRPE using fingerprints as cipher keys to the KPAs. By means of computational experiments, we estimated the encryption key and restored the fingerprint image using the estimated key. Further, we propose a method for avoiding the KPA on the DRPE that employs the phase retrieval algorithm. The proposed method makes the amplitude component of the encrypted image constant in order to prevent the amplitude component of the encrypted image from being used as a clue for phase retrieval. Computational experiments showed that the proposed method not only avoids revealing the cipher key and the fingerprint but also serves as a sufficiently accurate verification system.

Volcano-structured double-gated field emitter arrays (VDG-FEAs) with different focusing electrode height have been fabricated and the focusing characteristics for each VDG-FEAs were evaluated in detail. The authors experimentally proved that lowering the focusing electrode was very effective to keep a high emission current and successfully removed the electric field relaxation at the tip during the focusing operation. The anode current of about 1.9μA was maintained for the VDG-FEA with the height of the focusing electrode relative to the extraction electrode, hf=−470nm, even in applying 5V to the focusing electrode, and the current was 84.4 times larger, compared with the sample with hf=220nm under the same focusing condition. It was found that the emitted electrons returned back to the extraction electrode by the potential barrier caused by the low focusing potential below 3V in every sample.

Background Reactive oxygen species (ROS) is deeply involved in the process of ventricular remodeling after myocardial infarction (MI). Under oxidative stress, endothelial nitric oxide synthase (eNOS) can be converted to a ROS generator, because a relative lack of tetrahydrobiopterin (BH4), an essential cofactor for NO synthesis, leads to eNOS uncoupling. The uncoupled eNOS generates superoxide rather than NO. The possible role of ROS generated by eNOS in ventricular remodeling after MI was investigated. Methods and Results Rats were treated with oral BH4 supplementation starting at 3 days before coronary artery ligation. At 4 weeks after MI, there was augmented superoxide production in association with reduced BH4/dihydrobiopterin (BH2) ratio and eNOS dimer/monomer protein ratio in the heart. Treatment with BH4 increased BH4/BH2 ratio and eNOS dimer/monomer ratio, and decreased superoxide production. In BH4-treated MI rats, left ventricular size was smaller, thickness of the non-infarcted posterior wall was thinner, and cardiac function was preserved compared with the control MI rats. Conclusions The present study suggested that ventricular remodeling process after MI leads to BH4 oxidation and resulted in uncoupled eNOS-derived superoxide generation, which further augmented the remodeling process and deteriorated cardiac function. (Circ J 2008; 72: 1512 - 1519)

We proposed a novel CdTe X-ray image sensor, which was driven by the FEA, to obtain high spatial resolution X-ray images and have demonstrated the principle operation by using the CdTe image sensor with one pixel. We have also fabricated a FEA matrix with 12×12 pixels to obtain X-ray images. For the further improvement of spatial resolution in the CdTe image sensor, we have proposed a novel double-gated FEA with a focusing lens, which was fabricated by using the etch-back method. The double-gated FEA showed a good focusing characteristic without significant decrease of the emission current, when the height of the focus electrode was optimized. The CdTe image sensor driven by the double-gated FEA is promising for an ultra-high-resolution X-ray image sensor.

Atherosclerosis is a complex chronic inflammatory disease in which macrophages play a critical role, and the intervention of the inflammatory process in atherogenesis could be a therapeutic strategy. In this study, we investigated the efficacy of xenogenic macrophage immunization on the atherosclerotic lesion formation in a model of murine atherosclerosis. Apolipoprotein E knockout (apoE-KO) mice were repeatedly immunized with formaldehyde-fixed cultured human macrophages (phorbol ester-stimulated THP-1 cells), using human serum albumin as a control protein or HepG2 cells as human control cells, once a week for four consecutive weeks. The vehicle phosphate-buffered saline was injected in the nonimmunized controls. THP-1 immunization induced antibodies that are immunoreactive with mouse macrophages. Although the plasma lipid levels were unchanged by the immunization, the atherosclerotic lesion area in the aortic root was significantly reduced by >50% in 16-wk-old THP-1-immunized apoE-KO mice compared with that in control mice. THP-1 immunization reduced in vivo macrophage infiltration, reduced in vitro macrophage adhesion, and changed cytokine production by macrophages to the antiatherogenic phenotype. Xenogenic macrophage immunization protects against the development of atherosclerosis in apoE-KO mice by modulating macrophage function in which antibodies induced by the immunization are likely to be involved. This method is a novel and potentially useful cell-mediated immune therapeutic technique against atherosclerosis.

Background Accumulating evidence suggests that the balance between pathogenic effector T cells (Teffs) and regulatory T cells (Tregs) may be important for controlling atherosclerotic disease. We hypothesized that a combination therapy with anti‐ CD 3 antibody ( CD 3‐Ab) and IL ‐2/anti‐ IL ‐2 monoclonal antibody complex ( IL ‐2 complex) aimed at increasing the ratio of Tregs to Teffs would effectively inhibit atherosclerosis in mice. Methods and Results We treated apolipoprotein E‐deficient mice fed a high‐cholesterol diet with vehicle, CD 3‐Ab, IL ‐2 complex, or their combination. Mice receiving the combination therapy had markedly reduced atherosclerotic lesions than mice treated with CD 3‐Ab or IL ‐2 complex alone. In addition, a striking increase in the Treg/Teff ratio of lymphoid organs and atherosclerotic lesions, along with plaque stabilization characterized by decreased macrophage content and increased collagen content was observed. The combination treatment also markedly reduced splenic Ly6C high inflammatory monocytes and might induce a favorable macrophage phenotype change in atherosclerotic lesions. Conclusions Our results indicate that in addition to suppressing Teff responses, enhancing Treg‐mediated immune responses is more efficacious in preventing atherosclerosis, suggesting a novel therapeutic approach for atherosclerosis.

application/pdf, c-Ski is a transcriptional corepressor that interacts strongly with Smad2, Smad3, and Smad4 but only weakly with Smad1 and Smad5. Through binding to Smad proteins, c-Ski suppresses signaling of transforming growth factor-{beta} (TGF-{beta}) as well as bone morphogenetic proteins (BMPs). In the present study, we found that a mutant of c-Ski, termed c-Ski (ARPG) inhibited TGF-{beta}/activin signaling but not BMP signaling. Selectivity was confirmed in luciferase reporter assays and by determination of cellular responses in mammalian cells (BMP-induced osteoblastic differentiation of C2C12 cells and TGF-{beta}–induced epithelial-to-mesenchymal transdifferentiation of NMuMG cells) and Xenopus embryos. The ARPG mutant recruited histone deacetylases 1 (HDAC1) to the Smad3-Smad4 complex but not to the Smad1/5-Smad4 complex. c-Ski (ARPG) was unable to interact with Smad4, and the selective loss of suppression of BMP signaling by c-Ski (ARPG) was attributed to the lack of Smad4 binding. We also found that c-Ski interacted with Smad3 or Smad4 without disrupting Smad3-Smad4 heteromer formation. c-Ski (ARPG) would be useful for selectively suppressing TGF-{beta}/activin signaling.

Classical double-random phase encoding (C-DRPE) is an optical symmetric-key encryption technique. C-DRPE is reported to be vulnerable to a known-plaintext attack (KPA) that uses a phase retrieval algorithm. However, although phase-only DRPE (PO-DRPE) is reported to be more resistant to KPAs than C-DRPE, it is not obvious yet that PO-DRPE is sufficiently resistant to a KPA under any condition, because the vulnerability to KPA varies depending on various factors, such as the number of the known plaintext-ciphertext pairs that are given for the KPA, or the gray level of the known-plaintext image (i.e., binary or multivalued image). In this paper, we investigate the resistance of C-DRPE and PO-DRPE to KPA under various conditions related to the number of known plaintext-ciphertext pairs and to the gray level of the known-plaintext image.

To realize cardiac regeneration using human induced pluripotent stem cells (hiPSCs), strategies for cell preparation, tissue engineering and transplantation must be explored. Here we report a new protocol for the simultaneous induction of cardiomyocytes (CMs) and vascular cells [endothelial cells (ECs)/vascular mural cells (MCs)], and generate entirely hiPSC-engineered cardiovascular cell sheets, which showed advantageous therapeutic effects in infarcted hearts. The protocol adds to a previous differentiation protocol of CMs by using stage-specific supplementation of vascular endothelial cell growth factor for the additional induction of vascular cells. Using this cell sheet technology, we successfully generated physically integrated cardiac tissue sheets (hiPSC-CTSs). HiPSC-CTS transplantation to rat infarcted hearts significantly improved cardiac function. In addition to neovascularization, we confirmed that engrafted human cells mainly consisted of CMs in >40% of transplanted rats four weeks after transplantation. Thus, our HiPSC-CTSs show promise for cardiac regenerative therapy.

Aims Although recent animal studies have investigated the cellular and molecular mechanisms underlying the process of atherosclerosis regression, it remains unknown whether adaptive immune responses including T cells are involved in this process. We investigated the role of T cells in atherosclerosis regression. Methods and results LDL receptor-deficient mice were fed a high-cholesterol diet for 8 weeks to form atherosclerotic lesions and were then changed to a standard diet, and atherosclerosis was assessed 4 weeks later. Just before changing the diet, the mice received an iv injection of anti-CD3 antibody (CD3-Ab) or control immunoglobulin G for 5 consecutive days. CD3-Ab treatment regressed atherosclerosis and decreased the accumulation of macrophages and CD4+ T cells in the plaques. CD3-Ab treatment also dramatically reduced CD4+ T cells and increased the proportion of regulatory T cells (Tregs). Depletion of Tregs by anti-CD25 antibody injection abolished the regression of atherosclerosis seen in CD3-Ab-treated mice, indicating the essential role for Tregs in this process. Conclusion CD3-Ab treatment induced rapid regression of established atherosclerosis via reducing CD4+ T cells and increasing the proportion of Tregs. These findings suggest that therapeutic intervention for T-cell-mediated immune responses may represent a novel strategy to induce atherosclerosis regression in combination with lipid-lowering therapy.

Atherosclerosis is believed to be an inflammatory condition of the arterial wall. It has become apparent that various types of cells of innate and adaptive immunity participate in atherogenesis. T cells are of particular interest because they mediate pathogenic immune responses involved in the acceleration of atherosclerosis. Recent studies from several independent groups indicated that subsets of regulatory T cells (Tregs) actively mediate immunologic tolerance and inhibit atherosclerosis development or progression through the down-regulation of effector T-cell responses. It is likely that there is an imbalance between pathogenic effector T cells and Tregs under atherosclerotic conditions. Recent evidence suggests that in addition to the thymus, gut-associated lymphoid tissues are the main sites for the generation of several subsets of peripherally inducible Tregs. This indicates that intervention in the gut environment to promote an endogenous regulatory immune response may serve as a possible therapeutic approach to suppress atherosclerotic diseases. In this review, we discuss not only the possible role of Tregs in the prevention of atherosclerosis, but also promising strategies to prevent or cure atherosclerotic diseases by promoting an endogenous regulatory immune response, particularly by oral immune modulation.

We have applied an imaging system of phase-contrast X-ray CT to the detection of atherosclerotic plaque components by means of the differences of tissue mass densities. In this study, we investigated the effect of the anti-platelet therapies, widely used for secondly prevention of cardiovascular events, on plaque stability and examined whether this novel technique could detect the changes of plaque components under the therapy. Apolipoprotein E-deficient mice were fed on high-cholesterol diet alone and either with 0.1% cilostazol or clopidogrel for 10 weeks. We assessed atherosclerotic lesion volumes and components at brachiocephalic artery by the phase-contrast X-ray CT imaging and histochemistry. The phase-contrast X-ray CT imaging could reveal that cilostazol and clopidogrel significantly decreased atherosclerotic lesion volumes at brachiocephalic artery (31.2% reduction in cilostazol group and 37.4% reduction in clopidogrel group), compared with control group. In addition, the mass densities calculated by this method revealed the anti-platelet treatment increased stable plaque areas including high collagen content, but decreased unstable plaque areas including lipid and macrophage content. These findings were confirmed by histological analyses. Real-time PCR analyses indicated that anti-platelets inhibited gene expressions of cytokines and adhesion molecules, such as IFNγ and ICAM-1. Anti-platelet therapies had a beneficial effect on plaque stability maybe due to anti-inflammatory actions. Phase-contrast X-ray CT imaging could quantify the plaque volume and qualify the plaque components affected by anti-platelet therapies. This novel phase-contrast X-ray CT imaging system could be a plausible method to detect the unstable plaque non-invasively in the future.

STUDY DESIGN A prospective, randomized laboratory investigation. OBJECTIVE To investigate whether administration of minocycline attenuates hind-limb motor dysfunction and gray and white matter injury after spinal cord ischemia. SUMMARY OF BACKGROUND DATA Minocycline, a semisynthetic tetracycline antibiotic, has been shown to have neuroprotective effects in models of focal and global cerebral ischemia. However, there have been no data available regarding the effects of minocycline in a model of spinal cord ischemia. METHODS Thirty-six rats were randomly allocated to one of three groups; control (C) group (n = 11), minocycline (M) group (n = 13), or sham group (n = 12). Minocycline or saline was intraperitoneally administered for 3 days beginning at 12 hours before 10 minutes of spinal cord ischemia or sham operation. Spinal cord ischemia was induced with intraaortic balloon catheter and blood withdrawal. Seventy-two hours after reperfusion, hind-limb motor functions were assessed using Basso, Beattie, Bresnahan (BBB) Scale (0 = paraplegia, 21 = normal). For histologic assessments, the gray and white matter injury was evaluated using the number of normal neurons and the extents of vacuolations in the white matter, respectively. Activated microglia was also evaluated using Iba-1 immunohistochemistry. RESULTS BBB scores and the numbers of normal neurons in the M group were significantly higher than those in the C group. The percentage areas of vacuolations in the white matter and the number of Iba-1 positive cells were significantly lower in the M group compared with those in the C group. CONCLUSION The results indicated that minocycline administration improved hind-limb motor function and attenuated gray and white matter injury and microglial activation after spinal cord ischemia in rats.

Objective— To determine whether the administration of an active form of vitamin D 3 (calcitriol) could prevent atherosclerosis through anti-inflammatory actions. Methods and Results— Recent clinical studies have shown that lack of vitamin D 3 is a risk factor for cardiovascular events. Oral calcitriol administration decreased atherosclerotic lesions, macrophage accumulation, and CD4 + T-cell infiltration at the aortic sinus, when compared with the corresponding observations in control mice. We observed a significant increase in Foxp3 + regulatory T cells and a decrease in CD80 + CD86 + dendritic cells (DCs) in the mesenteric lymph nodes, spleen, and atherosclerotic lesions in oral calcitriol–treated mice in association with increased interleukin 10 and decreased interleukin 12 mRNA expression. CD11c + DCs from the calcitriol group showed reduced proliferative activity of T lymphocytes, suggesting the suppression of DC maturation. Neutralization of CD25 in vivo revealed that calcitriol inhibited atherosclerosis mainly in a regulatory T cell–dependent manner but also partly because of a decrease in DC maturation. Conclusion— Oral calcitriol treatment could prevent the development of atherosclerosis by changing the function or differentiation of DCs and regulatory T cells. These findings suggest that intestinal and systemic immune modulation by calcitriol may be a potentially valuable therapeutic approach against atherosclerosis.

Although endothelium-dependent vasodilatation has been used as a marker of endothelial dysfunction (ED), there have been no reliable plasma markers for ED. Oxidative stress, which is a major determinant of ED, oxidizes tetrahydrobiopterin (BH4), an essential cofactor of endothelial type nitric oxide synthase (eNOS), and resulted in the relative deficiency of BH4.In 163 patients with cardiovascular disorders, the plasma levels of BH4 and 7, 8-dihydrobiopterin (BH2) by high performance liquid chromatography were measured and compared with the flow-mediated (FMD) vasodilatory response of the brachial artery, which was measured by ultrasonography. The effects of atorvastatin on plasma pteridine levels and FMD were examined in patients with multiple coronary risk factors. There was a positive relationship between FMD and plasma BH4 levels and a negative relationship between FMD and plasma BH2 levels. Subsequently, a strong positive relationship between FMD and the BH4/BH2 ratio (r=0.585, P0.0001) was found. Although we did not find any significant relationship between pteridine levels and individual traditional risk factors, the BH4/BH2 ratio in patients with more than 2 risk factors showed significant reductions compared with that in those without risk factors. Statin treatment improved FMD in association with an increase in the plasma BH4/BH2 ratio.Plasma pteridine levels were associated with endothelial dysfunction in cardiovascular disorders.

Thioredoxin, a redox-regulating protein that scavenges reactive oxygen species, appears to show an excellent antiinflammatory effect in treating animal models of various human inflammatory diseases. The aim of this study was to clarify whether thioredoxin is useful for treating inflammatory skin diseases, such as contact dermatitis, caused by epicutaneous exposure to environmental and occupational antigens. The allergic contact hypersensitivity response was suppressed in thioredoxin-transgenic mice. This suppressive effect of thioredoxin appeared to be via the inhibition of the efferent limb of contact hypersensitivity because administration of recombinant thioredoxin suppressed the inflammatory response in the elicitation phase but not in the induction phase. Adoptive-transfer studies revealed that the host environment, but not donor leukocytes, is critical in this suppressive effect. In thioredoxin-transgenic mice, the infiltration of neutrophils in the elicitation site was diminished, whereas the migratory function of cutaneous dendritic cells and hapten-specific cell proliferation were not disturbed. Thioredoxin-transgenic mice had also an attenuated inflammatory response to croton oil. These findings suggest that thioredoxin prevents skin inflammatory responses and could be a suitable candidate for the treatment of contact dermatitis.

Objective— Diabetes mellitus is associated with increased oxidative stress, which induces oxidation of tetrahydrobiopterin (BH4) in vessel wall. Without enough BH4, eNOS is uncoupled to L-arginine and produces superoxide rather than NO. We examined the role of uncoupled eNOS in vascular remodeling in diabetes. Methods and Results— Diabetes mellitus was produced by streptozotocin in C57BL/6J mice. Under stable hyperglycemia, the common carotid artery was ligated, and neointimal formation was examined 4 weeks later. In diabetic mice, the neointimal area was dramatically augmented. This augmentation was associated with increased aortic superoxide formation, reduced aortic BH4/dihydrobiopterin (BH2) ratio, and decreased plasma nitrite and nitrate (NOx) levels compared with nondiabetic mice. Chronic BH4 treatment (10 mg/kg/d) reduced the neointimal area in association with suppressed superoxide production and inflammatory changes in vessels. BH4/BH2 ratio in vessel wall was preserved, and plasma NOx levels increased. Furthermore, in the presence of diabetes, overexpression of bovine eNOS resulted in augmentation of neointimal area, accompanied by increased superoxide production in the endothelium. Conclusions— In diabetes, increased oxidative stress by uncoupled NOSs, particularly eNOS, causes augmentation of vascular remodeling. These findings indicate restoration of eNOS coupling has an atheroprotective benefit in diabetes.

Background: Reliable non-invasive imaging modalities to characterize atherosclerotic plaque components are clinically desirable for detecting unstable coronary plaques, which cause acute coronary syndrome or sudden death. Although recent clinical developments in computed tomography (CT) have enabled the visualization of luminal narrowing and calcified plaques in coronary arteries, the evaluation of non-calcified plaque components remains difficult. Phase-contrast X-ray CT imaging has great potential to reveal the structures inside soft tissues because its sensitivity to light elements is almost 1000 times greater than that of absorption-contrast clinical X-ray imaging. We for the first time examined mouse atherosclerotic plaques using phase-contrast X-ray CT and found promising results. Methods and Results: Ex vivo phase-contrast X-ray CT was performed using a synchrotron radiation source (SPring-8, Japan) to investigate atherosclerotic plaque components in mice. Samples were also histologically analyzed. Phase-contrast X-ray CT at a spatial resolution of 10 –20 μm revealed atherosclerotic plaque components, and thin fibrous caps could be easily detected. The specific mass densities of these components were estimated using dδ (differences in the refractive indexes relative to water). While lipid-rich areas showed low dδ (0.79 ± 0.13 × 10 −8 ) and mass density (1.011 ± 0.001 g/ml), the smooth muscle- and collagen-rich areas showed high dδ (4.18 ± 0.10 × 10 −8 and 5.93 ± 0.13 × 10 −8 , respectively) and mass density (1.057 ± 0.001 g/ml and 1.08 ± 0.002 g/ml, respectively). It was rather easy to evaluate or differentiate the atherosclerotic plaque components using this novel phase-contrast X-ray CT imaging. Moreover, the three-dimensional assessment of plaques was possible, and it enabled the imaging of their anatomical information. Conclusions: Phase-contrast X-ray CT can estimate the tissue-mass density of atherosclerotic plaques and distinguish the lipid-rich areas from the collagen-rich areas. This is a promising non-invasive technique for the investigation of plaque components and detection of unstable coronary plaques.

A 61-year-old man with hypertrophic obstructive cardiomyopathy was treated twice with percutaneous transluminal septal myocardial ablation (PTSMA). The first procedure improved the left ventricular outflow tract pressure gradient (LVOTG) from 148 to 48 mmHg and the New York Heart Association (NYHA) class from III to II in a week. However, the LVOTG increased to 197 mmHg and the NYHA class worsened to III within 3 months. In spite of medical treatment with beta-blocker, syncope attack occurred suddenly. Repeated PTSMA was performed. Just after the second procedure, the LVOTG did not decrease. However, the LVOTG decreased to 81 mmHg and the NYHA class improved to II with 3 months. The different response of pressure gradient in the acute and chronic phase with repeated PTSMA was interesting.

c-Ski and SnoN are transcriptional co-repressors that inhibit transforming growth factor-beta signaling through interaction with Smad proteins. Among receptor-regulated Smads, c-Ski and SnoN bind more strongly to Smad2 and Smad3 than to Smad1. Here, we show that c-Ski and SnoN bind to the "SE" sequence in the C-terminal MH2 domain of Smad3, which is exposed on the N-terminal upper side of the toroidal structure of the MH2 oligomer. The "QPSMT" sequence, located in the vicinity of SE, supports the interaction with c-Ski and SnoN. Sequences similar to SE and QPSMT are found in Smad2, but not in Smad1. The N-terminal MH1 domain and linker region of Smad3 protrude from the N-terminal upper side of the MH2 oligomer toroid. Smurf2 induces ubiquitin-dependent degradation of SnoN, since it appears to be located close to SnoN through binding to the linker region of Smad2. In contrast, transcription factors Mixer and FoxH3 (FAST1) bind to the bottom side of the Smad3 MH2 toroid; therefore, c-Ski does not affect the interaction of Smads with these transcription factors. Our findings thus demonstrate the stoichiometry of how multiple molecules can associate with the Smad oligomers and how the Smad-interacting proteins functionally interact with each other.

Activin A induces growth arrest of rat hepatocytes in vitro and in vivo. The alpha(1)-adrenergic agonist, norepinephrine (NE), enhances epidermal growth factor-stimulated DNA synthesis and inhibits activin A-induced growth inhibition, but the mechanisms of these actions are unclear. Smad proteins have recently been identified as intracellular signaling mediators of transforming growth factor-beta family members. In the present study, we explored how NE modulates the Smad signaling pathway in rat cultured hepatocytes. We demonstrate that NE inhibits activin A-induced nuclear accumulation of Smad2/3 and that NE rapidly induces inhibitory Smad7 mRNA expression. Infection of Smad7 adenovirus into rat hepatocytes inhibited activin A-induced nuclear accumulation of Smad2/3, enhanced epidermal growth factor-stimulated DNA synthesis, and abolished the growth inhibitory effect of activin A. We also demonstrated that the induction of Smad7 by NE is dependent on nuclear factor-kappa B (NF-kappa B). The amount of active NF-kappa B complex rapidly increased after NE treatment. Preincubation of the cells with an NF-kappa B pathway inhibitor N-tosyl-l-phenylalanine chloromethyl ketone or infection of the cells with an adenovirus expressing an I kappa B super-repressor (Ad5I kappa B) abolished the NE-induced Smad7 expression. These results indicate a mechanism of transmodulation between the Smad and trimeric G protein signaling pathways in rat hepatocytes.

It has been shown that biometric information can be used as a cipher key for binary data encryption by applying double random phase encoding. In such methods, binary data are encoded in a bit pattern image, and the decrypted image becomes a plain image when the key is genuine; otherwise, decrypted images become random images. In some cases, images decrypted by imposters may not be fully random, such that the blurred bit pattern can be partially observed. In this paper, we propose a novel bit coding method based on a Fourier transform hologram, which makes images decrypted by imposters more random. Computer experiments confirm that the method increases the randomness of images decrypted by imposters while keeping the false rejection rate as low as in the conventional method.

In order to control electric field relaxation at the tips of practical emitters, we found that volcano-structured double-gated field emitter arrays (VDG-FEAs) could be improved by placing the focusing electrode 470 nm below the electron extraction electrode. We demonstrated that this approach enables excellent endurance in terms of focusing potential, and confirmed its superior focusing characteristics. Even under strong focusing operation at a focusing electrode voltage of 5 V, this VDG-FEA maintained the anode current of 1.9 ?A, which was 5 times larger than that of the VDG-FEA with the same height of the focusing and electron extraction electrodes.