The chemokine receptors CXCR4 and CCR5 are considered to be potential targets for the inhibition of HIV-1 replication. We have reported that T134 and T140 inhibited X4 HIV-1 infection specifically ...because they acted as CXCR4 antagonists. In the present study, we have generated a T134-resistant virus (trHIV-1(NL4-3)) in a cell culture with gradually increasing concentrations of the compound. The EC(50) of T134 against trHIV-1(NL4-3) recovered after 145 passages was 15 times greater than that against wild-type HIV-1(NL4-3). This adapted virus was resistant to other CXCR4 antagonists, T140, AMD3100, and ALX40-4C, and SDF-1; from 10 to 145 times greater than that against wild-type HIV-1(NL4-3). On the other hand, T134, T140, and ALX40-4C were still active against AMD3100-resistant viruses (arHIV-1(018A)). The trHIV-1(NL4-3) contained the following mutations in the V3 loop of gp120: N269K, Q278T, R279K, A284V, F285L, V286Y, I288T, K290E, N293D, M294I, and Q296K; an insertion of T at 290; and Delta274-275 (SI). In addition, many other mutations were recognized in the V1, V2, and V4 domains. Thus, resistance to T134 may be the consequence of amino acid substitutions in the envelope glycoprotein of X4 HIV-1. The trHIV-1(NL4-3) could not utilize CCR5 as an HIV infection coreceptor, although many amino acid substitutions were recognized. The trHIV-1(NL4-3) acquired resistance to vMIP II, which could inhibit both X4 and R5 HIV-1 infection. However, neither the ligands of CCR5, RANTES, and MIP-1alpha, nor a CCR5 low molecular antagonist, TAK-779, were able to influence the infection of trHIV-1(NL4-3). Those results indicated that alternation of coreceptor usage of trHIV-1(NL4-3) was not induced.
Abstract Background Data regarding long-term mortality and factors influencing appropriate therapies in Japanese patients with implantable cardioverter defibrillators (ICD), who satisfy the ...Multicenter Automatic Defibrillator Implantation Trial II (MADIT II) criteria for primary prevention, remain scarce. Methods A total of 118 consecutive patients who underwent ICD implantation without any prior ventricular arrhythmic event, from January 2000 to December 2012, were enrolled based on the MADIT II criteria: left ventricular ejection fraction (LVEF) of ≤30% with ischemic heart disease and at least 4 weeks after a myocardial infarction. We investigated the mortality and factors influencing appropriate ICD therapies in this population. Results The mean age was 69±10 years, and the mean LVEF was 25.1±4.5%. During the median follow up of 1406 days, the mortality rate was 20%, and the incidence of appropriate ICD therapy was 37% at 3 years. Multivariate analysis by using Cox regression model showed that left ventricular diastolic diameter ≥60 mm (hazard ratio HR, 2.31; 95% confidence interval CI, 1.07–5.38; P =0.033) and the presence of non-sustained ventricular tachycardia (NSVT) before implantation (HR, 2.26; 95% CI, 1.17-4.39; P =0.015) were independent predictors of appropriate ICD therapy. Conclusions The mortality and incidence of appropriate ICD therapy were 20% and 37%, respectively, at 3 years in Japanese patients who met the MADIT II criteria during ICD implantation for primary prevention of sudden cardiac death. The presence of NSVT and dilated left ventricle independently predicted the incidence of appropriate ICD therapy after implantation.
Aim: Previous studies have demonstrated that methyl mercaptan (CH3SH), one of the main causes of oral malodour, might contribute to the initiation and progression of periodontal disease. These ...studies suggested that CH3SH may affect the epithelial cells of the gingival crevice, which form a barrier to the penetration of microbial substances. In this study, the effects of CH3SH on the epithelial cells and gingival fibroblasts were investigated. Method: Human oral epithelial carcinoma cell line (KB), human oral squamous cell carcinoma cell line (HSC‐2), and human gingival fibroblasts (HGF) derived from healthy gingiva were used in this study. These cells were cultured in conditions of 5% CO2/95% air with or without CH3SH (10ng/ml or 50ng/ml) for 5 days. Cell numbers, proliferation and cytotoxicity were evaluated. Results: CH3SH inhibited epithelial cell growth and proliferation at the concentration of 50ng/ml, and a cytotoxic effect of CH3SH was also noted. On the other hand, HGF cells were not affected by 50ng/ml CH3SH. Conclusion: High concentrations of CH3SH such as 50ng/ml have an inhibitory effect on the growth and proliferation of epithelial cells, but not on those of fibroblasts.
Abstract Background Lead extraction using laser sheaths is performed mainly for cardiac implantable electronic device (CIED) infections. However, there are few reports concerning the management of ...CIED infections in Japan. Methods and results Lead extraction procedures were performed in 183 patients targeting 450 leads (atrial leads: 170, ventricular: 181, implantable cardioverter-defibrillators (ICDs): 79, and coronary sinus: 20). One hundred twenty patients (65.6%) presented with pocket infections without the presentation of an endovascular infection. Blood cultures were positive at least once in 63 patients (34.4%). Complete procedure success was achieved for 437 leads (97.1%) while partial removal occurred in nine, and failure in four leads. Major complications directly related to the procedure occurred in five patients (2.7%). Two of the four patients with a cardiac tamponade required a surgical repair. All patients received intravenous antibiotics, at least, one week after the procedure. Pocket or systemic infections were successfully controlled in 181 patients (98.9%). Coagulase-negative staphylococci (30.1%) and Staphylococcus aureus (37.1%) were the most common causes of CIED infections. Conclusion The current status of CIED infections in Japan seems to be similar to that previously reported from foreign countries. The optimal treatment of CIED infections involves the complete explantation of all hardware, followed by antibiotic therapy.
There is no effective treatment for hepatocellular carcinoma (HCC) with extrahepatic metastases. This study investigated the survival and causes of death in HCC patients with extrahepatic metastases.
...We retrospectively analyzed 34 HCC patients with extrahepatic metastases who received systemic chemotherapy without other anticancer treatment except prior hepatectomy. We classified causes of death as cancer death and death from other causes, and subclassified cancer deaths into hepatic cause, extrahepatic cause and cachectic cause. Each cause of death was analyzed in the two subgroups comprised of 10 patients with bone metastases alone and 22 patients with metastatic lesions in sites other than bone.
Thirty-two of the 34 patients had died at the time of analysis. The median survival time and the 1-year survival rate were 4.6 mo and 20.3%, respectively. Incidence of hepatic cause, extrahepatic cause, cachectic cause and death from other causes were 21 (66%), 7 (22%), 2 (6%) and 2 (6%), respectively. In the subgroup of 10 patients with bone metastases alone, nine (90%) died from hepatic causes, but none died from extrahepatic causes. In the group of 22 patients with metastatic lesions in sites other than bone, 7 (32%) patients died from extrahepatic causes.
The causes of death in HCC patients with extrahepatic metastases depended on metastatic site at the time of diagnosis. The results of this study may be useful in the design and analysis of future clinical trials of the HCC therapy.
Be-7 radioactive nuclei with a half-life of 53.3 days result from spallation reactions of galactic cosmic rays(GCR) and solar energetic particles (SEP) with N and O nuclei in the Earth's atmosphere. ...We calculate the average global production of Be-7 in the atmosphere by GCR and SEP The result indicates that an intense SEP event produces a large amount of Be-7 in the polar stratosphere and part of them could be transported to the surface at lower latitudes. The ground-level measurement of Be-7 in Japan exhibits the possibility of enhancement in the Be-7 radioactivity associated with the intense SEP event on July 14, 2000. In addition, the present experiment shows seasonal variations in the surface Be-7 concentration which peaks in spring and autumn. We discuss the possible air mass mixing between the stratosphere and troposphere to explain the measured seasonal variations. The surface concentration of Pb-210 nuclei indicates a similar trend to that of Be-7 and we suggest two possible explanations.
In contrast to the relatively stable climate of the past 10,000 years, during glacial times the North Atlantic region experienced large-amplitude transitions between cold (stadial) and warm ...(interstadial) states. In this modeling study, we demonstrate that hydrological interactions between the Atlantic thermohaline circulation (THC) and adjacent continental ice sheets can trigger abrupt warming events and also limit the lifetime of the interstadial circulation mode. These interactions have the potential to destabilize the THC, which is already more sensitive for glacial conditions than for the present-day climate, thus providing an explanation for the increased variability of glacial climate.
Abstract Background Catheter ablation can reduce episodes of ventricular tachycardia (VT) after myocardial infarction (MI). However, the optimal endpoint of the ablation procedure remains unclear. ...Methods Fifty-one consecutive patients who received catheter ablation for VT after MI were included. The procedures targeted the isthmus of all the induced, sustained VTs. When the patients with induced VTs were hemodynamically stable, radiofrequency energy was delivered at the mid-diastolic potential recording site during VT. When the patients with VTs were hemodynamically unstable, the critical channel was identified at the delayed potential recording site, showing a good pace map, with a long stimulus-QRS interval. We delivered radiofrequency energy along the identified isthmus and across the exit of the circuit. Results At the end of the procedure, all VTs became non-inducible in 30 patients (59%) and some VTs were inducible in 21 patients (41%). During a mean of 40±29 months of follow-up, no VT or ventricular fibrillation recurred in 24 patients (80%) in the non-inducible group and in 12 patients (57%) in the inducible group, respectively ( P =0.03). The identification of the channel during VT mapping tended to associate with no recurrence, although the difference was not statistically significant ( P =0.2). Fourteen patients (27%) died during the follow-up period, mostly due to non-cardiac causes. Conclusions The catheter ablation targeting the isthmus of prior-MIVT and non-inducibility at the end of the procedure can provide a satisfactory follow-up result.
This study discusses how much of the biases in top-of-atmosphere (TOA) radiation and clouds can be removed by parameter tuning in the present-day simulation of a climate model in the Coupled Model ...Inter-comparison Project phase 5 (CMIP5) generation. We used output of a perturbed parameter ensemble (PPE) experiment conducted with an atmosphere–ocean general circulation model (AOGCM) without flux adjustment. The Model for Interdisciplinary Research on Climate version 5 (MIROC5) was used for the PPE experiment. Output of the PPE was compared with satellite observation data to evaluate the model biases and the parametric uncertainty of the biases with respect to TOA radiation and clouds. The results indicate that removing or changing the sign of the biases by parameter tuning alone is difficult. In particular, the cooling bias of the shortwave cloud radiative effect at low latitudes could not be removed, neither in the zonal mean nor at each latitude–longitude grid point. The bias was related to the overestimation of both cloud amount and cloud optical thickness, which could not be removed by the parameter tuning either. However, they could be alleviated by tuning parameters such as the maximum cumulus updraft velocity at the cloud base. On the other hand, the bias of the shortwave cloud radiative effect in the Arctic was sensitive to parameter tuning. It could be removed by tuning such parameters as albedo of ice and snow both in the zonal mean and at each grid point. The obtained results illustrate the benefit of PPE experiments which provide useful information regarding effectiveness and limitations of parameter tuning. Implementing a shallow convection parameterization is suggested as a potential measure to alleviate the biases in radiation and clouds.
Abstract Background Catheter ablation of ventricular tachycardia (VT) is feasible. However, the long-term outcomes for different underlying diseases have not been well defined. Methods Eighty-eight ...consecutive patients who underwent catheter ablation of VT using a three-dimensional mapping system were analyzed. The primary endpoint was any VT or ventricular fibrillation (VF) recurrence. Secondary endpoints were a composite of death or any VT/VF recurrence. Underlying heart diseases were remote myocardial infarction (remote MI) in 51 patients and non-ischemic cardiomyopathy in 37 (arrhythmogenic right ventricular cardiomyopathy ARVC in 18 patients, and dilated cardiomyopathy NIDCM in 19). Results Acute success was achieved in 82 of 88 (93%) patients. During a follow-up period of 39.2±4.6 months, VT recurred in 26 of 87 (30%), and VT/VF recurrence or death occurred in 39 of 87 (45%) patients. ARVC had better outcomes than NIDCM for the primary ( p <0.05) and secondary endpoints ( p <0.05). Remote MI-VT revealed a midrange outcome. Conclusions The long-term outcomes after catheter ablation of VT varied according to the underlying heart disease. ARVC-VT ablation was associated with better long-term prognosis than NIDCM. Remote MI-VT demonstrated a midrange outcome.
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