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Herein, we describe the design and synthesis of cimetidine analogs, as well as their inhibitory activity toward the human multidrug and toxin extrusion transporter 1 (hMATE1), which is related to nephrotoxicity of drugs. Cimetidine is the histamine H2-receptor antagonist, but also inhibits hMATE1, which is known to cause renal impairment. We designed and synthesized cimetidine analogs to evaluate hMATE1 inhibitory activity to reveal whether the analogs could reduce the inhibition of hMATE1. The results showed that all analogs with an unsubstituted guanidino group exhibited hMATE1 inhibitory activity. On the other hand, there was a clear difference in the hMATE1 inhibitory activity for the other compounds. That is, compounds with a methylimidazole ring exhibited hMATE1 inhibition, while compounds with a phenyl ring did not. The results suggest that the ability to form hydrogen bonds at the azole moiety is strongly involved in the hMATE1 inhibition.

Drug efflux pump inhibitors for the multidrug resistance protein HmrM, a member of the multidrug and toxin extrusion (MATE) family of transporters, were investigated to increase the drug susceptibility of multidrug-resistant bacteria and restore the antimicrobial effect of fluoroquinolones, such as norfloxacin. The lead inhibitor, prepared from the known hMATE1 inhibitor cimetidine, reduced the norfloxacin resistance of HmrM-expressing strains by 92% at non-cytotoxic concentrations in human cells, and multidrug resistance protein MdtK-expressing strains by 86%. These results indicated that the inhibitor is a lead candidate for the development of drugs with a novel mechanism of action against infections caused by multidrug-resistant bacteria that act synergistically with antimicrobial drugs.

ObjectivesIt has been hypothesised that smoking intensity may be related to occupational stress. This study aimed to investigate whether stress, including problems with superiors or co-workers, is a driver of smoking.DesignCross-sectional study.Setting and participants59 355 employees (34 865 men and 24 490 women) across multiple occupations who completed a self-reported questionnaire-based occupational stress survey between April 2016 and March 2017 in Niigata Prefecture.Main outcome measuresStress scores for the Brief Job Stress Questionnaire subscales summed up after assigning high points for high stress and converted to Z-scores based on the mean of all participants. Heavy smokers (HS) smoked ≥15 cigarettes/day and light smokers (LS) smoked ResultsThe main subscale items that were significantly associated with smoking status in both genders included ‘physical burden’, ‘irritation’ and ‘physical symptoms’. In the analysis that included smoking intensity, the stress score for ‘co-workers’ support’ was significantly lower for LS men than NS men (NS 0.091±0.98, LS −0.027±1.00, HS 0.033±0.99), and was significantly higher for HS women than NS women (NS −0.091±1.00, LS −0.080±1.05, HS 0.079±1.03). However, the stress score for ‘co-workers’ support’ was low among LS women aged ≤39 years in the manufacturing industry.ConclusionsIt was speculated that LS men and some LS women gained ‘co-workers’ support’ using smoking as a communication tool while reducing the degree of smoking. The existence of such ‘social smokers’ suggested that to promote smoking cessation, measures are essential to improve the communication between workers in addition to implementing smoking restrictions in the workplace.

Background The honeycomb-like structure (HLS) is a rare cause of myocardial ischaemia characterized by multiple communicating channels divided by thin septa. The aetiology of this specific structure remains speculative. Case summary A 55-year-old man was admitted due to worsening effort angina during the previous 2 months. Diagnostic coronary angiography revealed occlusion of the distal right coronary artery (RCA) with good collateral flow from the left coronary artery. We considered this lesion as a recent total occlusion, and planned a percutaneous coronary intervention (PCI). At the time of PCI, 7 days after admission, an angiogram showed a spontaneous recanalization of the occlusive RCA. Intravascular ultrasound (IVUS) depicted a HLS at the recanalized lesion, including atherosclerotic stenosis. We managed these lesions with drug-eluting stents. Discussion A recanalized thrombus may manifest as a HLS. In this case, the patient suffered from worsening effort angina during the previous 2 months, we confirmed a spontaneous recanalization of the occluded coronary lesion by serial angiographic images, and observed HLS adjacent to the atherosclerotic attenuated plaque by using high-resolution IVUS. Recanalized organizing thrombus is considered an entity of HLS. However, all previous studies on the HLS in vivo have detected the structure in an already recanalized state. Therefore, the aetiology remained speculative and evidence has been indirect. This present case demonstrates that recanalized atherosclerotic thrombosis might be one of the causes of HLS.

Multidrug and toxic compound extrusion (MATE) transporters are primarily expressed in the kidneys and liver, where they contribute to the excretion of organic cations. Our previous study suggested that pig MATE2 (class III) participates in testosterone secretion from Leydig cells. In humans, it is unclear which MATE class is involved in testosterone transport. In this study, we aimed to clarify whether human MATE1 (hMATE1) or human MATE2K (hMATE2K) mediates testosterone transport. To confirm that testosterone inhibits transporter-mediated tetraethylammonium (TEA) uptake, a cis-inhibition assay was performed using cells that stably expressed hMATE1 or hMATE2K. Docking simulations were performed to characterize differences in the binding of hMATE1 and hMATE2K to testosterone. Transport experiments in LLC-PK1 cells that stably expressed hMATE1 were used to test whether hMATE1 mediates testosterone transport. We detected differences between the amino acid sequences of the substrate-binding sites of hMATE1 and hMATE2K that could potentially be involved in testosterone binding. Testosterone and estradiol inhibited TEA uptake mediated by hMATE1 but not that mediated by hMATE2K. Transport experiments in LLC-PK1 cells indicated that testosterone might be transported via hMATE1. This study suggested that hMATE1, but not hMATE2K, is involved in human testosterone transport.

Background Lead perforation is one of the major complications of pacemaker implantation, but cases of right ventricular (RV) lead perforation through the septum and left ventricle are rarely reported. We described a rare case of left ventricular (LV) free wall perforation by an RV lead and the management of this complication. Case summary An 84-year-old man was admitted with a dual-chamber pacemaker due to pacing failure caused by an RV lead fracture. New lead implantation was performed on the next day, but pacing failure occurred again on the second post-operative day (POD). We found the lead perforation on the fluoroscopy during temporary pacemaker insertion. Computed tomography scan and transthoracic echocardiogram showed that the added lead perforated through both the septum and LV free wall. A new lead was inserted on the fourth POD, and an off-pump open chest surgery for extraction of the penetrating lead was performed uneventfully on the 20th POD. Discussion We considered that some features of the lead (SelectSecure 3830-69, Medtronic) may be related to this complication, as the lead was very thin, had a non-retractable bare screw and was inserted with a dedicated delivery catheter. We have to be careful when performing implantation of this kind of lead to avoid such a rare complication.

Key Clinical Message However, the common strategy for eliminating premature ventricular contractions (PVCs) is to explore the exit site and ablate, which may be difficult in some cases. The origin and the preferential pathway, an insulated pathway connected to the exit, may also become targets for eliminating PVCs.

Cardiac involvement secondary to polymyositis is not infrequent. In addition, it sometimes presents various forms of arrhythmia, including atrial tachycardia (AT). A 72-year-old female who had 5-years history of polymyositis was referred to our clinic with symptomatic supraventricular tachycardia with 2:1 atrioventricular conduction. Electrophysiological study revealed a total of three focal AT in right atrium with the origin of the basal right atrial appendage (AT1), coronary sinus ostium (AT2), and low lateral right atrium (AT3), respectively. Endocardial bipolar voltage mapping showed low voltage area in the limited area, partially overlapping with the focus of AT3. We finally terminated AT2 targeting an early fractionated potential and AT3 at early activation site with a support of flexibly-bended deflectable sheath while accidentally eliminating AT3 with the bumping of a catheter. With the additional applications, we completely eliminated all AT. AT were never provoked by any inductions with isoproterenol infusion. .

The charge-injection barrier from metal electrodes to thin-film pentacene is investigated using accumulated charge measurements. When a gold electrode is deposited on a pentacene film, the interface forms a Schottky contact with a hole-injection barrier of 0.2 eV. However, interfacial carrier motion is reversible between charge injection and discharge. The result suggests that the reported electrical hysteresis in typical pentacene transistors is caused by carrier traps that are localized primarily in the SiO2/pentacene interface. The Ag/pentacene junction has a large barrier height of 0.5 eV. The barrier height is significantly reduced, and an Ohmic contact is realized by using molybdenum oxide (MoO3) as a buffer layer.

Testosterone is considered to be released from Leydig cells via passive diffusion because of its hydrophobicity; however, the exact mechanism underlying testosterone secretion and the transporter involved are both unknown. Multidrug and toxic compound extrusion (MATE) transporters are predominantly found in the kidneys and liver and are thought to function in the elimination of metabolic organic cations during the final step of excretion in the kidney. In contrast, mMATE2 has been shown to be predominantly expressed in testicular Leydig cells. Although the physiological function of mMATE2 in Leydig cells is unknown, we hypothesized that mMATE2 acts as a testosterone exporter and is responsible for the secretion of testosterone from Leydig cells. Therefore, in the present study, we investigated the involvement of the MATE transporter in testosterone secretion from pig Leydig cells. Immunohistochemical analysis with anti-pig MATE2 antiserum indicated that the MATE transporter is present in pig Leydig cells. Additionally, treatment with the MATE inhibitors cimetidine and pyrimethamine reduced the testosterone secretion from pig Leydig cells but increased the intracellular testosterone levels. Estradiol release and intracellular estradiol level induced by human chorionic gonadotropin (hCG) further increased with cimetidine treatment. These results indicated that testosterone produced by hCG treatment is secreted from Leydig cells via the MATE transporter; however, in the presence of cimetidine or pyrimethamine, this MATE transporter-mediated secretion was inhibited, resulting in increased intracellular testosterone levels and estradiol production in Leydig cells. Thus, the MATE transporter may be responsible for testosterone secretion from Leydig cells.

Quantitative flow ratio (QFR) is an image-based fractional flow reserve (FFR) computed by three-dimensional quantitative coronary angiography and estimated flow velocity. Several studies have reported that QFR was rapidly computed within approximately 5 min and had a good diagnostic performance as compared with FFR. However, studies comparing QFR with instantaneous wave-free ratio (iFR) as an index with a prognostic value comparable to that of FFR are limited. Thus, we investigated the applicability of QFR with respect to iFR, both being easy-to-measure indices not requiring pharmacological hyperaemic induction. We computed QFR in prospectively enrolled 150 coronary lesions (including 50 lesions for onsite QFR analysis) in consecutive patients with intermediate stenosis evaluated by iFR. The correlation and diagnostic performance of QFR were compared using iFR as a reference. The mean QFR and iFR were 0.81 ± 0.12 and 0.89 ± 0.11, respectively. QFR and iFR exhibited a good correlation in all subjects (R = 0.70, p < 0.0001) and the onsite-analysed vessels (R = 0.74, p < 0.0001). In the receiver-operating characteristics analysis, the area under the curve of QFR predicting iFR ≤ 0.89 was 0.91. Applying the cut-off value of QFR ≤ 0.80 and iFR ≤ 0.89, the sensitivity, specificity, positive and negative predictive values were 85%, 83%, 72%, and 91%, respectively, in all subjects, and 82%, 82%, 78%, and 85%, respectively, in the onsite-analysed vessels. QFR including onsite analysis demonstrated a good correlation with iFR and a diagnostic performance comparable to that of iFR in consecutive patients with intermediate coronary stenosis, suggesting its potential as a rapidly derived index for evaluating myocardial ischaemia in clinical settings.

Cardiac tumors are rare, and multiple myxomas are even rarer. The latter phenomenon is mostly associated with the Carney complex, a dominantly inherited disease characterized by multiple primary cardiac myxomas, endocrinopathy, and spotty pigmentation of the skin. We report the rare case of a patient who did not have the Carney complex but had multiple primary cardiac tumors. A 78-year-old woman with a past history of breast cancer was referred to our hospital for further examination of multiple cardiac tumors. Echocardiography showed 4 tumors in the left atrium and left ventricle. We could not diagnose them preoperatively and decided to resect them surgically because they were mobile and could have caused embolism and obstruction. The postoperative pathological findings of all 4 tumors were myxomas, although the patient did not meet the diagnostic criteria of the Carney complex. Therefore, a rare case of multiple primary cardiac myxomas was diagnosed.

Although the efficacy of catheter ablation of the accessory pathway (AP) has been established, there are subgroups of APs with an intermittent conduction property, which is sometimes difficult to diagnose accurately. A 57-year-old man with a history of catheter ablation was referred to our clinic due to frequent faintness. He had undergone concealed AP ablation 8 years previously and bilateral circumferential pulmonary vein isolation (CPVI) 6 years previously. During regular electrocardiogram monitoring, it was suggested that irregular wide QRS tachycardia, which was considered to be atrial fibrillation with antegrade AP conduction, was the cause of the present symptoms. In the present electrophysiological study, we noticed a residual antegrade AP in the left lateral wall that was not observed during the previous session. We achieved abolition of overt accessory conduction, bilateral CPVI, and superior vena cava isolation with several radiofrequency applications without any recurrence. We also confirmed the absence of dormant conduction in the AP and the left atrium-PV connection with 20 mg adenosine triphosphate. This case demonstrated the possibility of sudden exposure of overt AP conduction late after catheter ablation of the concealed AP and the importance of confirming the absence of dormant conduction by means of adenosine triphosphate, which has the potential benefit of revealing latent AP conduction.

Sphingosine 1-phosphate (S1P) is an intercellular signaling molecule present in blood. Erythrocytes have a central role in maintaining the S1P concentration in the blood stream. We previously demonstrated that S1P is exported from erythrocytes by a glyburide-sensitive S1P transporter. However, the gene encoding the S1P transporter in erythrocytes is unknown. In this study, we found that the mouse erythroid cell line, MEDEP-E14, has S1P export activity and exhibits properties that are consistent with those of erythrocytes. Using microarray analysis of MEDEP-E14 cells and its parental cell line, E14TG2a, we identified several candidate genes for S1P export activity. Of those genes, only one gene, Mfsd2b, showed S1P transport activity. The properties of S1P release by MFSD2B were similar to those in erythrocytes. Moreover, knockout of MFSD2B in MEDEP-E14 cells decreased S1P export from the cells. These results strongly suggest that MFSD2B is a novel S1P transporter in erythroid cells.

Introduction The efficacy of thoracic vein isolation (TVI), an approach to trigger atrial fibrillation (AF), for the management of AF has been established. Our goal was to identify the predictors for late recurrence of atrial tachyarrhythmias (ATAs), for which the patients and procedural and/or echocardiographic parameters were retrospectively analyzed. Although substrate modification in the atrium for the treatment of AF ablation remains controversial, the background associated with the outcome has not been fully investigated. We retrospectively studied 33 patients with paroxysmal AF and 21 with persistent AF undergoing defragmentation followed by TVI. We evaluated the late/early recurrences, defined as ATA at 3 months after/within the single procedure. Methods and Results During a median follow-up period of 22 (11-37) months, 28 patients (52%) experienced a late recurrence. There was a higher incidence of late recurrences in the patients with disease durations of ≥12.4 months, which was the optimal cut-off point measured in the receiver operating characteristic curve analysis, or in those with left atrial diameter >50 mm or with earlier recurrences than the others (19% versus 72%, p=0.01; 0% versus 37%, p=0.02; or 13% versus 53%, p

A 39-year-old woman with no coronary risk factors was admitted due to repetitive morning chest pain. Coronary angiography revealed subtotal occlusion of the distal obtuse marginal branch that was not recanalized by intracoronary nitroglycerin administration. Intravascular ultrasound and optical frequency domain imaging showed tandem intramural hematomas in the culprit vessel. We performed cutting balloon angioplasty successfully with dual intracoronary imaging modality guidance. The 4-month follow-up angiography revealed favorable vascular healing and the provocation test induced multiple spasms, including in the culprit vessel, by intracoronary acetylcholine administration. .

BACKGROUND Quantitative flow ratio (QFR) is a newly developed image-based index for estimating fractional flow reserve (FFR).Methods and Results:We analyzed 151 coronary arteries with intermediate stenosis in 142 patients undergoing wire-based FFR measurement using dedicated software. Predefined contrast flow QFR, which was derived from 3-dimensional quantitative coronary angiography (3-D QCA) withThrombolysis in Myocardial Infarction (TIMI) frame counts, was compared with FFR as a reference. QFR had good correlation (r=0.80, P

A 67-year old male with a dual-chamber pacemaker visited for a regular check-up. An unfamiliar message emerged on the display just after placing the programmer wand. We could recognize that the pacemaker had already been in the safe back-up mode of DDI, and the programmer prompted a re-initialization request. We are so surprised because there was no indication of device malfunction the day before in daily monitoring and a 12-lead electrocardiogram revealed normally working in the DDD mode just before checking the device. The pacemaker was immediately re-programmed to the former setting. This phenomenon has not recurred for 12 months. Keywords: Power-on reset, Electromagnetic interference, Pacemaker, Daily monitoring, Transmission interference

Slow-fast atrioventricular nodal tachycardia (AVNRT) has various electrophysiological aspects due to atrioventricular (AV) nodal physiology. In addition, concomitantly another form of arrhythmia with AVNRT, especially atrial tachycardia (AT), was an infrequent arrhythmia. A 38-year-old female with narrow QRS tachycardia underwent electrophysiological study due to frequent faintness. The electrophysiological study disclosed the coexistence of AT originating from coronary sinus (CS) with slow-fast AVNRT. We easily diagnosed AT originating from CS and terminated with several radiofrequency ablations (RFA) around CS. The diagnosis of slow-fast AVNRT, however, was somewhat difficult due to the following findings: (1) small amount of adenosine triphosphate (ATP) could terminate slow-fast AVNRT reproducibly; (2) we could provoke slow-fast AVNRT only by RV pacing with isoproterenol infusion. With other electrophysiological findings, we diagnosed slow-fast AVNRT. Radiofrequency energy was delivered initially in the posteroseptal region, followed by inside CS, and finally in the middle septal region, which completed the slow pathway ablation. After the procedure, we could never provoke these arrhythmias.

Adipocyte fatty acid binding protein (A-FABP; FABP4), which is predominantly expressed in macrophages and adipose tissue, regulates fatty acid storage and lipolysis, and is also an important mediator of inflammation. Here, we report a synthesis of (14)C-labeled 2-[2'-(5-ethyl-3,4-diphenyl-1H-pyrazol-1-yl)biphenyl-3-yloxy]acetic acid (BMS309403), a potent and selective small-molecular FABP4 inhibitor, as a chemical tool for investigating the roles of FABP4 in inflammatory and metabolic disorders. The structure-activity relationship of several BMS derivatives for inhibition of FABP4 is also reported.

経年車より採取したポリブチレンテレフタレート（PBT）製成形部品を用い時間－温度換算則を適用することにより，実用的な温度における熱酸化劣化度及びその熱エージング時間を推定することを試みた．その熱酸化劣化度の指標には，反応熱分解GC/MS法で観測されるメチル4-メトキシブチレート（MMB）の生成量を用いた．3水準の温度におけるベンチ試験の結果より，MMB量と熱エージング時間の関係を100℃基準のマスターカーブに纏めることができた．一例として走行距離が4.6万kmの経年車のエンジン付近から採取した部品に適用したところ，0.0071 wt％ のMMB量に対して，DSC法で求めた熱履歴温度84℃あるいは100℃における熱エージング時間に換算すると，各々4200時間，3500時間と推定された．このように熱酸化劣化度が任意の想定温度における熱エージング時間として表せるようになった．その結果，熱酸化劣化度がMMB量と走行距離の関係からよりも100℃における熱エージング時間との関係からのほうが的確に評価できることが分かった．また，MMB量と機械的物性値の関係を把握することにより寿命推定にも適用できる．よって，本法が汎用的な劣化度評価手法として展開できる可能性が示唆された．

ポリプロピレン（PP）の熱酸化劣化に及ぼす銅系金属の影響及び劣化度に対応した分析手法の検討を行った．熱安定性の異なるPPで成形したコネクターに端子を挿入することで接触性を保ち，140℃で120時間熱エージングを行った．端子は黄銅1種あるいは高銅合金をそのまま使用した場合と，それを基材としてスズめっきした計4種類を用いた．PPの熱酸化劣化はその熱安定性の優劣と端子構成材に依存しており，基材に高銅合金よりも黄銅1種を用い，更に厚み1～2 μmのスズめっきをすることで改善されるが，特に熱安定性の劣るPPには有効であった．これをSEMによるスズめっき中のスズ銅合金層の観察及びICPによるPP中の銅の定量より確認することができた．酸化劣化の分析法は汎用的な高温GPC，FT-IRによる顕微ATR，DSCによるOOT（Oxidation Onset Temperature），ヨードメトリー滴定法による過酸化物量を用いた．OOTと劣化度の関係をマスターカーブで整理することにより，初期品から劣化の進行した様々な段階の劣化度の評価に活用ができるようになった．更に，OOTと分子量の変化との相関関係も得られた．ヨードメトリー法が急激な分子量の低下の予測に高感度で検出できることが確認された．

Human multidrug and toxic compound extrusion 1 (hMATE1) is an electroneutral H+/organic cation exchanger responsible for the final excretion step of structurally unrelated toxic organic cations in kidney and liver. To elucidate the molecular basis of the substrate recognition by hMATE1, we substituted the glutamate residues Glu273, Glu278, Glu300, and Glu389, which are conserved in the transmembrane regions, for alanine or aspartate and examined the transport activities of the resulting mutant proteins using tetraethylammonium (TEA) and cimetidine as substrates after expression in human embryonic kidney 293 (HEK-293) cells. All of these mutants except Glu273Ala were fully expressed and present in the plasma membrane of the HEK-293 cells. TEA transport activity in the mutant Glu278Ala was completely absent. Both Glu300Ala and Glu389Ala and all aspartate mutants exhibited significantly decreased activity. Glu273Asp showed higher affinity for cimetidine, whereas it has reduced affinity to TEA. Glu278Asp showed decreased affinity to cimetidine. Both Glu300Asp and Glu389Asp had lowered affinity to TEA, whereas the affinity of Glu389Asp to cimetidine was fourfold higher than that of the wild-type transporter with about a fourfold decrease in Vmax value. Both Glu273Asp and Glu300Asp had altered pH dependence for TEA uptake. These results suggest that all of these glutamate residues are involved in binding and/or transport of TEA and cimetidine but that their individual roles are different.

Mammalian multidrug and toxic compound extrusion 1 (MATE1) are polyspecific H+-coupled exporters of organic cations (OCs) and responsible for excretion of metabolic waste products and xenobiotics. Here, we report a novel variant of mouse MATE1, mMATE1b, that has a long carboxyl terminal hydrophobic tail homologous to other MATE1 transporter proteins. Mouse MATE1b mediates tetraethylammonium (TEA) uptake with properties similar to that of mMATE1 and is localized in renal brush border membranes. Thus, mMATE1b is a functional variant of mMATE1 and seems to be the true counterpart to other MATE1 transporters.

Objective: To evaluate the performance of dual source CT coronary angiography (DSCT-CA) in the detection of in-stent restenosis (>= 50% luminal narrowing) in symptomatic patients referred for conventional angiography (CA). Design/patients: 100 patients (78 males, age 62 (SD 10)) with chest pain were prospectively evaluated after coronary stenting. DSCT-CA was performed before CA. Setting: Many patients undergo coronary artery stenting; availability of a non-invasive modality to detect in-stent restenosis would be desirable. Results: Average heart rate (HR) was 67 (SD 12) (range 46-106) bpm. There were 178 stented lesions. The interval between stenting and inclusion in the study was 35 (SD 41) (range 3-140) months. 39/100 (39%) patients had angiographically proven restenosis. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of DSCT-CA, calculated in all stents, were 94%, 92%, 77% and 98%, respectively. Diagnostic performance at HR,70 bpm (n = 69; mean 58 bpm) was similar to that at HR >= 70 bpm (n = 31; mean 78 bpm); diagnostic performance in single stents (n = 95) was similar to that in overlapping stents and bifurcations (n = 83). In stents >= 3.5 mm (n = 78), sensitivity, specificity, PPV, NPV were 100%; in 3 mm stents (n = 59), sensitivity and NPV were 100%, specificity 97%, PPV 91%; in stents (2.75 mm (n = 41), sensitivity was 84%, specificity 64%, PPV 52%, NPV 90%. Nine stents (2.75 mm were uninterpretable. Specificity of DSCT-CA in stents >= 3.5 mm was significantly higher than in stents (2.75 mm (OR = 6.14; 99%CI: 1.52 to 9.79). Conclusion: DSCT-CA performs well in the detection of in-stent restenosis. Although DSCT-CA leads to frequent false positive findings in smaller stents ((2.75 mm), it reliably rules out in-stent restenosis irrespective of stent size.

Aims: To investigate if three-dimensional (3D) based quantitative techniques are comparable to each other and to explore possible differences with respect to the reference method of 2D-QCA in the acute phase and to study whether non-invasive MSCT could potentially be applied to quantify luminal dimensions of a stented coronary segment with a novel bioabsorable drug-eluting stent made of poly-l-lactic-acid (PLLA). Methods and results: Quantitative imaging data derived from 16 patients enrolled at our institution in a first-in-man trial (ABSORB) receiving a biodegradable stent and who were imaged with standard coronary angiography and intravascular ultrasound were compared. Shortly, after stenting the patients also underwent a MSCT procedure. Standard 2D-QCA showed significant smaller stent lengths (p

Background: Noninvasive assessment of coronary atherosclerotic plaque may be useful for risk stratification and treatment of atherosclerosis. Materials and Methods: We studied 47 patients to investigate the accuracy of coronary plaque volume measurement acquired with 64-slice multislice computed tomography (MSCT), using newly developed quantification software, when compared with quantitative intracoronary ultrasound (QCU). Quantitative MSCT coronary angiography (QMSCT-CA) was performed to determine plaque volume for a matched region of interest (regional plaque burden) and in significant plaque defined as a plaque with >= 50% area obstruction in QCU, and compared with QCU. Dataset with image blurring and heavy calcification were excluded from analysis. Results: In 100 comparable regions of interest, regional plaque burden was highly correlated (coefficient r = 0.96; P < 0.001) between QCU and QMSCT-CA, but QMSCT-CA overestimated the plaque burden by a mean difference of 7 +/- 33 mm(3) (p = 0.03). In 76 significant plaques detected within the regions of interest, plaque volume determined by QMSCT-CA was highly correlated (r = 0.98; P < 0.001) with a slight underestimation of 2 +/- 17 mm(3) (p = not significant) when compared with QCU. Calcified and mixed plaque volume was slightly overestimated by 4 +/- 19 mm(3) (P = ns) and noncalcified plaque volume was significantly underestimated by 9 11 mm(3) (P < 0.001) with QMSCT-CA. Overall, the limits of agreement for plaque burden/volume measurement between QCU and QMSCT-CA were relatively large. Reproducibility for the measurements of regional plaque burden with QMSCT-CA was good, with a mean intraobserver and interobserver variability of 0% +/- 16% and 4% +/- 24%, respectively. Conclusions: Quantification of coronary plaque within selected proximal or middle coronary segments without image blurring and heavy calcification with 64-slice CT was moderately accurate with respect to intravascular ultrasound and demonstrated good reproducibility. Further improvement in CT resolution is required for more reliable measurement of coronary plaques using quantification software.

Objectives Our objective was to prospectively evaluate the diagnostic performance of the high-speed dual-source computed tomography scanner (DSCT), with an increased temporal resolution (83 ms), for the detection of significant coronary lesions (≥50% lumen diameter reduction) in a clinically wide range of patients. Background Cardiac motion artifacts may decrease coronary image quality with use of earlier computed tomography scanners that have a limited temporal resolution. Methods We prospectively studied 100 symptomatic patients (79 men, 21 women, mean age 61 ± 11 years) with atypical (18%) or typical (55%) angina pectoris, or unstable coronary artery disease (27%) scheduled for conventional coronary angiography. Mean scan time was 8.58 ± 1.52 s. Mean heart rate was 68 ± 11 beats/min. Quantitative coronary angiography was used as the standard of reference. Irrespective of image quality or vessel size, all segments were included for analysis. Results Invasive coronary angiography demonstrated no significant disease in 23%, single-vessel disease in 31%, and multivessel disease in 46% of patients; 1,489 coronary segments, containing 220 significant (14.8%) stenoses, were available for analysis. Sensitivity, specificity, and positive and negative predictive values of DSCT coronary angiography for the detection of significant lesions on a segment-by-segment analysis were 95% (95% confidence interval [CI] 90 to 97), 95% (95% CI 93 to 96), 75% (95% CI 69 to 80), 99% (95% CI 98 to 99), respectively, and on a patient-based analysis 99% (95% CI 92 to 100), 87% (95% CI 65 to 97), 96% (95% CI 89 to 99), and 95% (95% CI 74 to 100), respectively. Conclusions Noninvasive DSCT coronary angiography is highly sensitive to detect and to reliably rule out the presence of a significant coronary stenosis in patients presenting with atypical or typical angina pectoris, or unstable coronary artery disease.

Threonine was oxidized into acetaldehyde at 0 degrees C for 30 min with periodic acid. The acetaldehyde formed was converted to a hydrazone with 2,4-dinitrophenyhydrazine. The hydrazone was extracted with n-heptane and quantified by gas liquid chromatography with electron capture detection. An internal standard, 2-amino-3-hydroxyhexanoic acid, was used. The calibration curve of threonine was linear up to 200 nmol in 200 microl sample solution and the determination limit of threonine was 1 nmol in 200 microl sample solution. The recoveries were 100.0, 94.0 and 100.0% from homogenates of octopus tentacles and blood plasma and rat livers, respectively. This method was applied to the determination of threonine in tissues of rats given threonine and starved octopuses. This threonine determination method has been used for studies on the metabolism of d-lactate.

In mammals, toxic electrolytes of endogenous and exogenous origin are excreted through the urine and bile. Before excretion, these compounds cross numerous cellular membranes in a transporter-mediated manner. However, the protein transporters involved in the final excretion step are poorly understood. Here, we show that MATE1, a human and mouse orthologue of the multidrug and toxin extrusion family conferring multidrug resistance on bacteria, is primarily expressed in the kidney and liver, where it is localized to the luminal membranes of the urinary tubules and bile canaliculi. When expressed in HEK293 cells, MATE1 mediates H + -coupled electroneutral exchange of tetraethylammonium and 1-methyl-4-phenylpyridinium. Its substrate specificity is similar to those of renal and hepatic H + -coupled organic cations (OCs) export. Thus, MATE1 appears to be the long searched for polyspecific OC exporter that directly transports toxic OCs into urine and bile.

Background Many clinicians have seen the reperfusion phenomenon, a paradoxical response that includes a transient increase of chest pain, additional ST-segment elevation or ventricular arrhythmias immediately after coronary reperfusion, in patients with acute myocardial infarction (AMI). The aim of the present study was to investigate the impact of this phenomenon during coronary reperfusion on left ventricular (LV) remodeling in patients with AMI. Methods and Results One hundred and thirty-eight consecutive patients with a first anterior-wall AMI, undergoing coronary reperfusion treatment within 24 h of onset were prospectively evaluated for reperfusion phenomenon and followed up with scheduled evaluations of LV function and morphology with left ventriculography for 1 year. Of the 138 enrolled patients, 77 underwent serial left ventriculography at the acute, subacute and 1-year phases. Of these 77 patients, 39 demonstrated the reperfusion phenomenon. The LV end-diastolic volume index significantly increased from the acute to subacute phase and to the 1-year phase, but was unchanged in the 38 patients without reperfusion phenomenon. In multivariate analysis, reperfusion phenomenon was the only determinant of LV dilatation after AMI. Conclusions Reperfusion phenomenon was a strong predictor of LV remodeling after reperfusion therapy for AMI. (Circ J 2005; 69: 884 - 889)

Islets of Langerhans contain gamma-aminobutyrate (GABA) and may use it as an intercellular transmitter. In beta-cells, GABA is stored in synaptic-like microvesicles and secreted through Ca(2+)-dependent exocytosis. Vesicular inhibitory amino acid transporter (VIAAT), which is responsible for the storage of GABA and glycine in neuronal synaptic vesicles, is believed to be responsible for the storage and secretion of GABA in beta-cells. However, a recent study by Chessler et al. indicated that VIAAT is expressed in the mantle region of islets. In the present study, we investigated the precise localization of VIAAT in rat islets of Langerhans and clonal islet cells and found that it is present in alpha-cells, a minor population of F-cells and alphaTC6 cells, and clonal alpha-cells but not in beta-cells, delta-cells, or MIN6 m9-cells (clonal beta-cells). Combined biochemical, immunohistochemical, and electronmicroscopical evidence indicated that VIAAT is specifically localized with glucagon-containing secretory granules in alpha-cells. ATP-dependent uptake of radiolabeled GABA, which is energetically coupled with a vacuolar proton pump, was detected in digitonin-permeabilized alphaTC6 cells as well as in MIN6 m9 cells. These results demonstrate that functional neuronal VIAAT is present in glucagon-containing secretory granules in alpha-cells and suggest that the ATP-dependent GABA transporter in beta-cells is at least immunologically distinct from VIAAT. Because glucagon-containing secretory granules also contain vesicular glutamate transporter and store L-glutamate, as demonstrated by Hayashi et al., the present results suggest more complex features of the GABAergic phenotype of islets than previously supposed.

A vesicular glutamate transporter (VGLUT) is responsible for the accumulation of l-glutamate in synaptic vesicles in glutamatergic neurons. Two isoforms, VGLUT1 and VGLUT2, have been identified, which are complementarily expressed in these neurons. Mammalian pinealocytes, endocrine cells for melatonin, are also glutamatergic in nature, accumulate l-glutamate in synaptic-like microvesicles (SLMVs), and secrete it through exocytosis. Although the storage of l-glutamate in SLMVs is mediated through a VGLUT, the molecular nature of the transporter is less understood. We recently observed that VGLUT2 is expressed in pinealocytes. In the present study, we show that pinealocytes also express VGLUT1. RT-PCR and northern blot analyses indicated expression of the VGLUT1 gene in pineal gland. Western blotting with specific antibodies against VGLUT1 indicated the presence of VGLUT1 in pineal gland. Indirect immunofluorescence microscopy with a section of pineal gland and cultured cells indicated that VGLUT1 and VGLUT2 are co-localized with process terminal regions of pinealocytes. Furthermore, immunoelectronmicroscopy as well as subcellular fractionation studies revealed that both VGLUT1 and VGLUT2 are specifically associated with SLMVs. These results indicate that both VGLUTs are responsible for storage of l-glutamate in SLMVs in pinealocytes. Pinealocytes are the first exception as to complementary expression of VGLUT1 and VGLUT2.

A 52-year-old woman, a hemodialysis patient, was admitted because of exertional dyspnea. Echocardiography showed left ventricular (LV) dilatation and reduced contraction. Coronary angiography showed no fixed stenosis. She had elevated levels of parathyroid hormone (PTH) as a result of secondary hyperparathyroidism with advanced renal failure. After parathyroidectomy, marked improvement of LV function following immediate decrease of blood levels of PTH was observed. It is suggested that PTH might have a significant role in the pathogenesis of LV dysfunction and that parathyroidectomy might be effective as a therapy for heart failure in some patients with secondary hyperparathyroidism and LV dysfunction.

Vesicular glutamate transporter is present in neuronal synaptic vesicles and endocrine synaptic-like microvesicles and is responsible for vesicular storage of L-glutamate. A brain-specific Na(+)-dependent inorganic phosphate transporter (BNPI) functions as a vesicular glutamate transporter in synaptic vesicles, and the expression of this BNPI defines the glutamatergic phenotype in the central nervous system (Bellocchio, E. E., Reimer, R. J., Fremeau, R. T., Jr., and Edwards, R. H. (2000) Science 289, 957-960; Takamori, S., Rhee, J. S., Rosenmund, C., and Jahn, R. (2000) Nature 407, 189-194). However, since not all glutamatergic neurons contain BNPI, an additional transporter(s) responsible for vesicular glutamate uptake has been postulated. Here we report that differentiation-associated Na(+)-dependent inorganic phosphate cotransporter (DNPI), an isoform of BNPI (Aihara, Y., Mashima, H., Onda, H., Hisano, S., Kasuya, H., Hori, T., Yamada, S., Tomura, H., Yamada, Y., Inoue, I., Kojima, I., and Takeda, J. (2000) J. Neurochem. 74, 2622-2625), also transports L-glutamate at the expense of an electrochemical gradient of protons established by the vacuolar proton pump when expressed in COS7 cells. Molecular, biological, and immunohistochemical studies have indicated that besides its presence in neuronal cells DNPI is preferentially expressed in mammalian pinealocytes, alphaTC6 cells, clonal pancreatic alpha cells, and alpha cells of Langerhans islets, these cells being proven to secrete L-glutamate through Ca(2+)-dependent regulated exocytosis followed by its vesicular storage. Pancreatic polypeptide-secreting F cells of Langerhans islets also expressed DNPI. These results constitute evidence that DNPI functions as another vesicular transporter in glutamatergic endocrine cells as well as in neurons.