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Genetic changes conferring drug resistance are generally believed to impose fitness costs to pathogens in the absence of the drug. However, the fitness of resistant parasites against sulfadoxine/pyrimethamine has been inconclusive in Plasmodium falciparum. This is because resistance is conferred by the complex combination of mutations in dihydropteroate synthase (dhps) and dihydrofolate reductase (dhfr), which makes it difficult to separately assess the extent and magnitude of the costs imposed by mutations in dhps and dhfr. To assess the fitness costs imposed by sulfadoxine resistance alone, we generated a transgenic rodent malaria parasite, P. berghei clone harboring an A394G mutation in dhps (PbDHPS-A394G), corresponding to the causative mutation for sulfadoxine resistance in P. falciparum (PfDHPS-A437G). A four-day suppressive test confirmed that the PbDHPS-A394G clone was resistant to sulfadoxine. PbDHPS-A394G and wild-type clones showed similar growth rates and gametocyte production. This observation was confirmed in competitive experiments in which PbDHPS-A394G and wild-type clones were co-infected into mice to directly assess the survival competition between them. In the mosquitoes, there were no significant differences in oocyst production between PbDHPS-A394G and wild-type. These results indicate that the PbDHPS-A394G mutation alters the parasites to sulfadoxine resistance but may not impose fitness disadvantages during the blood stages in mice and oocyst formation in mosquitoes. These results partly explain the persistence of the PfDHPS-A437G mutant in the natural parasite populations., (Copyright © 2021. Published by Elsevier B.V.)

In Uganda, artemether-lumefantrine was introduced as an artemisinin-based combination therapy (ACT) for malaria in 2006. We have previously reported a moderate decrease in ex vivo efficacy of lumefantrine in Northern Uganda, where we also detected ex vivo artemisinin-resistant Plasmodium falciparum. Therefore, it is necessary to search for candidate partner alternatives for ACT. Here, we investigated ex vivo susceptibility to four ACT partner drugs as well as quinine and chloroquine, in 321 cases between 2013 and 2018. Drug-resistant mutations in pfcrt and pfmdr1 were also determined. Ex vivo susceptibility to amodiaquine, quinine, and chloroquine was well preserved, whereas resistance to mefloquine was found in 45.8%. There were few cases of multi-drug resistance. Reduced sensitivity to mefloquine and lumefantrine was significantly associated with the pfcrt K76 wild-type allele, in contrast to the association between chloroquine resistance and the K76T allele. Pfmdr1 duplication was not detected in any of the cases. Amodiaquine, a widely used partner drug for ACT in African countries, may be the first promising alternative in case lumefantrine resistance emerges. Therapeutic use of mefloquine may not be recommended in this area. This study also emphasizes the need for sustained monitoring of antimalarial susceptibility in Northern Uganda to develop proper treatment strategies., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Atrial fibrillation (AF) and chronic kidney disease (CKD) are closely related. The present study aimed to evaluate the association between estimated glomerular filtration rate (eGFR) and outcomes after cryoballoon catheter ablation for AF., Methods: We included a total of 110 patients (64.0±10.1 years, 64% men) with paroxysmal AF who underwent second-generation cryoballoon catheter ablation in this study. Recurrence and change in renal function after ablation were assessed by stratification of eGFR sub-groups., Results: During a mean follow-up period of 9 months, 20 (18%) patients had AF recurrence after the first catheter ablation procedure. Multivariate Cox regression analysis showed that eGFR [hazard ratio (HR) 0.97, 95% confidence interval (CI) 0.93-0.99, p=0.047], non-pulmonary vein (PV) ectopic beats at initial ablation (HR 2.92, 95% CI 1.03-8.27, p=0.043), and history of stroke (HR 7.47, 95% CI 2.30-24.2, p=0.001) were independent predictors of recurrence after the ablation. Among the CKD groups, recurrence was found in 7% (1/15), 12% (9/73), and 46% (10/22) of the eGFR ≥90mL/min/1.73m 2 , eGFR 60-89.9mL/min/1.73m 2 , and eGFR 30-59.9mL/min/1.73m 2 groups, respectively (p=0.001). Kaplan-Meier survival curves demonstrated that patients with eGFR 30-59.9mL/min/1.73m 2 had significantly worse prognosis than did the other groups (log-rank p<0.001). In addition, non-PV ectopic beats at initial ablation were detected in 7% (1/15), 14% (10/73), and 50% (11/22) of the patients among the three CKD groups, respectively (p<0.001). No patients developed contrast-induced nephropathy after the catheter ablation procedure., Conclusions: Low eGFR at baseline was an independent predictor of recurrence after cryoballoon ablation for paroxysmal AF. The presence of non-PV ectopic beats was significantly increased in patients with impaired renal function, which might be associated with a poor outcome., (Copyright © 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Close monitoring of intraoperative activated clotting time (ACT) is crucial to prevent complications during the periprocedural period of atrial fibrillation (AF) ablation. However, little is known about the ACT in patients receiving new oral anticoagulant agents (NOACs)., Objective: The purpose of this study was to evaluate change in the ACT among anticoagulant agents used during the periprocedural period of AF ablation., Methods: We examined 869 consecutive patients who underwent AF ablation between April 2012 and August 2014 and received NOACs (n = 499), including dabigatran, rivaroxaban, and apixaban, or warfarin (n = 370) for uninterrupted periprocedural anticoagulation. Changes in intraprocedural ACT were investigated among the anticoagulant agents. Furthermore, the incidence of periprocedural events was estimated., Results: The average time in minutes required for achieving a target ACT >300 seconds was significantly longer in the dabigatran group (DG) and apixaban group (AG) than in the warfarin group (WG) and rivaroxaban group (RG) (60 and 70 minutes vs 8 and 9 minutes, respectively; P < .001). In addition, the proportion of patients who achieved the target ACT after initial heparin bolus was significantly lower in the DG and AG than in the WG and RG (36% and 26% vs 84% and 78%, respectively; P < .001). Furthermore, the incidence of periprocedural complications was equivalent among the groups., Conclusion: The average time required to reach the target ACT was longer in the DG and AG than in the WG and RG., (Copyright © 2015 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Atovaquone, a coenzyme Q analogue has been indicated to specifically target the cytochrome bc1 complex of the mitochondrial respiratory chain in the malarial parasite and other protozoan. Various mutations in the quinone binding site of the cytochrome b gene of Plasmodium spp. such as M133I, L144S, L271V, K272R, Y268C, Y268S, Y268N, and V284F are suggesting to associate with resistance to atovaquone. There is no direct evidence of relation between the mutations and resistance to atovaquone in Plasmodium parasite that has been available. Technical difficulties in isolating active assayable mitochondria in the malarial parasite hinder us to obtain direct biochemical evidence to support the relation between the mutations and drug resistance. The establishment of a mitochondrial isolation method for the malaria parasite has allowed us to test the degree of resistance of Plasmodium berghei isolates to atovaquone directly. We have tested the activity of dihydroorotate (DHO)-cytochrome c reductase in various P. berghei atovaquone resistant clones in the presence of a wide concentration range of atovaquone. Our results show the IC(50) of P. berghei atovaquone resistant clones is much higher (1.5 up to 40 nM) in comparison to the atovaquone sensitive clones (0.132-0.465 nM). The highest IC(50) was revealed in clones carrying Y268C and Y268N mutations (which play an important role in atovaquone resistance in Plasmodium falciparum), with an approximately 100-fold increase. The findings indicate the importance of the mutation in the quinone binding site of the cytochrome b gene and that provide a direct evidence for the atovaquone inhibitory mechanism in the cytochrome bc1 complex of the parasite., (Copyright © 2014. Published by Elsevier Ireland Ltd.)

Background: Dipeptidyl peptidase-4 (DPP-4) inhibitors were recently reported to have cardioprotective effects via amelioration of ventricular function. However, the role of DPP-4 inhibition in atrial remodeling, especially of the arrhythmogenic substrate, remains unclear., Objective: We investigated the effects of a DPP-4 inhibitor, alogliptin, on atrial fibrillation (AF) in a rabbit model of heart failure caused by ventricular tachypacing (VTP)., Methods: Rabbits subjected to VTP at 380 bpm for 1 or 3 weeks, with or without alogliptin treatment, were assessed using echocardiography, electrophysiology, histology, and immunoblotting and compared with nonpaced animals., Results: VTP rabbits exhibited increased duration of atrial burst pacing-induced AF, whereas administration of alogliptin shortened this duration by 73%. The extent of atrial fibrosis after VTP was reduced by 39% in the alogliptin-treated group. VTP rabbits treated with alogliptin displayed a 1.6-fold increase in left atrial myocardial capillary density compared with nontreated rabbits. A 2-fold increase in endothelial nitric oxide synthase (eNOS) phosphorylation was observed in the left atrium of alogliptin-treated rabbits compared with nontreated rabbits. Moreover, a nitric oxide synthase inhibitor (N(ω)-nitro-l-arginine methyl ester) blocked the beneficial effects of alogliptin on AF duration, fibrosis, and capillary density., Conclusion: Alogliptin shortened the duration of AF caused by VTP-induced fibrotic atrial tissue by augmenting atrial angiogenesis and activating eNOS. Our findings suggest that DPP-4 inhibitors may be useful in the prevention of heart failure-induced AF., (Copyright © 2015 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

The intraerythrocytic form of the human malaria parasite Plasmodium falciparum relies on glycolysis for its energy requirements. In glycolysis, lactate is an end product. It is therefore known that lactate accumulates in in vitro culture; however, its influence on parasite growth remains unknown. Here we investigated the effect of lactate on the development of P. falciparum during in vitro culture under lactate supplementation in detail. Results revealed that lactate retarded parasite development and reduced the number of merozoites in the schizont stage. These findings suggest that lactate has the potential to affect parasite development., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Malaria parasites in human hosts depend on glycolysis for most of their energy production, and the mitochondrion of the intraerythrocytic form is acristate. Although the genes for all tricarboxylic acid (TCA) cycle members are found in the parasite genome, the presence of a functional TCA cycle in the intraerythrocytic stage is still controversial. To elucidate the physiological role of Plasmodium falciparum mitochondrial complex II (succinate-ubiquinone reductase (SQR) or succinate dehydrogenase (SDH)) in the TCA cycle, the gene for the flavoprotein subunit (Fp) of the enzyme, pfsdha (P.falciparum gene for SDH subunit A, PlasmoDB ID: PF3D7&#95;1034400) was disrupted. SDH is a well-known marker enzyme for mitochondria. In the pfsdha disruptants, Fp mRNA and polypeptides were decreased, and neither SQR nor SDH activity of complex II was detected. The suppression of complex II caused growth retardation of the intraerythrocytic forms, suggesting that complex II contributes to intraerythrocytic parasite growth, although it is not essential for survival. The growth retardation in the pfsdha disruptant was rescued by the addition of succinate, but not by fumarate. This indicates that complex II functions as a quinol-fumarate reductase (QFR) to form succinate from fumarate in the intraerythrocytic parasite., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: Although several ECG algorithms have been proposed for differentiating the origins of outflow tract ventricular arrhythmia (OT-VA), their accuracy still is limited in cases with cardiac rotation., Objective: The purpose of this study was to assess whether a novel "cardiac rotation-corrected" transitional zone (TZ) index would be a useful marker for differentiating right ventricular outflow tract (RVOT) origin from aortic sinus cusp (ASC) origin., Methods: Surface ECGs of OT-VAs with left bundle branch block morphology and inferior axis in 112 patients who were successfully ablated in the RVOT (n = 87) or the ASC (n = 25) were analyzed. The TZ index was defined according to the site of R-wave transition of sinus beats and OT-VAs., Results: The TZ index was significantly lower in the ASC origin than in the RVOT origin (-1.2 ± 0.9 vs 0.3 ± 0.7, P <.0001). A cutoff value of the TZ index <0 predicted the ASC origin with 88% sensitivity and 82% specificity. The previously reported R-wave duration index ≥ 50% had a high specificity of 85% but a low sensitivity of 44%, and R/S-wave amplitude index ≥ 30% had 68% sensitivity and 79% specificity. The area under the curve by receiver operating characteristic curve analysis was 0.90 for the TZ index, which was significantly higher than the R-wave duration index and R/S-wave amplitude index of 0.74 and 0.76, respectively., Conclusion: This novel TZ index can be a more useful marker for differentiating RVOT origin from ASC origin., (Copyright © 2011 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Cerebral malaria (CM) is the most severe complication of Plasmodium infection. Although inappropriate immune responses to Plasmodium falciparum are reported as the major causes of CM, the precise mechanisms for development remain unclear. IL-23 and IL-17 have critical roles in the onset of autoimmunity and inflammatory diseases triggered by microbial infections. Thus, we investigated the influence of IL-23 and IL-17 on experimental CM (ECM) using Plasmodium berghei ANKA infection of C57BL/6 mice. Both IL-23 deficient mice and wild-type (WT) mice developed ECM. IL-17 deficient mice also developed ECM, while IL-17 producing cells other than CD4(+) T cells (Th17) were increased in WT mice that developed ECM. In conclusion, this study showed that IL-23 and IL-17 are not involved in ECM development., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Malaria parasites perform sexual reproduction in mosquitoes where a pair of gametes fertilizes and differentiates into zygotes, and a single zygote produces several thousands of progeny infectious to next vertebrates. Although the parasite fertilization step has been considered as Achilles' heel of parasite life cycle and thus a critical target for blocking malaria transmission in the mosquito, its molecular mechanisms are largely unknown. Previously, we identified that GENERATIVE CELL SPECIFIC 1 (GCS1) is a reproduction factor in angiosperm. Subsequently, it was found that rodent malaria parasite, Plasmodium berghei and green algae, Chlamydomonas reinhardtii possess GCS1 homologues which also play essential roles in gamete interaction. Moreover, intensive database mining revealed that GCS1-like gene homologues exist in the genomes of various organisms. Thus, it appears that GCS1 is an ancient and highly conserved molecule functioning at gamete interaction. In this mini-review, we describe the mechanisms of gametogenesis and fertilization in malaria parasites, comparing with other eukaryotic reproduction, and also speculate GCS1 functions in gamete interaction. We discuss the possibility of whether malaria GCS1 is a novel type of transmission blocking vaccine, by which anti-malaria GCS1 antibody may halt parasite fertilization and subsequent developments in the mosquitoes., (Copyright (c) 2009 Elsevier B.V. All rights reserved.)

Background: Mechanical dyssynchrony is an important factor in the response to cardiac resynchronization therapy (CRT). However, no echocardiographic measure can improve prediction of case selection for CRT., Objective: The purpose of this study was to assess the efficacy of a newly combined echocardiographic index for ventricular dyssynchrony and contractility using speckled tracking strain analysis to predict responders to CRT., Methods: Forty-seven patients with severe heart failure in New York Heart Association functional class III/IV, left ventricular ejection fraction /=130 ms were included in the study. Echocardiography was performed, and a novel index (i-Index), the product of radial dyssynchrony and radial strain, was calculated. Responder to CRT was defined as a patient with a >/=15% decrease in left ventricular end-systolic volume at 6-month follow-up., Results: Thirty-two patients (68%) were classified as responders. The i-Index was significantly higher in responders than in nonresponders (3,450 +/- 1180 vs 1,481 +/- 841, P <.001). The area under receiver operator characteristic curve was 0.92 for the i-Index, which was better than the index of radial dyssynchrony only (0.74). A cutoff value of i-Index >2,000 predicted responders with 94% sensitivity and 80% specificity. The index using only radial dyssynchrony had 81% sensitivity and 53% specificity. Furthermore, i-Index decreased in responders (1,985 +/- 1261, P <.001) but not in nonresponders (1,684 +/- 866, P = .48)., Conclusion: Our findings suggest that a novel combined index by radial strain echocardiography might be a predictor of response to CRT. The value of this novel echocardiographic index requires further assessment in larger studies., (Copyright 2010 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Plasmodium knowlesi has a relatively broad host range extending to humans, in whom it causes zoonotic malaria. Recent studies have shown that human infection with P. knowlesi is widely distributed in forested areas of Southeast Asia. In the present study, we evaluated commercial rapid diagnostic tests (RDTs) for human malaria to assess their reactivity and sensitivity in detecting P. knowlesi parasites using blood samples obtained from infected monkeys. The blood samples were assayed using two commercial RDTs based on immunochromatographic assays: (i) the OptiMAL-IT, designed to detect parasite lactate dehydrogenase (pLDH) of both P. falciparum and other plasmodia, and (ii) the Entebe Malaria Cassette (MC), designed to detect P. falciparum-specific histidine-rich protein 2 (PfHRP2) and P. vivax-specific pLDH. Interestingly, when the P. knowlesi-infected blood samples were examined with the RDTs, OptiMAL test results were interpreted as falciparum malaria-positive, while Entebe MC test results were interpreted as vivax malaria-positive. The sensitivities of both tests in detecting P. knowlesi parasite were similar to those for P. falciparum and higher than P. vivax. Thus, commercial RDTs based on detection of pLDH should be used with great caution, and should not replace conventional microscopy in the diagnosis of suspected cases of P. knowlesi malaria.

Background: The left atrial appendage (LAA) is one of the major sources of focal atrial tachycardias (ATs)., Objective: The purpose of this study was to investigate the detailed electrophysiologic characteristics and catheter ablation of focal ATs originating from the LAA., Methods: The study population consisted of 47 consecutive patients with 50 focal ATs originating from the left atrium (LA): LAA in 13, left pulmonary veins (PVs) in 14, right PVs in 12, and mitral annulus in 11. Programmed electrical stimulation and pharmacologic testing were performed to examine the mechanism of LAA AT. Left atriography was performed prior to radiofrequency ablation to identify the focus in the LAA., Results: The mechanism of LAA AT was automaticity in 11 and triggered activity in 2. The 13 LAA foci were located mainly at the LAA base: 11 on the medial side and 2 on the lateral side. Atrial activation sequences within the distal coronary sinus were helpful in differentiating these LAA foci. The criterion of a negative P wave in leads I and aVL indicating an LAA AT focus was associated with sensitivity of 92.3%, specificity 97.3%, positive predictive value 92.3%, and negative predictive value 97.3%. No complications occurred in any of the 13 patients. All 13 patients were free of atrial arrhythmias without any antiarrhythmic drugs during follow-up of 8 +/- 3 years., Conclusion: LAA ATs have typical electrophysiologic and electrocardiographic characteristics that are helpful in guiding radiofrequency catheter ablation.

Background: How extensive should an appropriate pulmonary vein (PV) ablation be is a matter of controversy., Objective: The study's aim was to investigate the efficacy of minimally extensive PV ablation for isolating the PV antrum (PVA) with the guidance of electrophysiological parameters., Methods: Fifty-five consecutive symptomatic paroxysmal atrial fibrillation (PAF) patients underwent PV mapping with a multielectrode basket catheter (MBC). A 31-mm MBC was deployed in 3-4 PVs as proximally as possible without dislodgement, and the longitudinal PV mapping enabled us to recognize single sharp potentials formed by the total fusion of the PV and left atrial potentials around the PV ostium or the transverse activation patterns that were observed. Those potentials were defined as PVA potentials. Radiofrequency ablation was performed circumferentially targeting PVA potentials with the end point being their elimination., Results: After circumferential PVA ablation, electrical disconnection was achieved in 77% and residual PVA conduction gaps were observed in 23% of all targeted PVs. Those residual conduction gaps were mainly located at the border between ipsilateral PVs (42%) and between the left PVs and left atrial appendage (33%) and were eliminated by a mean of 3 +/- 2 minutes of local radiofrequency deliveries. During the follow-up period (11 +/- 5 months), 46 (84%) patients were free of symptomatic PAF without any anti-arrhythmic drugs. No PV stenosis or spontaneous left atrial flutter occurred., Conclusions: Electrophysiological PVA ablation with an MBC is feasible and effective for curing PAF because this minimally extensive PVA isolation technique targets the optimal sites, achieving both high efficacy and safety.

Grb2-associated binder-1 (Gab1) is a docking protein closely related to insulin receptor substrates. We previously reported that tyrosine 1062 in RET receptor tyrosine kinase activated by glial cell line-derived neurotrophic factor (GDNF) represents a binding site for the Shc-Grb2-Gab1 complex, and that the p85 subunit of phosphatidylinositol 3-kinase (PI3K) and SHP2 tyrosine phosphatase is associated with Gab1 in GDNF-treated cells. In the present study, we further analyzed the physiological roles of Gab1 downstream of RET, using Gab1 mutants that lack the binding sites for PI3K (Gab1 PI3K-m) or SHP-2 (Gab1 SHP2-m). Expression of Gab1 PI3K-m in SK-N-MC human primitive neuroectodermal tumor cells expressing wild-type RET markedly impaired Akt phosphorylation, Rac1 activation, and lamellipodia formation that were induced by GDNF whereas expression of Gab1 SHP2-m partially impaired Erk activation. Furthermore, expression of Gab1 PI3K-m, but not Gab1 SHP2-m, in TT human medullary thyroid carcinoma cells expressing RET with a multiple endocrine neoplasia 2A mutation enhanced cytochrome c release, and apoptosis induced by etoposide, suggesting that PI3K is involved in survival of TT cells via a mitochondrial pathway. These findings demonstrated that coupling of Gab1 to PI3K is important for biological responses in RET-expressing cells., (Copyright 2004 Elsevier Inc.)

Objectives: The purpose of this study was to investigate the efficacy of a novel catheter mapping technique for predicting atrial fibrillation (AF) foci., Background: Most AF originates from pulmonary veins (PVs), but some originate from the right atrium., Methods: We developed an algorithm by correlating the cardiac recordings obtained from multielectrode catheters placed in the posterior right atrium (RA) and esophagus during pacing from the PVs and superior vena cava (SVC) or crista terminalis (CT) in 10 AF patients. We tested the algorithm's accuracy prospectively in 46 AF patients., Results: During pacing from the left PVs, the esophageal potentials preceded all other potentials. During pacing from both the right PVs and SVC-CT, the first component (FP) of the double potential (DP) recorded in the posterior RA preceded all other potentials. The amplitude of the FP was higher than that of the second DP component during pacing from the SVC-CT, whereas the reverse occurred from the right PVs. The activation sequence of the FPs and esophageal potentials was from superior to inferior during pacing from the superior PVs, whereas the reverse occurred from the inferior PVs. The accuracy of predicting 34 foci in the right PVs, 28 foci in left PVs, and 6 foci in SVC-CT was 100% for all, respectively. The accuracy of discriminating foci in the superior PVs from those in the inferior PVs was 97% in the right PVs and 96% in the left PVs., Conclusions: The technique using mapping catheters placed in the posterior RA and esophagus is feasible and effective for mapping and ablating AF.

Background: Although exercise-induced electrocardiographic ST segment changes are used to detect coronary artery disease (CAD), their diagnostic value is markedly decreased in patients with left ventricular (LV) hypertrophy. There have been no reports concerning postexercise systolic blood pressure (SBP) response in patients with ultrasound echocardiographic (UCG) LV hypertrophy and CAD., Methods: Sixty-six patients with both UCG-LV hypertrophy (LV mass index 134 g/m2 or greater for men or 110 g/m2 or greater for women) and positive ST depression of at least 0.1 mV during treadmill exercise testing were studied. Coronary cineangiograms showed normal coronary arteries in 19 patients (group 1) and significant CAD in 47 patients (group 2). The SBP ratio was calculated by dividing the SBP 3 min after exercise (3 min SBP) by the SBP at peak exercise (peak SBP)., Results: There were no significant differences between the two groups in LV mass index, SBP at rest, exercise duration, ST depression (at rest and exercise-induced) or 3 min SBP. However, the SBP ratio was significantly higher in group 2 compared with group 1 (0.87+/-0.11 versus 1.01+/-0.18; P=0.004). Analysis of relative cumulative frequency distributions revealed an SBP ratio of 0.92 as the cutoff point for distinguishing a UCG-LV hypertrophy patient with CAD from one without CAD. The sensitivity, specificity and accuracy with an SBP ratio of 0.92 and an ST segment depression of at least 0.1 mV on treadmill exercise testing for detecting CAD in patients with UCG-LV hypertrophy were 77%, 74% and 76%, respectively., Conclusion: These findings suggest that the ratio of early post-exercise SBP to peak exercise SBP may be diagnostically useful in detecting CAD in patients with positive ST depression during an exercise test and UCG-LV hypertrophy.

Plasminogen activator inhibitor-1 (PAI-1) plays a critical role in tissue fibrosis by inactivating matrix metalloproteinases, which might effect on the progression of left ventricular dysfunction. However, little has been known about the expression of PAI-1 during cardiac remodeling. We used a mouse model of myocardial infarction (MI) by coronary ligation, in which the progression of left ventricular remodeling was confirmed by echocardiography. Histological examination showed that interstitial and perivascular fibrosis progressed in the post-MI (PMI) heart at 4 weeks after the procedure. We observed the dramatic induction of cardiac PAI-1 mRNA and PAI-1 antigen in plasma in the PMI mice, as compared with the sham-operated (sham) mice. In situ hybridization analysis demonstrated that strong signals for PAI-1 mRNA were localized to cardiomyocytes in the border of infarct area and around fibrous lesions, and to perivascular mononuclear cells, which seemed to be mast cells, only in hearts of the PMI mice. Importantly, less development of cardiac fibrosis after MI was observed in mice deficient in PAI-1 as compared to wild-type mice. The mRNA expression of cytokines, transforming growth factor-beta, and tumor necrosis factor-alpha, was also increased in hearts of the PMI mice, but not in the sham mice. These observations suggest that cardiomyocytes and mast cells contribute to the increased PAI-1 expression, resulting in the development of interstitial and perivascular fibrosis in the PMI heart, and that the regional induction of cytokines may be involved in this process.

Background: We have investigated the effects of various vasodilators on smooth muscle relaxation during acute recoil with guinea-pig aorta to find effective therapies to prevent acute recoil at percutaneous transluminal coronary angioplasty (PTCA)., Methods: Muscle strips from guinea-pig aorta without endothelium were placed in a bath filled with modified Krebs solution. The strip was isotonically stretched with a tension of 9 mN for 1 min, and then isometric tension was measured until the tension reached a steady state. Various vasodilators were applied during isometric tension measurement., Results: When no drug was applied (control), isometric tension reached a steady state within 20 min. The steady state was approximately 10% lower (more relaxed) than the stretched level. When isosorbide dinitrate (ISDN, 1 mM) was applied during isometric measurement, 18.7+/-5.3% greater relaxation occurred than in control relaxation (P<0.05, n=5). When nicorandil (1 mM) was applied, the following relaxation was 18.6+/-5.7% greater than control (P<0.05, n=8). The simultaneous application of glibenclamide (1 mM) completely inhibited such additional relaxation by nicorandil. Application of nifedipine (10 microM) caused a 12.9+/-2.5% greater relaxation than control (P=0.066, n=4). The first metabolite of sarpogrelate (BP984, 10 microM) caused much greater relaxation than control (23.7+/-7.9%, P<0.05, n=6). Amlodipine (10 microM), phentolamine (10 microM), and sarpogrelate (10 microM) had no influence on the relaxation of the strip., Conclusions: ISDN, nicorandil and BP984 significantly increase relaxation of the muscle strips after stretching compared to the control. These vasodilators may reduce acute recoil of the smooth muscle after PTCA.

We found that infection of a rodent malaria, Plasmodium berghei, occurred when the sporozoites were injected into the skin, the muscle, the peritoneal cavity and the tail end. Mice, which were injected with sporozoites in the tail end and had the site cut 5 min later, did not develop malaria. We also found that mice developed malaria when malaria infective mosquitoes, Anopheles stephensi, were forced not to take blood but only to probe into the skin. Moreover, the mice probed by the infective mosquitoes were protected from malaria infection if the site was treated with Kyu (heat treatment) after the mosquitoes had probed. These findings indicate that malaria infection occurs not only by blood feeding of the infective mosquito but also by probing of the mosquito. Sporozoites injected into the skin remain at the injected site for at least 5 min, then migrate to the blood vessels and invade into the blood stream. At present, the mechanism is not clear, although we propose here the existence of the skin stage of malaria parasites before the liver stage and the blood stage.