Detection of drug-resistant malaria in resource-limited settings: efficient and high-throughput surveillance of artemisinin and partner drug resistance.

OBJECTIVES: Artemisinin-resistant Plasmodium falciparum malaria is currently spreading globally, including in Africa. Artemisinin resistance also leads to resistance to partner drugs used in artemisinin-based combination therapies. Sequencing of kelch13, which is associated with artemisinin resistance, culture-based partner drug susceptibility tests, and ELISA-based growth measurement are conventionally used to monitor resistance; however, their application is challenging in resource-limited settings. METHODS: An experimental package for field studies with minimum human/material requirements was developed. RESULTS: First, qPCR-based SNP assay was applied in artemisinin resistance screening, which can detect mutations within 1 h and facilitate sample selection for subsequent processes. It had 100% sensitivity and specificity compared with DNA sequencing in the detection of the two common artemisinin resistance mutations in Uganda, C469Y and A675V. Moreover, in the partner drug susceptibility test, the cultured samples were dry-preserved on a 96-well filter paper plate and shipped to the central laboratory. Parasite growth was measured by ELISA using redissolved samples. It well reproduced the results of direct ELISA, reducing significant workload in the field (Pearson correlation coefficient: 0.984; 95% CI: 0.975-0.990). CONCLUSIONS: Large-scale and sustainable monitoring is required urgently to track rapidly spreading drug-resistant malaria. In malaria-endemic areas, where research resources are often limited, simplicity and feasibility of the procedure is especially important. Our approach combines a qPCR-based rapid test, which is also applicable to point-of-care diagnosis of artemisinin resistance and centralized analysis of ex vivo culture. The approach could improve efficiency of field experiments and accelerate global drug resistance surveillance.

[Surgically Resected Cases of Mediastinal Ganglioneuroma Detected in Adults].

A ganglioneuroma is a rare, benign, neurogenic tumor originating from the sympathetic ganglion. Mediastinal ganglioneuroma are mostly detected in children, typically around 10 years of age, and are rarely identified in adults. Herein, we report two surgically resected cases of mediastinal ganglioneuroma in adults. In Case 1, a 53-year-old man, without any symptom, underwent a computed tomography, revealing a 3.2 cm well-defined paravertebral superior mediastinal tumor with long craniocaudal axis. In case 2, a 29-year-old woman presented with newly-developed ptosis and a history of left-sided facial hypohidrosis since the age of 10. Chest computed tomography (CT) revealed a 7.8 cm well-defined paravertebral superior mediastinal tumor with long craniocaudal axis. Both patients were initially suspected to have neurogenic tumors, particularly schwannomas. They underwent mediastinal tumor resections, requiring sympathetic nerve trunk dissection. Pathological examination confirmed the diagnosis of ganglioneuromas in both cases. Mediastinal ganglioneuroma must be differentiated from schwannoma, the most common neurogenic tumor in adults. Unlike schwannoma, ganglioneuroma cannot be enucleated, therefore attention should be focused on complications associated with sympathetic nerve trunk dissection, such as Horner's syndrome, hyperhidrosis, and arrhythmia. Identifying this rare entity and its characteristic imaging aids in preoperative differentiation, strategizing surgical approaches, and predicting complications.

Emergence of artemisinin-resistant Plasmodium falciparum with kelch13 C580Y mutations on the island of New Guinea.

The rapid and aggressive spread of artemisinin-resistant Plasmodium falciparum carrying the C580Y mutation in the kelch13 gene is a growing threat to malaria elimination in Southeast Asia, but there is no evidence of their spread to other regions. We conducted cross-sectional surveys in 2016 and 2017 at two clinics in Wewak, Papua New Guinea (PNG) where we identified three infections caused by C580Y mutants among 239 genotyped clinical samples. One of these mutants exhibited the highest survival rate (6.8%) among all parasites surveyed in ring-stage survival assays (RSA) for artemisinin. Analyses of kelch13 flanking regions, and comparisons of deep sequencing data from 389 clinical samples from PNG, Indonesian Papua and Western Cambodia, suggested an independent origin of the Wewak C580Y mutation, showing that the mutants possess several distinctive genetic features. Identity by descent (IBD) showed that multiple portions of the mutants' genomes share a common origin with parasites found in Indonesian Papua, comprising several mutations within genes previously associated with drug resistance, such as mdr1, ferredoxin, atg18 and pnp. These findings suggest that a P. falciparum lineage circulating on the island of New Guinea has gradually acquired a complex ensemble of variants, including kelch13 C580Y, which have affected the parasites' drug sensitivity. This worrying development reinforces the need for increased surveillance of the evolving parasite populations on the island, to contain the spread of resistance.

Increased afternoon step count increases heart rate variability in patients with cardiovascular risk factors.

AIMS AND OBJECTIVES: The present study investigated whether morning or afternoon activity is more effective at increasing the high-frequency (HF) index, a parasympathetic index, in patients with cardiovascular risk factors. BACKGROUND: A decreased HF index, a heart rate variability (HRV) parameter, is a well-established marker of poor cardiovascular prognosis. Because blood pressure and sympathetic tone are higher in the morning, physical activity and exercise in the afternoon has been recommended for patients with cardiovascular diseases. However, there have been no reports concerning the superior effects of afternoon exercise on parasympathetic activity and sleep. DESIGN: This observational study was a post hoc comparison. METHODS: Patients' physical activity was measured for 1 month to determine their habits. Patients' HF index was measured by 24-h Holter electrocardiography. The study enrolled 56 patients. Each patient's morning step count (before lunch) and afternoon step count (between lunch and dinner) were compared. We adhered to the STROBE guidelines in the present study. RESULTS: Thirty-one patients took more steps in the morning, and 25 patients took more steps in the afternoon. The present study showed that those who took more steps in the afternoon had a significantly higher HF index during the first hour after sleep onset and during sleep than those who took more steps in the morning (p = .003, .047). CONCLUSIONS: The present study showed that those who took more steps in the afternoon had a significantly higher HF index during the first hour after sleep onset and a higher HF index during sleep than those who took more steps in the morning. RELEVANCE TO CLINICAL PRACTICE: Exercise in the afternoon may improve the prognosis in patients with cardiovascular disease by not only preventing excessive blood pressure, afterload, and sympathetic tone but also positively influencing the parasympathetic system and sleep.

Postulated Process of Axoneme Organization in the Male Gametogenesis of Malaria Parasite Plasmodium berghei.

The ultrastructural features of axoneme organization within the cytoplasm and exflagellation were investigated in detail in microgametes of a malaria parasite, Plasmodium berghei, by electron and fluorescence microscopy. The kinetosomes (basal bodies) of the microgamete were characterized by an electron dense mass in which singlet microtubules (MTs) were embedded. Around the kinetosomes, several singlet and doublet MTs were recognized in transverse sections. Incomplete doublets with growing B-tubule were also observed. As precursors of the axoneme, arrays of over three doublets showed a tendency to encircle the central pair MTs. Some of the doublet MTs were already equipped with inner and outer dynein arms. In the microgamete, which lacks an intraflagellar transport (IFT) system, self-assembly of microtubular and associated components appeared to proceed stepwise from singlet MTs through arrays of one to nine doublet MTs, surrounding the central pair, to form the complete axoneme in a quite short time. At exflagellation, some extra doublets were occasionally included between the axoneme and the flagellar membrane. At high magnification, the outer dynein arm of the Plasmodium microgamete had a pistol-like shape representing a three-headed dynein molecule like that of other Alveolata.

Recovery and stable persistence of chloroquine sensitivity in Plasmodium falciparum parasites after its discontinued use in Northern Uganda.

BACKGROUND: Usage of chloroquine was discontinued from the treatment of Plasmodium falciparum infection in almost all endemic regions because of global spread of resistant parasites. Since the first report in Malawi, numerous epidemiological studies have demonstrated that the discontinuance led to re-emergence of chloroquine-susceptible P. falciparum, suggesting a possible role in future malaria control. However, most studies were cross-sectional, with few studies looking at the persistence of chloroquine recovery in long term. This study fills the gap by providing, for a period of at least 6 years, proof of persistent re-emergence/stable recovery of susceptible parasite populations using both molecular and phenotypic methods. METHODS: Ex vivo drug-susceptibility assays to chloroquine (n = 319) and lumefantrine (n = 335) were performed from 2013 to 2018 in Gulu, Northern Uganda, where chloroquine had been removed from the official malaria treatment regimen since 2006. Genotyping of pfcrt and pfmdr1 was also performed. RESULTS: Chloroquine resistance (≥ 100 nM) was observed in only 3 (1.3%) samples. Average IC50 values for chloroquine were persistently low throughout the study period (17.4-24.9 nM). Parasites harbouring pfcrt K76 alleles showed significantly lower IC50s to chloroquine than the parasites harbouring K76T alleles (21.4 nM vs. 43.1 nM, p-value = 3.9 × 10-8). Prevalence of K76 alleles gradually increased from 71% in 2013 to 100% in 2018. CONCLUSION: This study found evidence of stable persistence of chloroquine susceptibility with the fixation of pfcrt K76 in Northern Uganda after discontinuation of chloroquine in the region. Accumulation of similar evidence in other endemic areas in Uganda could open channels for possible future re-use of chloroquine as an option for malaria treatment or prevention.

T-wave changes of cardiac memory caused by frequent premature ventricular contractions originating from the right ventricular outflow tract.

INTRODUCTION: Cardiac memory is recognized as altered T-waves when the sinus rhythm resumes after an abnormal myocardial activation period that recovers slowly over several weeks. The T-wave changes after ablation of frequent premature ventricular contractions (PVCs) as cardiac memory was not known. OBJECTIVE: This study identified whether cardiac memory exists after successful ablation of PVCs from the right ventricular outflow tract (RVOT). METHODS: We investigated 45 patients who underwent successful ablation of PVCs from RVOT and 10 patients who underwent unsuccessful ablation. We analyzed the amplitude of the T-wave, QT intervals, and QRST time-integral values of a 12-lead electrocardiogram before ablation and 1 day, 3 days, and 1 month after ablation. RESULTS: In the successful ablation group, the amplitude of the T-wave and QRST time-integral values of lead II, III, aVR, aVL, and aVF significantly changed after ablation and gradually normalized within 1 month. In addition, if the number of pre-ablation PVCs was small, then the corresponding impact was also small. However, the greater the number of pre-ablation PVCs, the more prominent the changes. Significant changes were not observed in the unsuccessful ablation group. CONCLUSION: When ablation of PVCs from RVOT was successful, primary T-wave changes because of cardiac memory and the gradual normalization of the amplitude of the T-wave were observed. No significant T-wave changes were detected after unsuccessful ablation.

Artemisinin-Resistant Plasmodium falciparum with High Survival Rates, Uganda, 2014-2016.

Because ≈90% of malaria cases occur in Africa, emergence of artemisinin-resistant Plasmodium falciparum in Africa poses a serious public health threat. To assess emergence of artemisinin-resistant parasites in Uganda during 2014-2016, we used the recently developed ex vivo ring-stage survival assay, which estimates ring-stage-specific P. falciparum susceptibility to artemisinin. We conducted 4 cross-sectional surveys to assess artemisinin sensitivity in Gulu, Uganda. Among 194 isolates, survival rates (ratio of viable drug-exposed parasites to drug-nonexposed controls) were high (>10%) for 4 isolates. Similar rates have been closely associated with delayed parasite clearance after drug treatment and are considered to be a proxy for the artemisinin-resistant phenotype. Of these, the PfKelch13 mutation was observed in only 1 isolate, A675V. Population genetics analysis suggested that these possibly artemisinin-resistant isolates originated in Africa. Large-scale surveillance of possibly artemisinin-resistant parasites in Africa would provide useful information about treatment outcomes and help regional malaria control.

Lack of significant recovery of chloroquine sensitivity in Plasmodium falciparum parasites following discontinuance of chloroquine use in Papua New Guinea.

BACKGROUND: Chloroquine treatment for Plasmodium falciparum has been discontinued in almost all endemic regions due to the spread of resistant isolates. Reversal of chloroquine susceptibility after chloroquine discontinuation has been reported in dozens of endemic regions. However, this phenomenon has been mostly observed in Africa and is not well documented in other malaria endemic regions. To investigate this, an ex vivo study on susceptibility to chloroquine and lumefantrine was conducted during 2016-2018 in Wewak, Papua New Guinea where chloroquine had been removed from the official malaria treatment regimen in 2010. Genotyping of pfcrt and pfmdr1 was also performed. RESULTS: In total, 368 patients were enrolled in this study. Average IC50 values for chloroquine were 106.6, 80.5, and 87.6 nM in 2016, 2017, and 2018, respectively. These values were not significantly changed from those obtained in 2002/2003 (108 nM). The majority of parasites harboured a pfcrt K76T the mutation responsible for chloroquine resistance. However, a significant upward trend was observed in the frequency of the K76 (wild) allele from 2.3% in 2016 to 11.7% in 2018 (P = 0.008; Cochran-Armitage trend test). CONCLUSIONS: Eight years of chloroquine withdrawal has not induced a significant recovery of susceptibility in Papua New Guinea. However, an increasing tendency of parasites harbouring chloroquine-susceptible K76 suggests a possibility of resurgence of chloroquine susceptibility in the future.

Plasmodium Rab5b is secreted to the cytoplasmic face of the tubovesicular network in infected red blood cells together with N-acylated adenylate kinase 2.

BACKGROUND: Rab5 GTPase regulates membrane trafficking between the plasma membrane and endosomes and harbours a conserved C-terminal isoprenyl modification that is necessary for membrane recruitment. Plasmodium falciparum encodes three Rab5 isotypes, and one of these, Rab5b (PfRab5b), lacks the C-terminal modification but possesses the N-terminal myristoylation motif. PfRab5b was reported to localize to the parasite periphery. However, the trafficking pathway regulated by PfRab5b is unknown. METHODS: A complementation analysis of Rab5 isotypes was performed in Plasmodium berghei. A constitutively active PfRab5b mutant was expressed under the regulation of a ligand-dependent destabilization domain (DD)-tag system in P. falciparum. The localization of PfRab5b was evaluated after removing the ligand followed by selective permeabilization of the membrane with different detergents. Furthermore, P. falciparum N-terminally myristoylated adenylate kinase 2 (PfAK2) was co-expressed with PfRab5b, and trafficking of PfAK2 to the parasitophorous vacuole membrane was examined by confocal microscopy. RESULTS: PfRab5b complemented the function of PbRab5b, however, the conventional C-terminally isoprenylated Rab5, PbRab5a or PbRab5c, did not. The constitutively active PfRab5b mutant localized to the cytosol of the parasite and the tubovesicular network (TVN), a region that extends from the parasitophorous vacuole membrane (PVM) in infected red blood cells (iRBCs). By removing the DD-ligand, parasite cytosolic PfRab5b signal disappeared and a punctate structure adjacent to the endoplasmic reticulum (ER) and parasite periphery accumulated. The peripheral PfRab5b was sensitive to extracellular proteolysis after treatment with streptolysin O, which selectively permeabilizes the red blood cell plasma membrane, indicating that PfRab5b localized on the iRBC cytoplasmic face of the TVN. Transport of PfAK2 to the PVM was abrogated by overexpression of PfRab5b, and PfAK2 accumulated in the punctate structure together with PfRab5b. CONCLUSION: N-myristoylated Plasmodium Rab5b plays a role that is distinct from that of conventional mammalian Rab5 isotypes. PfRab5b localizes to a compartment close to the ER, translocated to the lumen of the organelle, and co-localizes with PfAK2. PfRab5b and PfAK2 are then transported to the TVN, and PfRab5b localizes on the iRBC cytoplasmic face of TVN. These data demonstrate that PfRab5b is transported from the parasite cytosol to TVN together with N-myristoylated PfAK2 via an uncharacterized membrane-trafficking pathway.

Elevated Red Blood Cell Distribution Width Predicts Recurrence After Catheter Ablation for Atrial Fibrillation in Patients With Heart Failure　- Comparison With Non-Heart Failure Patients.

BACKGROUND: Elevated red blood cell distribution width (RDW) predicts poor prognosis in patients with cardiovascular diseases. However, little is known about the association between RDW and outcomes after catheter ablation of atrial fibrillation (AF). METHODS AND RESULTS: A total of 757 patients who underwent radiofrequency catheter ablation of AF were divided into heart failure (HF, n=79) and non-HF (n=678) groups; RDW was assessed as a predictor after catheter ablation in each. During a 22.3-month follow-up period, the baseline RDW in the HF group was greater in the recurrence group than in the non-recurrence group (14.5±2.0% vs. 13.5±0.9%, P=0.013). In contrast, no significant difference in RDW at baseline was found in the non-HF group between the recurrence and non-recurrence groups (13.3±0.8% vs. 13.2±0.8%, P=0.332, respectively). Multivariate analysis demonstrated that RDW (hazard ratio 1.20, 95% confidence interval 1.01-1.40, P=0.034) was an independent predictor of AF recurrence in the HF group. The cut-off values of RDW for the recurrence of AF and major adverse events in the HF group were 13.9% and 14.8%, respectively. CONCLUSIONS: High RDW is an independent predictor for the recurrence of AF and major adverse events in patients with HF after catheter ablation. RDW is a potential noninvasive marker in AF patients complicated with HF. (Circ J 2016; 80: 627-638).

Decrease in B-Type Natriuretic Peptide Levels and Successful Catheter Ablation for Atrial Fibrillation in Patients with Heart Failure.

BACKGROUND: Little is known about the association between B-type natriuretic peptide (BNP) levels and catheter ablation of atrial fibrillation (AF) in patients with heart failure. This study aimed to examine the impact of elimination of AF by catheter ablation on BNP levels in patients with left ventricular systolic dysfunction. METHODS: Fifty-four AF patients with left ventricular ejection fraction (LVEF) ≤ 50%, who underwent radiofrequency catheter ablation therapy of AF, were included. BNP sampling was performed at baseline, 3 days, and 1 month after ablation. RESULTS: After a follow-up period of 6 months, the BNP levels decreased significantly in the nonrecurrence group (n = 35; median 126.3 [interquartile 57.2-206.5] pg/mL, 63.5 [23.9-180.2] pg/mL, and 45.9 [21.9-160.3] pg/mL, P < 0.001, respectively), but not in the recurrence group (n = 19; 144.7 [87.1-217.3] pg/mL, 88.8 [12.9-213.2] pg/mL, and 118.5 [51.6-298.2] pg/mL, P = 0.368, respectively). The patients in the nonrecurrence group had a higher percentage relative reduction in BNP levels from baseline to 1 month after ablation than those in the recurrence group (56.5 [-9.0-77.4]% vs -2.4 [-47.1-60.9]%, P = 0.027). Additionally, a relative reduction in BNP levels significantly correlated with an increase in LVEF after ablation (r = 0.486, P < 0.001). CONCLUSIONS: Plasma BNP levels decreased significantly with successful catheter ablation of AF in patients with impaired LVEF. The decrease in BNP levels might be associated with early recovery of cardiac function and subsequent maintenance of sinus rhythm at follow-up.

An ECG Index of P-Wave Force Predicts the Recurrence of Atrial Fibrillation after Pulmonary Vein Isolation.

BACKGROUND: Although several prognostic factors of atrial fibrillation (AF) recurrence after pulmonary vein isolation (PVI) have been investigated, the accurate prediction of AF recurrence remains difficult. We propose an electrocardiogram (ECG) index, the P-wave force (PWF), which is the product of the amplitude of the negative terminal phase of the P wave in the V1 electrode and the filtered P-wave duration, obtained by a signal-averaged P-wave analysis. This study was conducted to evaluate the impact of the PWF on the recurrence of AF after PVI. METHODS: We retrospectively evaluated 79 paroxysmal AF patients (64 ± 9 years, 56 males) who underwent PVI by cryoballoon ablation. Standard 12-lead ECG and a P-wave signal-averaged electrocardiogram (SAECG) were recorded the day before and 1 month after the PVI procedure. RESULTS: During the mean follow-up of 10.2 months, AF recurred in 11 (14%) patients. The PWF 1 month after ablation was significantly higher in the recurrence group compared to that in the nonrecurrence group (8.8 ± 3.1 mVms vs 6.5 ± 2.9 mVms, P = 0.017). The patients with a PWF value ≥9.3 mVms had a significantly greater risk of recurrence after the ablation compared to the patients with a PWF value <9.3 mVms (log-rank test, P < 0.001). CONCLUSION: Higher PWF after cryoballoon ablation was associated with poor prognosis during follow-up. The PWF may be a useful and noninvasive marker to predict the recurrence of AF.

Body mass index is associated with prognosis in Japanese elderly patients with atrial fibrillation: an observational study from the outpatient clinic.

The relationship between body mass index (BMI) and the prognosis of elderly patients with atrial fibrillation (AF) is unknown. We aimed to examine the association of body weight with the clinical outcomes among Japanese elderly patients with a history of documented AF. This observational study of AF patients from an outpatients clinic in Nagoya University Hospital included 413 patients ≥70 years old (99 obese: BMI ≥25 kg/m(2); 256 normal weight: BMI 18.5-24.9 kg/m(2); and 58 underweight patients: BMI <18.5 kg/m(2)). The mean age was 77.5 ± 5.6 years. During a mean follow-up of 19.0 months, all-cause death occurred in 23 patients (obese 1 %, normal weight 5.1 %, and underweight 16 %). The major adverse events including all-cause death, stroke or transient ischemic attack, heart failure requiring admission, and acute coronary syndrome were observed in 53 patients (obese 5.1 %, normal weight 13 %, and underweight 26 %). After adjusting for confounding factors, the underweight group had a significantly greater risk for all-cause death [hazard ratio (HR) 2.91, 95 % confidence interval (CI) 1.12-7.60, p = 0.029], and major adverse events (HR 2.45, 95 % CI 1.25-4.78, p = 0.009) than the normal weight group. In contrast, the obese group had a better prognosis in major adverse events compared with the normal weight group (HR 0.34, 95 % CI 0.13-0.89, p = 0.029). In conclusion, lower BMI was independently associated with poor outcomes among older AF patients. The association between obesity and better prognosis in elderly AF patients was also found.

Efficacy and safety of apixaban in the patients undergoing the ablation of atrial fibrillation.

INTRODUCTION: Apixaban, a factor Xa (FXa) inhibitor, is a new oral anticoagulant for stroke prevention in atrial fibrillation (AF). However, little is known about its efficacy and safety as a periprocedural anticoagulant therapy for patients who had undergone catheter ablation (CA) for AF. METHODS AND RESULTS: We evaluated 342 consecutive patients who underwent CA for AF between April 2013 and March 2014 and received apixaban (n = 105) and warfarin (n = 237) for uninterrupted periprocedural anticoagulation. We retrospectively investigated the occurrence of bleeding and thromboembolic complications during the procedural period and compared them between the apixaban group (AG) and warfarin group (WG). Thromboembolic complications occurred in one (0.4%) patient in the WG. Major and minor bleeding complications occurred in one (1%) and four (4%) patients in the AG, and three (1%) and 12 (5%) patients in the WG. No significant difference in complications was observed between the AG and WG. Of importance, adverse event rates did not differ between the two groups after adjusting by a propensity score analysis. In preoperative tests of blood coagulation, there were significant differences in the prothrombin time, activated partial thromboplastin time, FXa activity, and prothrombin fragment 1 + 2 (F1+2) levels between the AG and WG. CONCLUSION: The use of apixaban during the periprocedural period of AF ablation seemed as efficacious and safe as warfarin.

Effects of Defecation Strain at Various Bed Reclining Angles on Intrarectal Pressure and Cardiovascular Responses.

BACKGROUND: There is no clear information about the optimal bed reclining angle for promoting efficient and safe defecation in bedfast patients. OBJECTIVE: The aim of this study was to examine the optimal bed reclining angle for facilitating increases in intrarectal pressure without causing marked cardiovascular changes in order to develop an efficient and safe defecation position for bedfast patients. METHODS: Twelve healthy men participated in this study. The subjects were required to strain for 15 seconds at the end stage of inspiration while their bed was reclined at 0° (supine), 15°, 30°, or 60°. During straining, the subjects were asked to maintain (a) an intrarectal pressure of 20 mm Hg or (b) the maximal intrarectal pressure. Intrarectal pressure, blood pressure, heart rate, and abdominal muscle activity (electromyographic activity) were recorded continuously throughout the study period. RESULTS: During straining, intrarectal pressure increased with the reclining angle, and a significant linear correlation was detected between the sine of the reclining angle of the bed and intrarectal pressure (η = .57, p < .01). When subjects were straining with the aim of maintaining maximal intrarectal pressure, the extent of the observed changes (delta) in blood pressure and heart rate did not differ significantly across the reclining angles. When subjects were straining with the aim of maintaining an intrarectal pressure of 20 mm Hg, the delta blood pressure decreased as the reclining angle increased 0°: M = 23.7, SD = 15.3 mm Hg, 95% CI [11.9, 35.4]; 15°: M = 25.9, SD = 10.8 mm Hg, 95% CI [17.6, 34.2]; 30°: M = 17.7, SD = 9.4 mm Hg, 95% CI [10.4, 24.9]; 60°: M = 15.5, SD = 9.5 mm Hg, 95% CI [8.1, 22.8]; 15° versus 30°: p < .05; 15° versus 60°: p < .05. The amount of muscle activity observed during straining decreased as the reclining angle increased. DISCUSSION: In bedfast patients, it is suggested that higher reclining angles may enable safer and more efficient defecation, because it decreases the amount of muscle activity required to increase the intrarectal pressure and reduces the potentially deleterious effects of straining on the cardiovascular system to develop an efficient and safe defecation position for bedfast patients.

IL-23 protection against Plasmodium berghei infection in mice is partially dependent on IL-17 from macrophages.

Although IL-12 is believed to contribute to protective immune responses, the role played by IL-23 (a member of the IL-12 family) in malaria is elusive. Here, we show that IL-23 is produced during infection with Plasmodium berghei NK65. Mice deficient in IL-23 (p19KO) had higher parasitemia and died earlier than wild-type (WT) controls. Interestingly, p19KO mice had lower numbers of IL-17-producing splenic cells than their WT counterparts. Furthermore, mice deficient in IL-17 (17KO) suffered higher parasitemia than the WT controls, indicating that IL-23-mediated protection is dependent on induction of IL-17 during infection. We found that macrophages were responsible for IL-17 production in response to IL-23. We observed a striking reduction in splenic macrophages in the p19KO and 17KO mice, both of which became highly susceptible to infection. Thus, IL-17 appears to be crucial for maintenance of splenic macrophages. Adoptive transfer of macrophages into macrophage-depleted mice confirmed that macrophage-derived IL-17 is required for macrophage accumulation and parasite eradication in the recipient mice. We also found that IL-17 induces CCL2/7, which recruit macrophages. Our findings reveal a novel protective mechanism whereby IL-23, IL-17, and macrophages reduce the severity of infection with blood-stage malaria parasites.

Clinical outcome of implantable cardioverter defibrillators with recalled and non-recalled leads in Japanese patients. Increased failure rate of the Sprint Fidelis lead.

BACKGROUND: In recent years, there has been a series of recalls of popular implantable cardioverter defibrillators leads, and several reports have demonstrated an increasing rate of failure of such leads over time in Caucasian patients. However, little is known about the performance of these leads in Asian patients. The aim of this study was to investigate the rate of failure of the recalled leads and the characteristics as compared with non-recalled leads in Japanese patients. METHODS AND RESULTS: A retrospective chart review was conducted in 214 patients (75 Sprint Fidelis, 8 Riata, and 131 Sprint Quattro leads) who underwent implantation and follow-up at Nagoya University Hospital. During the follow-up period, 14 Sprint Fidelis leads (19%) and 1 Riata lead (13%) failed, but no abnormality was found in the Sprint Quattro, non-recalled leads. Five patients (4 Sprint Fidelis and 1 Riata, 33% of lead failure patients) received inappropriate shocks. The 3-, 4-, and 5-year lead survival rates in Sprint Fidelis leads were 95.1% (95% confidence interval [CI]: 89.6%-100%), 89.8% (95% CI: 82.1%-97.6%), and 88.0% (95% CI: 79.6%-96.4%), respectively. A previous device implantation before Sprint Fidelis lead was the only significant predictor for lead fracture (hazard ratio, 5.33; 95% CI: 1.55-18.4; P=0.008). CONCLUSIONS: The rate of Sprint Fidelis lead failure continues to increase over time in Japanese patients.

Clinical characteristics and predictors of super-response to cardiac resynchronization therapy: a combination of predictive factors.

BACKGROUND: Patients with greater improvement of cardiac function after cardiac resynchronization therapy (CRT) implantation are identified as "super-responders." However, it remains unclear which kind of preimplant assessments could accurately predict outcomes after CRT. Thus, we aimed to examine the essential predicting factors for super-response to CRT, and to construct an accurate predictable model. METHODS: We retrospectively analyzed the CRT patients who underwent implantation at Nagoya University Hospital. Super-responders are defined as those who show a relative reduction in left ventricular end-systolic volume ≥30% after 6 months of CRT. RESULTS: Eighty patients (mean age, 67.8 ± 10.2 years) were included. Twenty-two patients received upgrading procedure to CRT implantation. Six months after the implantation, 29 patients (36%) were super-responders. Multiple logistic regression analysis shows that consistent right ventricular pacing with a previous device (odds ratio [OR] 7.28, 95% confidence interval [CI] 1.52-34.9; P = 0.013), lack of prior history of ventricular arrhythmia (OR 5.32, 95% CI 1.52-18.6; P = 0.009), and smaller left atrial diameter (LAD) (OR 0.92, 95% CI 0.86-0.98; P = 0.014) are independent predictors for CRT super-responders. The use of a combination of these predictive factors could increase the certainty with which a greater response to CRT is predicted and the presence of such a combination could improve prognosis. CONCLUSION: Greater response to biventricular pacing occurs more frequently in patients with consistent right ventricular pacing, lack of prior history of ventricular arrhythmia, and smaller LAD. An association between patient background characteristics and a super-response to CRT was also identified.

Life activities improve heart rate variability in patients with mild hypertension and/or the initial stage of heart failure.

AIMS AND OBJECTIVES: To determine the effects on heart rate variability of home-based daily activity in patients with mild hypertension and/or stable angina pectoris and to clarify the relationship between daily activity and sympathovagal balance. BACKGROUND: Several prior studies have assessed the ability of exercise training to improve functional capacity and produce beneficial effects on mortality and physical capacity in patients with cardiovascular disease. DESIGN: A non-randomised six-month prospective longitudinal study. METHODS: This study consisted of 41 patients (59-83 years old) with mild hypertension and/or stable angina pectoris. The home-based daily activity and heart rate variability were measured at the start of the study (BASE) and six months after the start of the study (6MoA). At 6MoA, the active mass increased in 23 patients (the IC group), while it decreased in the remaining 18 patients (the DC group). RESULTS: There were significant increases in the high-frequency component in the IC group between the data at BASE and 6MoA. There were significant decreases in the low frequency to high-frequency ratio (low frequency/high-frequency) during sleep in the IC group between the data at BASE and 6MoA. The active mass was classified into life activities and walk activities in terms of intensity of activity. In a multivariate model, increased life activitiesrevealed a trend towards an association with increased high-frequency. CONCLUSIONS: In patients with mild hypertension and/or stable angina pectoris, an increase in active mass improved heart rate variability outcomes with increased high-frequency and decreased low frequency/high-frequency during sleep. To increase life activitiesmight improve heart rate variability and prognosis in patients. RELEVANCE TO CLINICAL PRACTICE: This study demonstrated that the potential importance of low-intensity daily activities in patients with mild hypertension and/or stable angina pectoris.