Real-world safety and effectiveness of tenofovir alafenamide for 144 weeks in Japanese patients with chronic hepatitis B.

Tenofovir alafenamide (TAF), a prodrug of tenofovir, delivers high levels of active drug to hepatocytes and is given in a lower dose than tenofovir disoproxil fumarate (TDF). TAF reduces viral replication in patients with chronic hepatitis B (CHB) similar to TDF and has shown a lower risk of the renal and bone toxicities associated with TDF use. This post-marketing surveillance study examined the safety and effectiveness of TAF in treatment-naïve and -experienced CHB patients who received TAF for 144 weeks at real-world clinical sites in Japan. Safety assessments included the incidence of adverse drug reactions (ADRs), renal and bone events, and changes in selected laboratory parameters. Effectiveness was based on the proportion of patients with HBV DNA levels below the lower limit of quantitation or <29 IU/mL. This analysis included 580 patients; 18.4% of whom were treatment-naïve. The cumulative incidence of ADRs was 0.21 per 100 person-months, and the incidence of serious ADRs was 0.01 (95% CI, 0.00-0.04) per 100 person-months. There were no ADRs of declines in estimated glomerular filtration rates, renal failure or proximal tubulopathy. The most common ADR was hypophosphataemia in seven (1.2%) patients. Two (0.4%) patients each had decreased blood phosphorus, bone mineral density decreased, dizziness and alopecia. Overall, the proportion of virologically suppressed patients increased from 68.8% at baseline to 97.5% at Week 144. These results confirm the real-world safety and effectiveness of TAF in Japanese patients with CHB and are consistent with the findings of other evaluations of the safety and efficacy of TAF in CHB.

Nucleic acid-triggered tumoral immunity propagates pH-selective therapeutic antibodies through tumor-driven epitope spreading.

Important roles of humoral tumor immunity are often pointed out; however, precise profiles of dominant antigens and developmental mechanisms remain elusive. We systematically investigated the humoral antigens of dominant intratumor immunoglobulin clones found in human cancers. We found that approximately half of the corresponding antigens were restricted to strongly and densely negatively charged polymers, resulting in simultaneous reactivities of the antibodies to both densely sulfated glycosaminoglycans (dsGAGs) and nucleic acids (NAs). These anti-dsGAG/NA antibodies matured and expanded via intratumoral immunological driving force of innate immunity via NAs. These human cancer-derived antibodies exhibited acidic pH-selective affinity across both antigens and showed specific reactivity to diverse spectrums of human tumor cells. The antibody-drug conjugate exerted therapeutic effects against multiple cancers in vivo by targeting cell surface dsGAG antigens. This study reveals that intratumoral immunological reactions propagate tumor-oriented immunoglobulin clones and demonstrates a new therapeutic modality for the universal treatment of human malignancies.

Danazol increases the oral bioavailability of midazolam by inactivation of hepatic and intestinal CYP3A in rats.

Danazol (DNZ) is a synthetic androgen derivative used for the treatment of intractable hematological disorders. In this study, we investigated the effects of DNZ on CYP3A activity in hepatic and small intestinal microsomes and the pharmacokinetics of midazolam (MDZ), a typical substrate for CYP3A, in rats.MDZ 4-hydroxylation activities in hepatic and small intestinal microsomes significantly decreased 24 h after DNZ (100 mg/kg, i.p.) treatment. Time-dependent inactivation of MDZ 4-hydroxylation activities was noted when microsomes were pre-incubated with DNZ in the presence of a NADPH-generating system.The Western blot analysis indicated that the decrease observed in enzyme activity was not due to changes in the protein expression of CYP3A.In contrast to the intravenous administration, serum MDZ concentrations in DNZ-treated rats were markedly higher than those in control rats when administered orally. DNZ treatment increased MDZ oral bioavailability by approximately 2.5-folds.We herein demonstrated that DNZ increased the bioavailability of orally administered MDZ through irreversible inactivation of hepatic and intestinal CYP3A in rats.

Surgeons' involvement in COVID-19 treatment: a practice by a regional core hospital in Japan to avoid physician burnout.

BACKGROUND: To prevent task accumulation on certain divisions, our institution developed a unique system of allocating inpatient treatment of COVID-19 patients to doctors who were not specialized in respiratory infections. The objective of this study was to investigate whether surgeons can be involved in the COVID-19 inpatient treatment without negatively affecting patient outcome, and how such involvement can affect the wellbeing of surgeons. METHODS: There were 300 patients diagnosed with COVID-19 and hospitalized from January to June 2021, and 160 of them were treated by the redeployed doctors. They were divided into 3 groups based on the affiliation of the treating doctor. Patient characteristics and outcomes were compared between the groups. In addition, the impact of COVID-19 duty on participating surgeons was investigated from multiple perspectives, and a postduty survey was conducted. RESULTS: There were 43 patients assigned to the Department of Surgery. There were no differences in the backgrounds and outcomes of patients compared with other groups. The surgeon's overtime hours were significantly longer during the duty period, despite no change in the number of operations and the complication rate. The questionnaire revealed that there was a certain amount of mental and physical burden from the COVID-19 duty. CONCLUSION: Surgeons can take part in inpatient COVID-19 treatment without affecting patient outcome. However, as such duty could negatively affect the surgeons' physical and mental wellbeing, further effort is needed to maintain the balance of fulfilling individual and institutional needs.

Halcyon: an accurate basecaller exploiting an encoder-decoder model with monotonic attention.

MOTIVATION: In recent years, nanopore sequencing technology has enabled inexpensive long-read sequencing, which promises reads longer than a few thousand bases. Such long-read sequences contribute to the precise detection of structural variations and accurate haplotype phasing. However, deciphering precise DNA sequences from noisy and complicated nanopore raw signals remains a crucial demand for downstream analyses based on higher-quality nanopore sequencing, although various basecallers have been introduced to date. RESULTS: To address this need, we developed a novel basecaller, Halcyon, that incorporates neural-network techniques frequently used in the field of machine translation. Our model employs monotonic-attention mechanisms to learn semantic correspondences between nucleotides and signal levels without any pre-segmentation against input signals. We evaluated performance with a human whole-genome sequencing dataset and demonstrated that Halcyon outperformed existing third-party basecallers and achieved competitive performance against the latest Oxford Nanopore Technologies' basecallers. AVAILABILITYAND IMPLEMENTATION: The source code (halcyon) can be found at https://github.com/relastle/halcyon.

Capturing the differences between humoral immunity in the normal and tumor environments from repertoire-seq of B-cell receptors using supervised machine learning.

BACKGROUND: The recent success of immunotherapy in treating tumors has attracted increasing interest in research related to the adaptive immune system in the tumor microenvironment. Recent advances in next-generation sequencing technology enabled the sequencing of whole T-cell receptors (TCRs) and B-cell receptors (BCRs)/immunoglobulins (Igs) in the tumor microenvironment. Since BCRs/Igs in tumor tissues have high affinities for tumor-specific antigens, the patterns of their amino acid sequences and other sequence-independent features such as the number of somatic hypermutations (SHMs) may differ between the normal and tumor microenvironments. However, given the high diversity of BCRs/Igs and the rarity of recurrent sequences among individuals, it is far more difficult to capture such differences in BCR/Ig sequences than in TCR sequences. The aim of this study was to explore the possibility of discriminating BCRs/Igs in tumor and in normal tissues, by capturing these differences using supervised machine learning methods applied to RNA sequences of BCRs/Igs. RESULTS: RNA sequences of BCRs/Igs were obtained from matched normal and tumor specimens from 90 gastric cancer patients. BCR/Ig-features obtained in Rep-Seq were used to classify individual BCR/Ig sequences into normal or tumor classes. Different machine learning models using various features were constructed as well as gradient boosting machine (GBM) classifier combining these models. The results demonstrated that BCR/Ig sequences between normal and tumor microenvironments exhibit their differences. Next, by using a GBM trained to classify individual BCR/Ig sequences, we tried to classify sets of BCR/Ig sequences into normal or tumor classes. As a result, an area under the curve (AUC) value of 0.826 was achieved, suggesting that BCR/Ig repertoires have distinct sequence-level features in normal and tumor tissues. CONCLUSIONS: To the best of our knowledge, this is the first study to show that BCR/Ig sequences derived from tumor and normal tissues have globally distinct patterns, and that these tissues can be effectively differentiated using BCR/Ig repertoires.

Spinal epidural abscess caused by Pasteurella multocida mimicking aortic dissection: a case report.

BACKGROUND: Pasteurella multocida (P. multocida) forms part of the normal flora of many animals. Although it is a common causative agent of skin and soft tissue infection after an animal bite or scratch, in rare cases it can cause spinal infections in humans. CASE PRESENTATION: A 68-year-old immunocompetent woman presented with fever and sudden onset of severe back pain mimicking aortic dissection. No findings related to the pain were revealed on enhanced computed tomography or initial magnetic resonance imaging (MRI) of the spine. The patient was found to be bacteremic with P. multocida, although she had no apparent injury related to animal contact. Repeated evaluation by MRI with gadolinium-contrast established the diagnosis of spinal epidural abscess. The patient was cured by the rapid initiation of antimicrobial therapy without surgery. CONCLUSIONS: We describe the successful treatment of an individual with a spinal epidural abscess due to P. multocida without surgery. P. multocida infections may occur as sudden presentations. Obtaining the patient history of recent animal contact is essential. Repeated MRI evaluation may be required when spinal infections are suspected. To the best of our knowledge, this is the first report which describes a case of spinal epidural abscess due to this organism.

Conflicting alterations in hepatic expression of CYP3A and enzyme kinetics in rats exposed to 5-fluorouracil: relevance to pharmacokinetics of midazolam.

1. 5-Fluorouracil (5-FU) is a pyrimidine derivative widely used for the treatment of cancer. In this study, we investigated the effects of 5-FU on the protein expression of hepatic CYP3A and their enzyme activity for metabolizing midazolam (MDZ), a typical substrate of CYP3A, in rat liver microsomes. We also examined the pharmacokinetic behavior of intravenously administered MDZ in rats treated with 5-FU (120 mg/kg, ip). 2. 5-FU was shown to induce hepatic CYP3A2 protein 2 days after administration without changing the expression of CYP3A1/3A23. However, affinity of 5-FU-inducible CYP3A protein to MDZ for its 4- and 1'-hydroxylation was decreased. Furthermore, the susceptibility of MDZ hydroxylation activity to a CYP3A inhibitor differed between the control and 5-FU groups. 3. Pharmacokinetic analysis of the MDZ disposition demonstrated no significant differences in the total clearance (CLtot) and elimination rate constant (ke) between the control and 5-FU-treated rats. Lack of alteration in the metabolic clearance of MDZ may be attributable to the induction of CYP3A protein with reduced affinity for the substrate of CYP3A enzymes. 4. Our findings provide novel information regarding the manifestation of inductive and interfering actions of 5-FU toward hepatic CYP3A to help in assessing the pharmacokinetics of CYP3A substrate drugs.

Pharmacokinetic interference of doxorubicin with tolbutamide due to reduced metabolic clearance with increased serum unbound fraction in rats.

The study examined the effect of doxorubicin (DOX) on the hepatic expression of CYP2C and its activity for metabolizing tolbutamide (TB), a specific CYP2C substrate, in rats and whether the pharmacokinetics of tolbutamide were altered by doxorubicin exposure. The expression level of hepatic CYP2C11 was depressed 1 day after doxorubicin administration (day 1), and this effect on CYP2C11 was augmented on day 4. However, the expression level of hepatic CYP2C6 remained unchanged. The activity of tolbutamide 4-hydroxylation in hepatic microsomes was decreased with time following doxorubicin administration. Regarding the enzyme kinetic parameters for tolbutamide 4-hydroxylation on day 4, the maximum velocity (Vmax ) was significantly lower in the DOX group than that in the control group, while the Michaelis constant (Km ) was unaffected. On pharmacokinetic examination, the total clearance (CLtot ) of tolbutamide on day 4 was increased, despite the decreased metabolic capacity. On the other hand, the serum unbound fraction (fu ) of tolbutamide was elevated with a reduced serum albumin concentration in the DOX group. Contrary to CLtot , CLtot /fu , a parameter approximated to the hepatic intrinsic clearance of unbound tolbutamide, was estimated to be significantly reduced in the DOX group. These findings indicate that the metabolic capacity of CYP2C11 in the liver is depressed time-dependently by down-regulation after doxorubicin exposure in rats, and that the decreased enzyme activity of TB 4-hydroxylation in hepatic microsomes reflects the pharmacokinetic change of unbound tolbutamide, not total tolbutamide, in serum.

Altered tolbutamide pharmacokinetics by a decrease in hepatic expression of CYP2C6/11 in rats pretreated with 5-fluorouracil.

1. We investigated the change in the pharmacokinetic profile of tolbutamide (TB), a substrate for CYP2C6/11, 4 days after single administration of 5-fluorouracil (5-FU), and the hepatic gene expression and activity of CYP2C6/11 were also examined in 5-FU-pretreated rats. 2. Regarding the pharmacokinetic parameters of the 5-FU group, the area under the curve (AUC) was significantly increased, and correspondingly, the elimination rate constant at the terminal phase (ke) was significantly decreased without significant change in the volume of distribution at the steady state (Vdss). 3. The metabolic production of 4-hydroxylated TB in hepatic microsomes was significantly reduced by the administration of 5-FU. 4. The expression level of mRNAs for hepatic CYP2C6 and CYP2C11 was significantly lower than in the control group when the rats were pretreated with 5-FU. 5. These results demonstrated that the pharmacokinetic profile of TB was altered by the treatment with 5-FU through a metabolic process, which may be responsible for the decreased CYP2C6/11 expression at mRNA levels.

Prevention of Doxorubicin-Induced Renal Toxicity by Theanine in Rats.

Doxorubicin (DOX) is a highly potent anti-neoplastic agent widely used in clinical practice, but its dosage and duration of administration are strictly limited due to dose-related organ damage. In the present study, we examined whether theanine, an amino acid derivative found in green tea leaves, can protect against DOX-induced acute nephrotoxicity in rats. Decreases in the creatinine clearance by DOX administration were attenuated by concurrent treatment with theanine, which was consistent with the change in histological renal images assessed by microscopic examination. Theanine had no effect on the distribution of DOX to the kidney. The production of lipid peroxide in the kidney after DOX administration was suppressed by concurrent treatment with theanine. Reduced glutathione content, but not superoxide dismutase activity, was decreased following DOX administration, whereas this change was suppressed when theanine was given in combination with DOX. These results suggest that theanine prevents DOX-induced acute nephrotoxicity through its antioxidant properties.

Pharmacokinetics and metabolic elimination of tolbutamide in female rats: Comparison with male rats.

As there are to be known gender differences in the expression profiles of rat hepatic CYP2C, we examined the pharmacokinetic behavior of tolbutamide (TB), a typical probe for CYP2C, and hepatic enzyme activities for metabolizing TB in female rats to compare with male rats. On the pharmacokinetic analysis of TB after intravenous administration to female rats, the elimination rate constant at the terminal phase (ke ), total clearance (CLtot ) and the apparent volume of distribution at steady-state (Vdss ) were significantly lower than in male rats. The binding rates of TB to serum protein were similar in male and female rats, indicating that the change in unbound TB concentration in serum is not associated with the difference in the pharmacokinetic disposition of TB. On metabolic examination using hepatic microsomes, the maximum reaction velocity (Vmax ) of the metabolic conversion from TB to 4-hydroxytolbutamide (4-OH-TB) in female rats was lower than that in male rats, although there was no significant difference in the Michaelis constant (Km ) between genders. Consistent with this, the Vmax -to-Km ratio (Vmax /Km ) was significantly lower in female rats than in male rats. Therefore, the low in vitro CYP2C-dependent activity for hepatic TB removal in female rats provided a clear explanation for the lower in vivo elimination clearance of TB. Our findings strongly suggest that there is a gender difference in the metabolic capacity to eliminate drugs that serve as substrates of hepatic CYP2C enzymes in rats.

Circulating intermediate CD14++CD16+monocytes are increased in patients with atrial fibrillation and reflect the functional remodelling of the left atrium.

AIMS: A recent large clinical study demonstrated the association between intermediate CD14++CD16+monocytes and cardiovascular events. However, whether that monocyte subset contributes to the pathogenesis of atrial fibrillation (AF) has not been clarified. We compared the circulating monocyte subsets in AF patients and healthy people, and investigated the possible role of intermediate CD14++CD16+monocytes in the pathophysiology of AF. METHODS AND RESULTS: This case-control study included 44 consecutive AF patients without systemic diseases referred for catheter ablation at our hospital, and 40 healthy controls. Patients with systemic diseases, including structural heart disease, hepatic or renal dysfunction, collagen disease, malignancy, and inflammation were excluded. Monocyte subset analyses were performed (three distinct human monocyte subsets: classical CD14++CD16-, intermediate CD14++CD16+, and non-classical CD14+CD16++monocytes). We compared the monocyte subsets and evaluated the correlation with other clinical findings. A total of 60 participants (30 AF patients and 30 controls as an age-matched group) were included after excluding 14 AF patients due to inflammation. Atrial fibrillation patients had a higher proportion of circulating intermediate CD14++CD16+monocytes than the controls (17.0 ± 9.6 vs. 7.5 ± 4.1%, P < 0.001). A multivariable logistic regression analysis demonstrated that only the proportion of intermediate CD14++CD16+monocytes (odds ratio: 1.316; 95% confidence interval: 1.095-1.582, P = 0.003) was independently associated with the presence of AF. Intermediate CD14++CD16+monocytes were negatively correlated with the left atrial appendage flow during sinus rhythm (r= -0.679, P = 0.003) and positively with the brain natriuretic peptide (r = 0.439, P = 0.015). CONCLUSION: Intermediate CD14++CD16+monocytes might be closely related to the pathogenesis of AF and reflect functional remodelling of the left atrium.

Predictors and Clinical Outcomes of Transient Responders to Cardiac Resynchronization Therapy.

BACKGROUND: Left ventricular end-systolic volume (LVESV) changes at 6 months and clinical status are useful for assessing responses to cardiac resynchronization therapy (CRT). Regression of the LVESV following CRT has not been described beyond 6 months. This study aimed to assess the proportion, predictors, and clinical outcomes of responders whose LVESVs had regressed. METHODS: We retrospectively analyzed 104 consecutive CRT patients. A responder was defined as a patient with a relative reduction in the LVESV ≥15% at 6 months after CRT. Fifty-six responders participated in this study. A transient responder was defined as a responder without a relative reduction in the LVESV ≥15% at 2 years after CRT or who died of cardiac events during the 24-month follow-up period. RESULTS: Of the 56 responders, 16 (29%) were transient responders. Multivariable logistic regression analysis showed that chronic atrial fibrillation (odds ratio [OR] = 19.2, 95% confidence interval [CI] [1.93, 190], P = 0.012) and amiodarone usage (OR = 60.9, 95% CI [4.18, 886], P = 0.003) were independent predictors of transient responses. Hospitalizations for heart failure were significantly higher among the transient responders than among the lasting responders during a mean follow-up period of 7.6 years (log-rank P < 0.001), and all-cause mortality tended to be higher among the transient responders (log-rank P = 0.093). CONCLUSIONS: One-third of the responders were transient responders at 2 years after CRT, and their long-term prognoses were poor. Careful attention should be paid to maintain the reduction in LVESV especially in patients with chronic AF.

Reversed Rivero-Carvallo's sign confirmed by blood flow analysis using cardiac magnetic resonance imaging in a patient with straight back syndrome.

An asymptomatic 45-year-old man was referred to our hospital for detailed evaluation of a systolic ejection murmur. The intensity of the murmur increased on deep expiration and decreased on deep inspiration, showing so-called reversed Rivero-Carvallo's sign. Using cardiac magnetic resonance imaging, we demonstrated a characteristic respiratory-induced change in peak flow velocity in the right ventricular outflow tract, which was the basic mechanism of the reversed Rivero-Carvallo's sign in a case with straight back syndrome. Concomitant anatomical changes in the entire heart in relation to the thoracic cage were also clarified.

Protective effects of taurine on doxorubicin-induced acute hepatotoxicity through suppression of oxidative stress and apoptotic responses.

The organ toxicity of doxorubicin (DOX), an anthracycline antineoplastic agent, narrows the therapeutic window despite its clinical usefulness. In the present study, we determined whether taurine protected against DOX-induced hepatic injury, and explored the molecular mechanisms underlying the suppressive effects of taurine in terms of alterations in oxidative stress and apoptotic responses. DOX-induced body weight loss was completely suppressed by taurine treatment. Elevations in the serum activity levels of lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase by DOX were also dose-dependently attenuated by a concurrent treatment with taurine. Superoxide dismutase activity and reduced glutathione content in the liver were decreased following the administration of DOX, whereas these changes were suppressed when 10 mg/kg taurine was given in combination with DOX. Taurine attenuated the increased expression of mRNAs for Fas and Bax after DOX exposure. Furthermore, the formation of cleaved caspase-3 protein in the group given DOX with taurine was lower than that in the group treated with DOX alone. Our results suggest that taurine can protect against DOX-induced acute hepatic damage, the underlying mechanism of which is attributable to the suppression of oxidative stress and apoptotic responses.

Characteristics of Residual Atrial Posterior Wall and Roof-Dependent Atrial Tachycardias after Pulmonary Vein Isolation.

BACKGROUND: Roof-dependent atrial tachycardia (roof AT) sometimes occurs after pulmonary vein isolation (PVI) of atrial fibrillation (AF). This study aimed to investigate the relationship between the anatomy of the residual left atrial posterior wall and occurrence of roof AT. METHODS: A total of 265 patients with AF who underwent PVI were enrolled. After the PVI, induced or recurrent roof AT was confirmed by an entrainment maneuver or activation mapping using a three-dimensional (3D) mapping system. To identify the predictors of roof AT, the minimum distance between both PVI lines (d-PVI) was measured by a 3D mapping system and the anatomical parameters, including the left atrial (LA) diameter, left atrial volume index (LAVi), and shape of the left atrial roof, were analyzed by 3D computed tomography. RESULTS: Roof AT was documented in 11 (4.2%) of 265 patients. A multivariable analysis demonstrated that the d-PVI, Deep V shape of the LA roof, and LAVi were associated with roof AT occurrences (d-PVI: odds ratio: 0.72, confidence interval [CI]: 0.61-0.86, P < 0.001; Deep V shape: odds ratio: 0.19, CI: 0.04-0.82, P = 0.03; LAVi: odds ratio: 1.05, CI: 1.02-1.07, P = 0.001). A receiver-operating characteristic curve analysis yielded an optimal cut-off value of 15.5 mm and 55.7 mL/m2 for the d-PVI and LAVi, respectively. CONCLUSION: The shorter d-PVI at the LA roof, greater LAVi, and Deep V shape were associated with the occurrence of a roof AT.

The Relationship Between Cardiac Vulnerability and Restitution Properties of the Ventricular Activation Recovery Interval.

INTRODUCTION: The restitution of the action potential duration (APD) is an important contributor to ventricular fibrillation (VF) initiation by a single critically timed ectopic beat. We hypothesized that a steep slope of the activation recovery interval restitution curve was related to the upper limit of vulnerability (ULV). METHODS AND RESULTS: Fifty-four consecutive patients with implantable cardioverter defibrillators (ICDs) implanted between April 2012 and July 2013 were included. At the implantation, pacing from the right ventricular (RV) coil to an indifferent electrode inserted in the ICD pocket was performed, and the unipolar electrograms from the RV coil were simultaneously recorded. We assessed the standard restitution by introducing extra-stimuli, while measuring the activation recovery interval (ARI). Our protocol for the vulnerability test consisted of delivering three 15 J shocks on the T-peak and within ±20 milliseconds of it. If VF was not induced by that procedure, a ULV of ≤15 J was defined. The relationship between the ULV and maximum slope of the restitution curve was analyzed. A restitution curve could finally be obtained in a total of 40 patients. The background characteristics were similar between the two groups. The maximum slope of the restitution curve was steeper in the ULV > 15 J group than ULV ≤ 15 J group (1.55 ± 0.45 vs. 0.91 ± 0.64, P < 0.05). A maximum slope exceeding 1.0 was the optimal point for discriminating patients with a ULV > 15 J from a ULV ≤ 15 J (sensitivity 61.5% and specificity 96.3%). CONCLUSION: The maximum slope of the restitution curve was significantly related to the ULV. High defibrillation threshold patients could be detected by the ARI dynamics.

Crista Terminalis as the Anterior Pathway of Typical Atrial Flutter: Insights from Entrainment Map with 3D Intracardiac Ultrasound.

BACKGROUND: The precise location of truly active reentry circuits of typical atrial flutter (AFL) has not been well identified. The purpose of this study was to verify our hypothesis that the posterior block line is located along the posteromedial right atrium (PMRA) and the crista terminalis (CT) is the anterior pathway of AFL, with real-time intracardiac echo (ICE). METHODS: The entire right atrium (RA) three-dimensional activation and entrainment mapping were evaluated during AFL in 18 patients using CARTO sound. RESULTS: The CT was clearly visualized by ICE and the local electrograms along the CT were single potentials in all the patients. The CT was recognized as the truly active anterior pathway based on entrainment mapping in all patients. Double potentials were recorded along the PMRA. Entire RA entrainment mapping could be performed in 16 patients. The reentry circuits were separated into three passages. The first was around the tricuspid annulus (TA), the second the anterior superior vena cava (SVC; AFL waves passed between the anterior SVC and RA appendage), and the last the posterior SVC (between the posterior SVC and upper limit of the PMRA). All three of these passages were active in four, around the TA and anterior SVC in eight, around the TA and posterior SVC in three, and around only the anterior SVC in one patient. CONCLUSIONS: The CT functions as the anterior pathway of typical AFL, and the posterior block line was located along the PMRA. Dual or triple circuits were recognized in the majority of AFL patients.

Decreased elimination clearance of midazolam by doxorubicin through reductions in the metabolic activity of hepatic CYP3A in rats.

1. We examined the effects of doxorubicin (DOX) on the expression level and metabolic activity of CYP3A in the liver as well as on the pharmacokinetics of midazolam (MDZ), a probe for CYP3A, in rats. Changes in the hepatic status of DOX-treated rats were confirmed. 2. Serum levels of the biomarkers of hepatic impairment were elevated by the DOX treatment, which was consistent with the results obtained from a histopathological evaluation of the liver. 3. No significant difference was observed in the expression of proteins for hepatic CYP3A1 and CYP3A2 between the DOX and control groups. The metabolic production of 1'-hydroxylated and 4'-hydroxylated MDZ by hepatic microsomes was significantly lower in DOX-treated rats than in control rats. 4. The area under the curve (AUC) and the half-life (t1/2) of intravenously administered MDZ were significantly increased, and the total clearance (CLtot) and the elimination rate constant at the terminal phase (ke) were significantly decreased without significant changes in the volume of distribution at a steady state (Vdss). 5. These results indicated that a DOX-induced depression in the metabolic activity, but not expression level of CYP3A contributed to a decrease in the elimination clearance of MDZ, and also that reduced CYP3A function may be associated with the hepatotoxicity of DOX.