Characteristics of preventive intervention acceptance for international travel among clients aged 60 years and older from a Japanese multicenter pretravel consultation registry.

OBJECTIVES: Pretravel consultation (PTC) is important for older adults owing to health problems associated with overseas travel. Although older adults in Japan, their PTC characteristics are less known. This study aimed to investigate the epidemiology of clients aged ≥ 60 years based on data from the Japan Pre-travel Consultation Registry (J-PRECOR). METHODS: Clients aged ≥ 60 years who visited J-PRECOR cooperative hospitals from February 1, 2018, to May 31, 2022, were included. The primary endpoint was a comparison of prescriptions for vaccines for hepatitis A, tetanus toxoid, and malaria prophylaxis in travelers to high-risk malaria countries in yellow fever vaccination (YFV)-available facilities with and without YFV. RESULTS: In total, 1000 clients (median age: 67 years) were included. Although 523 clients were immunized with YFV, only 38.6% of the 961 unimmunized clients were vaccinated with the tetanus toxoid-containing vaccine. Malaria chemoprophylaxis was prescribed to 25.7% of clients traveling for ≤55 days. At YFV-capable institutes, 557 clients traveling to yellow fever risk countries took PTC, 474 of whom received YFV and 83 were unvaccinated. Lower age (odds rate 0.85 per 1 year; 95% CI 0.80-0.90) and lower hepatitis A vaccination rate (0.29; 95% CI 0.14-0.63) were significantly associated with YFV. CONCLUSIONS: Preventive interventions other than YFV should be offered to older adults.

An Accelerated Failure Time Cure Model with Shifted Gamma Frailty and Its Application to Epidemiological Research.

Survival analysis is a set of methods for statistical inference concerning the time until the occurrence of an event. One of the main objectives of survival analysis is to evaluate the effects of different covariates on event time. Although the proportional hazards model is widely used in survival analysis, it assumes that the ratio of the hazard functions is constant over time. This assumption is likely to be violated in practice, leading to erroneous inferences and inappropriate conclusions. The accelerated failure time model is an alternative to the proportional hazards model that does not require such a strong assumption. Moreover, it is sometimes plausible to consider the existence of cured patients or long-term survivors. The survival regression models in such contexts are referred to as cure models. In this study, we consider the accelerated failure time cure model with frailty for uncured patients. Frailty is a latent random variable representing patients' characteristics that cannot be described by observed covariates. This enables us to flexibly account for individual heterogeneities. Our proposed model assumes a shifted gamma distribution for frailty to represent uncured patients' heterogeneities. We construct an estimation algorithm for the proposed model, and evaluate its performance via numerical simulations. Furthermore, as an application of the proposed model, we use a real dataset, Specific Health Checkups, concerning the onset of hypertension. Results from a model comparison suggest that the proposed model is superior to existing alternatives.

Characteristics and potential quality indicators for evaluating pre-travel consultations in Japan hospitals: the Japan Pretravel consultation registry (J-PRECOR).

BACKGROUND: Awareness of pre-travel consultations (PTCs) and prevention methods for overseas travel-related diseases, and the understanding of PTCs among Japanese travelers and medical professionals remains low in Japan. A multicenter registry was established to examine PTCs in Japan. This study assessed the PTC implementation rate and examined the indicators of PTCs that can be used as criteria for evaluating quality. METHODS: Clients who presented for their PTCs at 17 facilities and were registered between February 1, 2018, and May 31, 2020, were included. Medical information was extracted retrospectively via a web-based system. Correlations between vaccination risk categories and advice/intervention proportions by the facility were evaluated using Spearman's ordered phase relations (α = 0.05). RESULTS: Of the 9700 eligible clients (median age, 32 years; 880 [9.1%] aged < 16 years and 549 [5.7%] aged ≥65 years), the most common travel duration was ≥181 days (35.8%); higher among younger clients. The most common reason for travel was business (40.5%); the US (1118 [11.5%]) and Asia (4008 [41.3%]) were the most common destinations and continents, respectively. The vaccine number (median three per person) increased after the PTCs except for the tetanus toxoid. Only 60.8% of the clients recommended for malaria prophylaxis received anti-malarial agents. The gross national income; the incidence of human rabies, typhoid fever, falciparum malaria; and dengue risk category were associated with the percentage of hepatitis-A vaccines; explaining rabies post-exposure prophylaxis, typhoid-fever vaccinations, malaria-prophylaxis prescriptions; and mosquito repellants, respectively. CONCLUSIONS: Although the characteristics of the travelers differed, the quality of the PTCs should be improved to address, for example, the lower rate of acceptance of malaria prophylaxis in Japan.

Pulmonary vein isolation alone vs. more extensive ablation with defragmentation and linear ablation of persistent atrial fibrillation: the EARNEST-PVI trial.

AIMS: Previous studies could not demonstrate any benefit of more intensive ablation in addition to pulmonary vein isolation (PVI) including complex fractionated atrial electrogram (CFAE) and linear ablation for recurrence in the initial catheter ablation of persistent atrial fibrillation (AF). This study aimed to establish the non-inferiority of PVI alone to PVI plus these additional ablation strategies. METHODS AND RESULTS: Patients with persistent AF who underwent an initial catheter ablation (n = 512, long-standing persistent AF; 128 cases) were randomly assigned in a 1:1 ratio to either PVI alone (PVI-alone group) or PVI plus CFAE and/or linear ablation (PVI-plus group). After excluding 15 cases who did not receive procedures, we analysed 249 and 248 patients, respectively. The primary endpoint was recurrence of AF, atrial flutter, and/or atrial tachycardia, and the non-inferior margin was set at a hazard ratio of 1.43. In the PVI-plus group, 85.1% of patients had linear ablation and 15.3% CFAE ablation. After 12 months, freedom from the primary endpoint occurred in 71.3% of patients in the PVI-alone group and in 78.3% in the PVI-plus group [hazard ratio = 1.56 (95% confidence interval: 1.10-2.24), non-inferior P = 0.3062]. The procedure-related complication rates were 2.0% in the PVI-alone group and 3.6% in the PVI-plus group (P = 0.199). CONCLUSION: This randomized trial did not establish the non-inferiority of PVI alone to PVI plus linear ablation or CFAE ablation in patients with persistent AF, but implied that the PVI plus strategy was promising to improve the clinical efficacy (NCT03514693).

Oesophagobronchial perforations after placement of an oesophageal self-expanding metallic stent.

An oesophageal fully covered self-expanding metallic stent (SEMS) was placed in a 54-year-old Japanese man to relieve dysphagia owing to a stage cT1bN3M1c lung adenocarcinoma. High expression of programmed cell death-ligand 1 was microscopically confirmed, and pembrolizumab was subsequently administered. Several days later, the patient was hospitalized with septic shock, and severe mediastinitis and pneumonia caused by oesophageal SEMS-induced oesophageal and bronchial perforations were observed. Thoracoscopic surgery was performed to drain the mediastinal abscess, and an additional oesophageal SEMS was placed to close the oesophageal perforation. The patient gradually recovered from the potentially fatal infection, and the SEMS was retrieved after confirming perforation closure. We re-initiated pembrolizumab administration, and the patient responded well. The present report reveals the potential risk and effectiveness of SEMS, especially when administered with immune checkpoint inhibitors.

A nationwide randomized, double-blind, placebo-controlled physicians' trial of loxoprofen for the treatment of fatigue, headache, and nausea after hangovers.

Hangovers are associated with negative economic consequences due to decreased job performance or frequent visits to physicians. Thus, a new strategy for the alleviation of hangover-related symptoms is needed to avoid this detriment to society. The purpose of this nationwide randomized, double-blind, placebo-controlled physicians' trial was to evaluate the efficacy of loxoprofen sodium for the alleviation of fatigue, headache, and nausea after hangover. A total of 229 participants were randomized to receive loxoprofen sodium (60 mg once orally) or placebo. The study was closed when the first 150 participants (n = 74 in the loxoprofen vs. n = 76 in the placebo groups) experienced hangovers. The primary endpoint was set as the difference in severity of general fatigue before and 3 h after taking the test drugs and was evaluated using a visual analogue scale. Secondary endpoints included difference in severity of headache, nausea, and incidence of adverse events. The study participants were 34 (interquartile range; 30-39) years old, 92.0% were men, and both groups were comparable for baseline characteristics. The alleviation of general fatigue did not differ statistically between the loxoprofen and placebo groups (24 [14-49] vs. 19 [9-35], p = 0.07). However, the alleviation of headache was statistically greater in the loxoprofen group (25 [10-50] vs. 10 [2-30], adjusted difference 14, 95% confidence interval 8-21, p < 0.001), whereas, there was no difference in nausea (7 [0-27] vs. 10 [0-24], p = 0.68). The incidence of adverse symptoms such as epigastric discomfort was also comparable between groups (2.7% vs. 3.9%, p = 0.25). Loxoprofen sodium was effective for relieving headaches after hangovers but did not alleviate general fatigue or nausea.

Increase in Carbohydrate Antigen 19-9 Levels without Tumor Progression after Polaprezinc Administration that Induced Deep Vein Thrombosis in a Colon Cancer Patient.

Carbohydrate antigen 19-9 (CA 19-9) is a well-known tumor marker of adenocarcinoma (reference range, 37 U/mL). It can also be used, together with computed tomography, to monitor responses and resistance to chemotherapy in cancer patients. False elevation of CA 19-9 levels is often seen in conditions such as biliary tract obstruction and cholangitis. However, whether medication might induce false elevation of CA 19-9 levels has not yet been reported. A 74-year-old man was treated with third-line CPT-11 (irinotecan) plus panitumumab for stage IV cancer of the ascending colon. The patient developed chemotherapy-induced dysgeusia and was treated with polaprezinc. After polaprezinc administration, his CA 19-9 levels gradually increased from 18.9 to 1,699.4 U/mL. He developed deep vein thrombosis (DVT), although it was not associated with progressive disease or metastasis. Upon discontinuation of polaprezinc, CA 19-9 levels gradually decreased. This case demonstrates that polaprezinc may not only induce false elevation of CA 19-9 levels but also cause development of DVT induced by increased CA 19-9 levels, both of which are very rare events.

Effect of Extensive Ablation on Recurrence in Patients with Persistent Atrial Fibrillation Treated with Pulmonary Vein Isolation (EARNEST-PVI) trial: Design and rationale.

BACKGROUND: Although extensive substrate modification in addition to pulmonary vein isolation (PVI) has been recommended in catheter ablation for persistent atrial fibrillation (AF), recent randomized controlled trials have not demonstrated efficacy of such additional ablations. METHODS AND STUDY DESIGN: The Osaka Cardiovascular Conference will conduct a multicenter, randomized, open-label trial aiming to examine whether PVI alone is non-inferior to PVI plus additional ablation such as linear ablation and/or complex fractionated atrial electrogram ablation in patients with persistent AF. The primary outcome is recurrence of AF documented by scheduled or symptom-driven electrocardiogram tests during a 1-year follow-up period after the index ablation. The key secondary endpoints include all-cause death, occurrence of symptomatic stroke, complications related to the procedure, and quality of life assessment using the 36-item Short-Form Health Survey. The clinical impact of the presence or absence of AF trigger foci, and their origins in cases with them, on the results of catheter ablation will also be investigated as an exploratory endpoint. A total of 512 patients will be enrolled and followed up to 1 year. CONCLUSIONS: The EARNEST-PVI trial is a randomized controlled trial designed to assess whether PVI alone is non-inferior to extended substrate ablation for patients with persistent AF undergoing a first catheter ablation.

The power-integrated discriminant improvement: An accurate measure of the incremental predictive value of additional biomarkers.

The predictive performance of biomarkers is a central concern in biomedical research. This is often evaluated by comparing two statistical models: a "new" model incorporating additional biomarkers and an "old" model without them. In 2008, the integrated discrimination improvement (IDI) was proposed for cases when the response variable is binary, and it is now widely applied as a promising alternative to conventional measures, such as the difference of the area under the receiver operating characteristic curve. However, the IDI can erroneously identify a significant improvement in the new model even if no additional information has been provided by new biomarkers. In order to overcome problems with existing measures, in this study, we propose the power-IDI as a measure of incremental predictive value. Our study explains why the IDI cannot avoid false detection of apparent improvements in a new model and we show that our proposed measure is better able to capture improvements in prediction. Numerical simulations and examples using real empirical data reveal that the power-IDI is not only more powerful but also incurs fewer false detections of improvement.

Safety and pharmacokinetics of Alpha-1 MP (Prolastin®-C) in Japanese patients with alpha1-antitrypsin (AAT) deficiency.

BACKGROUND: Alpha1-Proteinase Inhibitor, Modified Process (Alpha-1 MP) is used for augmentation therapy in alpha1-antitrypsin deficiency (AATD), an extremely rare disease in Japan. Weekly doses of 60 mg/kg Alpha-1 MP have been shown to be safe and well tolerated in non-Japanese subjects, but the safety and pharmacokinetics (PK) have not been evaluated in Japanese subjects. The objectives of this study were to evaluate the safety and PK of 60 mg/kg Alpha-1 MP administered by weekly IV infusions over 8 weeks in Japanese subjects with AATD. METHODS: This was a multicenter, open-label trial in Japanese adults aged ≥20 years with AATD. Samples for evaluation of serum alpha1-PI concentration and PK parameters were collected at 10 time points until the seventh day after the last dose at Week 8: immediately before dosing, immediately after dosing (time 0), and 0.25, 2, 4, 8, 24, 48, 120, and 168 hours after dosing. RESULTS: Four subjects were analyzed. The median tmax was 0.534 h. Mean ± SD values for t½, Cmax, and AUC0-7days were 150.4 ± 36.18 h, 174.2 ± 30.51 mg/dL, and 14,913.2 ± 1633.45 mg*h/dL, respectively. Mean trough concentration at week 8 was 55.4 ± 7.23 mg/dL. Alpha-1 MP therapy was safe, with no serious adverse events or deaths reported. Two treatment-emergent adverse events of fatigue in one subject were considered to be possibly related. CONCLUSIONS: The PK and safety of Alpha-1 MP in Japanese subjects with AATD were consistent with the Alpha-1 MP profile in non-Japanese subjects (ClinicalTrials.gov: NCT02870309; JAPIC CTI: JapicCTI-163160).

Outcomes differ by first documented rhythm after witnessed out-of-hospital cardiac arrest in children: an observational study with prospective nationwide population-based cohort database in Japan.

Aims: To evaluate and compare outcomes and impacts of delay of time to cardiopulmonary resuscitation (CPR) by type of first documented rhythm in paediatric patients with out-of-hospital cardiac arrest (OHCA). Methods and results: We enrolled 3968 paediatric (aged <18 years) OHCA patients whose events were witnessed between 2005 and 2012 from a prospective nationwide population-based cohort database in Japan. We assessed and compared their neurologically favourable 1-month survival according to first documented rhythm: pulseless ventricular tachycardia/ventricular fibrillation (pVT/VF), pulseless electrical activity (PEA), or asystole. Out-of-hospital cardiac arrest patients with pVT/VF, PEA, and asystole totalled 556 (14.0%), 1249 (31.5%), and 2163 (54.5%), respectively. The proportion of overall neurologically favourable 1-month survival in patients with pVT/VF, PEA, and asystole was 36.5, 5.0, and 1.8%, respectively, in the entire study population, and 73.8, 27.7, and 13.8%, respectively, in patients who achieved pre-hospital return of spontaneous circulation (ROSC). As the time from collapse to CPR lengthened, the number of patients with asystole increased, whereas those of pVT/VF and PEA decreased (P < 0.001). After paediatric OHCA, earlier initiation of CPR resulted in higher rates of pre-hospital ROSC (adjusted odds ratio 0.97, 95% confidence interval 0.95-0.99, P = 0.018), which led to much better patient outcomes than in the total study population. Conclusion: We confirmed that pVT/VF and early ROSC in general were associated with better outcomes in patients with witnessed paediatric OHCA.

The first case report of emphysematous pyelonephritis and bacteremia due to Oligella urethralis.

Oligella urethralis (O. urethralis) is an organism that rarely causes infections in humans. We report the case of a 90-year-old bedridden woman with progressive dementia who was placed in a long-term-care facility. She was admitted to our hospital due to fever and unconsciousness with pyuria. The abdominal computed tomography showed left pneumatosis and urinary stone. Fluoroquinolones-resistant O. urethralis, which was identified by the Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS) and the 16S rRNA gene sequencing, was isolated form the blood and urine cultures at admission. To the best of our knowledge, this is the first case of emphysematous pyelonephritis caused by O. urethralis.

Prevalence and Characteristics of Salmonella and Campylobacter in Retail Poultry Meat in Japan.

This study was performed to determine the prevalence, antimicrobial susceptibility, and genetic relatedness of Salmonella enterica subsp. enterica and Campylobacter spp. in poultry meat, and to analyze the association of genetic types of these bacteria with their geographical distribution and antimicrobial resistance profiles. Salmonella and Campylobacter isolates have been detected, respectively, in 54 and 71 samples out of 100 samples tested. Nine Salmonella serotypes were found, including S. enterica subsp. enterica serovar Infantis (33%), Schwarzengrund (12%), Manhattan (9%), and others. Campylobacter jejuni and C. coli were detected in 64 (64%) and 14 (14%) samples, respectively. S. enterica subsp. enterica isolates were very frequently resistant to tetracycline (78.3%) and streptomycin (68.3%). Many C. jejuni and C. coli isolates were resistant to sulfamethoxazole/trimethoprim (90.5%), nalidixic acid (47.3%), ampicillin (45.9%), and ciprofloxacin (40.5%). Cluster analysis was performed for the Salmonella isolates using pulsed-field gel electrophoresis (PFGE) data. For Campylobacter isolates, the cluster analysis was based on both PFGE and comparative genomic fingerprinting. The molecular typing results were compared with the information about antimicrobial resistance and geographical locations in which the poultry meat was produced. This analysis revealed that C. jejuni strains with a particular genotype and antimicrobial resistance profile are spreading in specific areas of Japan.

Relationship between cell-mediated immunity to Varicella-Zoster virus and aging in subjects from the community-based Shozu Herpes Zoster study.

Age-related declines in cell-mediated immunity (CMI) are associated with the incidence and severity of Herpes Zoster (HZ) infection. However, the level of Varicella-Zoster virus (VZV)-specific CMI associated with disease onset is unclear. This study aimed to examine factors associated with VZV-specific CMI, as measured by an interferon-gamma (IFN-γ) enzyme-linked immunospot (ELISPOT) assay, in a Japanese cohort. The study enrolled 365 subjects aged 60 years and over, all of whom were taking part in the Shozu Herpes Zoster (SHEZ) study and had undergone four sets of blood and intradermal reaction tests during a 3 year follow-up period. The VZV-specific immunity profile of each subject was assessed, and linear mixed effects models were constructed to analyze IFN-γ ELISPOT results in association with a combination of factors. The model that best explained the IFN-γ ELISPOT results was selected using the Akaike Information Criteria. The best-fit model consisted of age group as the only explanatory fixed-effect variable. The model showed that VZV-specific CMI, quantified as numbers of spots on the ELISPOT assay, among subjects aged 70-79 was on average 10.30 points lower than that among subjects aged 60-69. There was no statistically significant difference between subjects aged 70-79 and those aged 80-89. Age was the only factor significantly associated with the level of VZV-specific CMI, as measured by the IFN-γ ELISPOT assay. These results may represent an important step towards quantifying the relationship between VZV-specific CMI and the onset of HZ. J. Med. Virol. 89:313-317, 2017. © 2016 Wiley Periodicals, Inc.

Prediction of Postoperative Intraocular Lens Position with Angle-to-Angle Depth Using Anterior Segment Optical Coherence Tomography.

PURPOSE: To evaluate the accuracy of a new formula for predicting postoperative anterior chamber depth (ACD) with preoperative angle-to-angle (ATA) depth using anterior segment (AS) optical coherence tomography (OCT) and to compare it with established methods. DESIGN: Retrospective consecutive case series. PARTICIPANTS: Three hundred four eyes (276 patients) implanted with acrylic intraocular lenses (IOLs) were divided randomly into a training set (152 eyes) and a validation set (152 eyes). METHODS: Based on the training set data, the postoperative ACD measured 1 month after surgery was analyzed via multiple linear regression analysis with 5 preoperatively measured variables: ATA depth, ATA width, preoperative ACD measured with AS OCT, axial length (AL), and corneal power. A new regression formula for predicting postoperative ACD was developed using the results of the stepwise analysis. In the validation set data, the coefficients of determination (R2) between the measured postoperative ACD and the predicted postoperative ACD obtained using the new formula were compared with those obtained using the Sanders-Retzlaff-Kraff theoretic (SRK/T) and Haigis formulas. The absolute prediction errors were compared with each formula. MAIN OUTCOME MEASURES: Postoperative ACD, median absolute prediction error of postoperative ACD, and ocular biometric parameters. RESULTS: In the training set, ATA depth yielded the highest standard partial regression coefficient value, indicating that ATA depth is the most effective parameter for predicting postoperative ACD. The new regression formula was developed with 3 variables; ATA depth, preoperative ACD, and AL. In the validation set, the postoperative ACDs of the new formula, the SRK/T formula, and Haigis formula were predicted with R2 of 0.71, 0.36, and 0.55, respectively, and the medians of the absolute prediction errors were 0.10 mm, 0.65 mm, and 0.30 mm, respectively. The absolute prediction error with the new formula was significantly smaller than those obtained with the SRK/T and Haigis formulas (P < 0.0001). CONCLUSIONS: The new formula with 3 preoperative parameters-ATA depth, preoperative ACD, and AL-predicted postoperative ACD more accurately than the SRK/T and Haigis formulas. It may be possible to improve the accuracy of IOL power calculation using an improved postoperative ACD prediction with the ATA depth measured by AS OCT.

Ectopic adrenocorticotropic hormone syndrome caused by neuroendocrine carcinoma of the colon.

A 48-year-old woman with a history of autoimmune hemolytic anemia and taking long-term corticosteroid therapy presented with a 3-month history of general fatigue, abdominal distension, and pigmentation. A computed tomography scan of the abdomen showed a tumor in the sigmoid colon and multiple metastatic nodules in the liver. A colonoscopy revealed an obstructing mass with the presence of an irregular ulcer in the sigmoid colon. Following biopsy and histopathological analysis, the patient was diagnosed with neuroendocrine carcinoma (NEC) of the colon. She received her first cycle of chemotherapy, with carboplatin and etoposide. During hospitalization, her pigmentation and hypertension worsened and hypokalemia was observed, all of which suggsted Cushing's syndrome. Her plasma adrenocorticotropic hormone (ACTH) and cortisol levels were high, and an ectopic ACTH-producing tumor was suspected. After a second chemotherapy cycle, she developed neutropenic fever and subsequently died. At autopsy, two histological types were found in the tumor: small cell carcinoma and large cell NEC. Immunohistochemical analysis revealed ACTH in the large cell NEC. This is the first reported case of an ectopic ACTH syndrome caused by NEC of the colon.

Injustice Experience Questionnaire, Japanese Version: Cross-Cultural Factor-Structure Comparison and Demographics Associated with Perceived Injustice.

OBJECTIVE: The Injustice Experience Questionnaire (IEQ) assesses injury-related perceived injustice. This study aimed to (1) develop a Japanese version (IEQ-J), (2) examine its factor structure, validity, and reliability, and (3) discover which demographic variable(s) positively contributed to prediction of IEQ-J scores. METHODS: Data from 71 patients (33 male, 38 female; age = 20+) with injury pain were employed to investigate factor structure by exploratory and confirmatory factor analyses. Concurrent validity was examined by Pearson correlation coefficients among the IEQ-J, Brief Pain Inventory (BPI), and Pain Catastrophizing Scale (PCS). Internal consistency was investigated by Cronbach's alpha, and test-retest reliability was indicated with intra-class correlations (ICCs) in 42 of 71 patients within four weeks. Relations between demographic variables and IEQ-J scores were examined by covariance analysis and linear regression models. RESULTS: IEQ-J factor structure differed from the original two-factor model. A three-factor model with Severity/irreparability, Blame/unfairness, and Perceived lack of empathy was extracted. The three-factor model showed goodness-of-fit with the data and sufficient reliability (Cronbach's alpha of 0.90 for total IEQ-J; ICCs = 0.96). Pearson correlation coefficients among IEQ-J, BPI, and PCS ranged from 0.38 to 0.73. Pain duration over a year (regression coefficient, 11.92, 95%CI; 5.95-17.89) and liability for injury on another (regression coefficient, 12.17, 95%CI; 6.38-17.96) predicted IEQ-J total scores. CONCLUSIONS: This study evidenced the IEQ-J's sound psychometric properties. The three-factor model was the latter distinctive in the Japanese version. Pain duration over a year and injury liability by another statistically significantly increased IEQ-J scores.

Mitochonic Acid 5 Binds Mitochondria and Ameliorates Renal Tubular and Cardiac Myocyte Damage.

Mitochondrial dysfunction causes increased oxidative stress and depletion of ATP, which are involved in the etiology of a variety of renal diseases, such as CKD, AKI, and steroid-resistant nephrotic syndrome. Antioxidant therapies are being investigated, but clinical outcomes have yet to be determined. Recently, we reported that a newly synthesized indole derivative, mitochonic acid 5 (MA-5), increases cellular ATP level and survival of fibroblasts from patients with mitochondrial disease. MA-5 modulates mitochondrial ATP synthesis independently of oxidative phosphorylation and the electron transport chain. Here, we further investigated the mechanism of action for MA-5. Administration of MA-5 to an ischemia-reperfusion injury model and a cisplatin-induced nephropathy model improved renal function. In in vitro bioenergetic studies, MA-5 facilitated ATP production and reduced the level of mitochondrial reactive oxygen species (ROS) without affecting activity of mitochondrial complexes I-IV. Additional assays revealed that MA-5 targets the mitochondrial protein mitofilin at the crista junction of the inner membrane. In Hep3B cells, overexpression of mitofilin increased the basal ATP level, and treatment with MA-5 amplified this effect. In a unique mitochondrial disease model (Mitomice with mitochondrial DNA deletion that mimics typical human mitochondrial disease phenotype), MA-5 improved the reduced cardiac and renal mitochondrial respiration and seemed to prolong survival, although statistical analysis of survival times could not be conducted. These results suggest that MA-5 functions in a manner differing from that of antioxidant therapy and could be a novel therapeutic drug for the treatment of cardiac and renal diseases associated with mitochondrial dysfunction.

[Molecular Characterization of Salmonella enterica subsp. enterica Serovar 4: b: -].

Salmonella is a major causative agent of food borne diseases. Recently, monophasic strains of Salmonella, such as S. enterica 4: i: -, have been frequently reported. Here, we investigated the genetic background of S. enterica 4: b: - using multilocus sequence typing (MLST) and pulsed-field gel electrophoresis. A total of 10 strains of S. enterica (I) 4: b: - were examined and compared with 34 strains including serovar Paratyphi B and Paratyphi B var Java, Schleissheim, and II b: -. All I 4: b: - strains were negative for hin which encodes an invertase that converts the H phases, and six were also negative for fljB, which encodes the second phase of the H antigen. An MLST analysis identified 12 sequence types (ST) and 6 ST complexes (STC) from the 44 strains. A clustering analysis of PFGE patterns almost corresponded to the STC. The monophasic I 4: b: - strains were assigned to 3 STCs (19, 32 and 155), corresponding to those of Paratyphi B var. Java or a monophasic strain according to the data of this and previous studies. These findings suggest that the monophasic strains examined in this study might have been derived from multiple clones of Paratyphi B var Java. This study shows the usefulness of molecular typing as complementation tools of the conventional serotyping system.