Hemostatic balance between pro- and anticoagulant is maintained during glucocorticoid treatment.

BACKGROUND: Glucocorticoids are associated with an increased risk of venous thrombosis. Glucocorticoid treatment increases coagulation factor and anticoagulant levels; however, its effect on hemostatic function remains unclear. This study aimed to investigate the changes in comprehensive coagulation profiles after glucocorticoid treatment in noninflammatory diseases to elucidate the direct contribution of glucocorticoids to hemostatic function. PROCEDURE: Patients diagnosed with primary immune thrombocytopenia requiring glucocorticoid treatment were prospectively enrolled in this study. Changes in coagulation factors and anticoagulants during glucocorticoid treatment and changes in thrombin generation potential were determined in the absence and presence of soluble thrombomodulin (sTM). RESULTS: Seven treatment cases (four for steroid pulse therapy and three for oral glucocorticoid therapy) in six patients with immune thrombocytopenia were examined. After glucocorticoid treatment, activated partial thromboplastin time significantly shortened, and activities of factor VIII, IX, XI, and XII significantly increased, except for von Willebrand factor antigen. Moreover, antithrombin and protein C (PC) activities significantly increased after glucocorticoid treatment. Two major parameters of thrombin generation potential, endogenous thrombin potential (ETP) and peak thrombin (Peak), significantly increased in the absence of sTM after glucocorticoid treatment. However, no significant increases in either parameter were observed in the presence of sTM. ETP-TM and Peak-TM ratios, which represent resistance to the anticoagulant effect of the PC pathway, significantly decreased after glucocorticoid treatment, suggesting that anticoagulant function via the PC pathway is elevated after glucocorticoid treatment. CONCLUSIONS: As glucocorticoids increase intrinsic coagulation factor and anticoagulant levels, hemostatic balance between pro- and anticoagulant functions is maintained.

A Japanese Case of COVID-19 Caused by Omicron Strain with Y453F Substitution.

Frequent mutations of SARS-CoV-2 change the strain more transmissible, leading to the pandemic in worldwide. We detected Y453F substitution on Omicron strain, isolated from a Japanese patient in July 2022. While Y453F substitution was identified B1.1.298 lineage in Netherlands and Denmark in 2020, the substitution has not been reported in Omicron strain especially in Japan. Y453F substitution is associated with higher viral infectivity because it is sited in the receptor-binding domain (RBD), and Y453F substitution contributes to increase binding affinity to angiotensin converting enzyme 2 (ACE2). Additionally, Y453F substitution has been reported to escape human leukocyte antigen (HLA), which is known to recognize non-self-antigens in virus-infected cells as cellular immunity, so it should be closely monitored.

Rare toxin A-negative and toxin B-positive strain of Clostridioides difficile from Japan lacking a complete tcdA gene.

INTRODUCTION: Clostridioides difficile (C. difficile) produces three kinds of toxins: toxin A (enterotoxin), toxin B (cytotoxin), and C. difficile transferase (CDT), a binary toxin. Some strains show positivity only for toxin B. These strains reportedly possess a gene for toxin A, tcdA. However, toxin A production is inhibited due to a mutated stop codon and/or deletion within the tcdA gene. Here for the first case in Japan, we describe toxin genomes and proteins of a strain possessing only toxin B and lacking a complete tcdA gene, along with clinical manifestations. METHODS: C. difficile was isolated from the bloody stool of a 60-year-old female patient treated with meropenem. Although a rapid detection kit of toxins (C. DIFF QUIK CHEK COMPLETE®, TechLab, Blacksburg, VA, USA) showed positivity, Western blotting detected no toxins. Therefore, we explored the strain's toxin genes and their sequences to determine whether the strain possessed a toxin. RESULTS: Polymerase chain reaction did not identify toxin genes. Whole-genome sequencing analysis showed that a gene for toxin A, tcdA, was completely deleted in the strain. Moreover, 701 mutations and some deletions/insertions were identified on the tcdB gene. CONCLUSIONS: We isolated a rare strain of C. difficile producing only toxin B and lacking a complete tcdA gene herein Japan. The possibility of a false negative needs to be considered with a genetic method for a diagnose of C. difficile infection.

Relationships between kidney dysfunction and left ventricular diastolic dysfunction: a hospital-based retrospective study.

BACKGROUND: Preclinical left ventricular diastolic dysfunction (LVDD) is a high-risk state for heart failure. Kidney dysfunction is a known risk factor for heart failure, but its association with asymptomatic LVDD is not well-known. METHODS: A hospital-based retrospective cohort study was conducted on patients who underwent echocardiogram between 2006 and 2016 to assess the association between baseline kidney function and LVDD on echocardiogram. E/e' ratio was defined as the ratio of peak velocity of early diastolic left ventricular inflow (E) to mitral annular velocity (e'). The primary outcome was time to development of LVDD, which was defined as E/e' ratio > 14. The changes in the E/e' ratio and other echocardiographic parameters were assessed using a mixed effects model. RESULTS: Among 1167 patients, the mean age was 61 years, and the mean baseline E/e' ratio and ejection fraction were 9.6 and 69%, respectively. During a median follow-up of 3.2 years, 231 (19.8%) people developed LVDD. According to eGFR (mL/min/1.73 m2), the risk for LVDD based on hazard ratio [95% confidence interval (95% CI)] was 1.20 (0.82, 1.75) for 60 to < 90, 1.42 (0.87, 2.31) for 45 to < 60, and 2.57 (1.61, 4.09) for < 45 (P trend < 0.001). The adjusted risks (95% CI) for annual change in E/e' ratio was 0.09 (0.03, 0.14) overall and 0.28 (0.11, 0.45) in the lowest eGFR group; the trend in changes in annual E/e' ratio by baseline eGFR was significant (P trend = 0.01). CONCLUSIONS: Relatively low kidney function was related with the risks for LVDD. Long-term cohort studies are warranted to confirm the association between LVDD and symptomatic heart failure in patients with kidney dysfunction.

A case with familial hypercholesterolemia complicated with severe systemic atherosclerosis intensively treated for more than 30 years.

We present a case of a Japanese patient with familial hypercholesterolemia (FH) caused by a low-density lipoprotein (LDL) receptor gene mutation. A 47-year-old female was referred to our hospital due to her systemic xanthomatosis associated with elevated LDL-cholesterolemia (292 mg/dl). She was diagnosed with heterozygous FH, and started to be treated with simvastatin 10 mg. During her clinical course, she underwent percutaneous coronary intervention (PCI) (at 69 years), coronary artery bypass grafting (CABG) twice (at 62 years, and 75 years), femoral popliteal bypass surgery (at 67 years), together with intensification of lipid-lowering therapies, including proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. She was admitted to our hospital due to dyspnea on effort, caused by severe aortic valve stenosis as well as sick sinus syndrome at the age of 78 years. transcatheter aortic valve implantation (TAVI) using balloon expandable valve was successfully performed after DDD pacemaker implantation. She was discharged from our hospital without any symptoms. During more than 30 years of treatment period in our institute, we have introduced the latest therapeutic strategies, and treated her intensively. We are proud that we can save life even in this severe case through multiple strategies developed over the decades; however, this case clearly suggests that lipid-lowering therapies should be started much earlier in patients with FH. .

Hokuriku-plus familial hypercholesterolaemia registry study: rationale and study design.

INTRODUCTION: Familial hypercholesterolaemia (FH) is an autosomal-dominant inherited genetic disease. It carries an extremely high cardiovascular risk associated with significantly elevated low-density lipoprotein (LDL) cholesterol. The diagnostic rate of this disease in some European nations is quite high, due to the presence of multiple prospective registries. On the other hand, few data-and in particular multicentre data-exist regarding this issue among Japanese subjects. Therefore, this study intends to assemble a multicentre registry that aims to comprehensively assess cardiovascular risk among Japanese FH patients while taking into account their genetic backgrounds. METHODS AND ANALYSIS: The Hokuriku-plus FH registry is a prospective, observational, multicentre cohort study, enrolling consecutive FH patients who fulfil the clinical criteria of FH in Japan from 37 participating hospitals mostly in Hokuriku region of Japan from April 2020 to March 2024. A total of 1000 patients will be enrolled into the study, and we plan to follow-up participants over 5 years. We will collect clinical parameters, including lipids, physical findings, genetic backgrounds and clinical events covering atherosclerotic and other important events, such as malignancies. The primary endpoint of this study is new atherosclerotic cardiovascular disease (ASCVD) events. The secondary endpoints are as follows: LDL cholesterol, secondary ASCVD events and the occurrence of other diseases including hypertension, diabetes and malignancies. ETHICS AND DISSEMINATION: This study is being conducted in compliance with the Declaration of Helsinki, the Ethical Guidelines for Medical and Health Research Involving Human Subjects, and all other applicable laws and guidelines in Japan. This study protocol has been approved by the Institutional Review Board at Kanazawa University. We will disseminate the final results at international conferences and in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: UMIN000038210.

In vivo evaluation of drug dialyzability in a rat model of hemodialysis.

It is important to calculate the drug removal by hemodialysis (HD) for drug dosing regimens in HD patients. However, there are limited and inconsistent information about the dialyzability of drugs by HD. Therefore, the aim of our study is to evaluate drug removal by utilizing a rat model of HD (HD rat) and to extrapolate this result to the drug removal rate in HD patients. HD rats received bilateral nephrectomy and HD for 2 h. The dialysis removal of 6 drugs was evaluated in HD rats. Dialysis efficiency, plasma protein binding rate (PBR) and distribution volume (Vd) of drugs were also measured. Furthermore, we examined the correlation between the dialyzability of drug in HD rats and humans and constructed the prediction formula of the drug dialyzability in HD patients. The clearance of urea and creatinine and normalized dialysis dose in HD rats were 0.83 ± 0.07 mL/min, 0.70 ± 0.08 mL/min, and 0.13 ± 0.06, respectively. The drug dialyzability in HD rats was similar to reported clinical data except for doripenem. A higher correlation was observed between drug dialyzability in reported clinical data and HD rats which were adjusted for PBR (r2 = 0.936; p < 0.001) compared to unadjusted (r2 = 0.812; p = 0.009). Therefore, we constructed the prediction formula of the drug dialyzability in HD patients by utilizing the HD rat model and PBR. This study is useful for evaluating the dialyzability of high-risk drugs in a clinical setting and might provide appropriate preclinical dialyzability data for new drug.

Clinical Impact of Carotid Plaque Score rather than Carotid Intima-Media Thickness on Recurrence of Atherosclerotic Cardiovascular Disease Events.

AIM: Carotid plaque score (cPS) reflecting throughout the carotid artery plaque burden may be a better marker than carotid intima-media thickness (cIMT) is. We aimed to compare the prognostic utility of these measurements in patients with atherosclerotic cardiovascular disease (ASCVD). METHODS: We retrospectively examined 2,035 Japanese patients with ASCVD who underwent carotid ultrasonography between January 2008 and December 2015 at Kanazawa University Hospital. Median follow-up period was 4 years. We used Cox models that adjusted for established risk factors of ASCVD, including age, gender, hypertension, diabetes, smoking, and serum lipids to assess the association of cIMT as well as cPS with major adverse cardiac events (MACE). MACE was defined as all-cause mortality or rehospitalization for a cardiovascular-related illness. RESULTS: During follow-up, 243 participants experienced MACE. After adjustment for established risk factors, cPS was associated with MACE (hazard ratio [HR]=3.38 for top quintile vs. bottom quintile of cPS; 95% confidence interval [CI] 1.82-6.27; P trend ＜0.001), while cIMT was not (HR=0.88, P=0.57). Addition of the cPS to established risk factors significantly improved risk discrimination (C-index 0.726 vs. 0.746; P=0.017). CONCLUSION: These results suggest that cPS, rather than cIMT may be a better marker to identify increased risk for recurrence of MACE among patients with secondary prevention setting.

Unusual Aorto-mitral Discontinuity Caused by Infective Endocarditis.

Aorto-mitral discontinuity is considered a relatively rare complication of infective endocarditis, usually requiring invasive surgical procedures, including double valve replacement in addition to aortic root replacement/repair. In the present case report, images were produced using transthoracic echocardiograms and transesophageal echocardiograms, which may assist in the planning of surgical procedures. The images captured using real-time three-dimensional transesophageal echocardiograms revealed aorto-mitral discontinuity and a perforated mitral valve aneurysm of the anterior leaflet.

Additive Prognostic Value of Carotid Plaque Score to Enhance the Age, Creatinine, and Ejection Fraction Score in Patients with Acute Coronary Syndrome.

AIM: To assess whether combining measurements obtained from carotid ultrasonography in addition to the age, creatinine, and ejection fraction (ACEF) score would improve the predictive ability of outcome in patients with acute coronary syndrome (ACS). METHODS: We examined 264 patients with ACS (194 men; mean age: 68±11 years) who underwent percutaneous coronary intervention. The carotid plaque score (cPS) and intima-media thickness (cIMT) were determined by carotid ultrasonography. The modified ACEF score was calculated using the following formula: (age/left ventricular ejection fraction) ＋1 point for every 10 mL/min reduction in creatinine clearance below 60 mL/min per 1.73 m2. The endpoint of this study was major adverse cardiovascular and cerebrovascular events (MACEs), defined as all-cause death, myocardial infarction, stoke, and target vessel revascularization. RESULTS: During the median 4-year follow-up, there were 121 incidents of MACEs. Multivariate Cox proportional hazard regression analysis revealed that cPS ≥9.8 (hazard ratio [HR], 1.52; 95% confidence interval [CI], 1.01-2.31) and ACEF score ≥1.20 (HR, 1.62; 95% CI, 1.11-2.39) were significantly associated with MACEs, whereas cIMT was not. When the new combined risk score was calculated by multiplying the cPS by the modified ACEF score, the freedom from MACEs at 5 years was 71% and 31% for the lower and higher scores, respectively (p＜0.001). The area under the receiver-operating characteristic curve for MACEs for the ACEF score, cPS, and combined risk score were 0.65, 0.66, and 0.71, respectively (p＜0.05). CONCLUSION: The cPS offers an incremental predictive value when combined to the simple ACEF score in ACS.

Huge right ventricular mass lesion associated with genital malignant tumor: a case report.

BACKGROUND: Primary heart tumors are rare, whereas metastatic heart tumors occur more frequently. CASE PRESENTATION: We report a case of a 75-year-old Japanese woman who had metastatic heart tumors of the right ventricle. Although she initially received antibiotic therapy following a diagnosis of pneumonia and pleuritis, her symptoms worsened, and she developed dyspnea and bilateral lower limb edema. Echocardiography showed a huge mass lesion occupying the entire right ventricle. Because the patient's tumor markers were elevated, we used computed tomography to search for the primary lesion, which was located in the vagina or the uterus. Histology demonstrated the presence of basaloid squamous cell carcinoma in the vaginal tissue. Chemotherapy with paclitaxel and carboplatin was initiated. CONCLUSIONS: These data suggest that the tumor in the right ventricle metastasized from the genital organs.

Regional colorectal cancer screening program using colonoscopy on an island: a prospective Nii-jima study.

Objective: Colorectal cancer screening program using fecal immunochemical test had been conducted on an isolated island named Nii-jima. However, the participation rate of the program had been approximately 12%, which was lower than average level of Japan. This study aimed to evaluate the participation rate, safety and efficacy of a colorectal cancer screening program using colonoscopy on the island. Methods: Educational campaigns were actively conducted every month using information bulletins and special propaganda pamphlets. The primary recommended modality was colonoscopy, followed by fecal immunochemical test. The participants of this program were 1671 individuals aged 40­79 years (men, 819; women, 852). Results: A total of 789 (47.2%) individuals provided consent for this screening program, and 89.2% (704/789) of participants chose colonoscopy as the primary screening procedure. The completion rate of total colonoscopy was 99.7%, and there was no complication during this program. Detection rates of invasive cancer, intramucosal cancer, advanced neoplasia and any adenoma were 0.9% (n = 6), 2.4% (n = 17), 11.8% (n = 83) and 50.0% (n = 352), respectively. The adenoma detection rate and incidence of advanced neoplasia were significantly higher in men than in women in all age groups. Conclusions: The colorectal cancer screening program using colonoscopy that was conducted on an island achieved considerably higher participation rate than the conventional screening program using fecal immunochemical test. Completion rate and safety of screening colonoscopy were excellent during this program.

First case report of hemophilia B Leyden in Japan.

Hemophilia B Leyden is a unique subtype of hemophilia B, characterized by increasing factor IX activity (FIX:C) after puberty and a lower normal range of FIX:C throughout adulthood. However, to date, no Japanese case has been reported. Here, we report a case of hemophilia B Leyden in a 22-year-old male. He suffered from subgaleal hematoma, and was subsequently diagnosed with hemophilia B (FIX:C 0.2%) in the neonatal period. Both his parents are Japanese. There was no history of hemophilia in his family. FIX:C gradually increased with age (8% at age = 1; 14% at age = 7; 19% at age = 12; 32% at age = 18). FIX:C is within the range 30-40% in recent several years. He once required administration of FIX concentrate against traumatic tongue bleeding at 7 years of age. Genotyping analysis of FIX was performed after informed consent at 21 years of age, and a point mutation (c.-35G>A) was detected. This mutation has been reported previously as the Leyden mutation. Although it has been reported that hemophilia B Leyden is seen in 1.9% of patients with hemophilia B, the present case is the first report of hemophilia B Leyden from Japan.

A cohort study of the usefulness of primary prophylaxis in patients with severe haemophilia A.

Primary prophylaxis is a method of haemostatic management to prevent bleeding and arthropathy in patients with severe haemophilia. The aim of this study was to evaluate the usefulness of primary prophylaxis in patients with severe haemophilia A. This study included 15 patients with haemophilia A who received primary prophylaxis at our institution for a minimum of 5 years. We evaluated the annualized bleeding ratio of joints or other sites, current joint function, and X-ray images and MRI scans taken when patients were 6 years old. The range of patients' ages at the end of the study was 6.2-16.8 years, and at the start of primary prophylaxis it was 0.8-2.4 years. Factor VIII concentrates (25-40 units kg(-1) dose(-1)) were administered 3 times/week or every other day, according to the Swedish protocol. Mean joint and non-joint annualized bleeding ratios were 0.49 ± 0.5 and 1.54 ± 1.69, respectively. At the final evaluation, all patients displayed a normal range of motion for both elbows, knees, and ankles. The radiography and MRI findings at the age of 6 were unremarkable in all patients. Overall, primary prophylaxis for patients with severe haemophilia A was performed safely, reduced the number of bleeding events, and prevented progression to arthropathy.

[Functional Residual Capacity Measurement Based on Lung Structure Model Analysis Using the Helium Gas Dilution Technique].

In the helium gas dilution method, functional residual capacity (FRC) is calculated from a helium concentra- tion equilibrium curve. In this study, we analyzed the helium concentration equilibrium curves of healthy patients, clarified the determinants of the equilibrium concentration, and studied the effects of an uneven lung distribution. We collected data from 200 patients (92 males and 108 females) whose FRC values had been measured at our institution over the past 6 years. Their FRC values ranged from 80% to 120%, and theit other pulmo- nary function values were within the normal range. In the compartmental model analysis, we discovered that the helium concentration equilibrium curve was composed of one compartment, and that it did not have a polyphasic structure. Each 0.25-minute (15-second) segment of the helium concentration equilibrium curve obtained from the patients was evaluated using univariate and multivariate regression analyses. The helium concentration equilibrium curve decreased exponentially over the time course of the analysis, and the multiple correlation coefficient for the relationship between the 0.25-minute to 0.75-minute segments and the 1.00-minute to 1.50-minute segments in the final model was 0.949. Finally, we examined the influence of an uneven peripheral lung distribution. A model based on the con- centration change seen between the initial and middle periods during at rest ventilation indicated that the latter parameter was not affected by the ventilation volume of the peripheral lung. [Original].

Abrupt progression of ventricular septal perforation after primary angioplasty for acute myocardial infarction.

A 61-year-old-man was transferred to our hospital because of progressive heart failure after reperfusion for acute myocardial infarction (MI). When he visited the local hospital with severe chest pain associated with inferior MI, transthoracic echocardiography revealed small ventricular septal perforation (VSP). The patient had emergent coronary angiography, which revealed total occlusion of the mid-portion of the right coronary artery. Primary angioplasty was successful for reperfusion. However, because of hemodynamic instability the patient was transferred to our hospital. Under these conditions, transthoracic echocardiography which was undertaken 3 hours after primary angioplasty, demonstrated progressive enlargement of the VSP probably due to reperfusion injury. The rupture site, which was further enlarged at the time of operation, was repaired using the patch exclusion technique. The patient could discharge without complications. We suggest that primary angioplasty may potentially induce late reperfusion injury in patients with VSP complicating MI.

Impact of real-time three-dimensional transesophageal echocardiography on procedural success for mitral valve repair.

BACKGROUND: For mitral valve repair, minimally invasive cardiac surgery as well as transcatheter valvular intervention have been developed. Under these conditions, three-dimensional transesophageal echocardiography (3D-TEE) plays a key role for planning the surgical treatment strategy. However, few data exist regarding the role of 3D-TEE in mitral valve repair. Therefore, we examined the impact of 3D-TEE on procedural success of mitral valve repair. METHODS AND RESULTS: We examined 86 consecutive patients who underwent mitral valve repair for degenerative mitral valve prolapse. Among them, 39 patients were examined by only two-dimensional transesophageal echocardiography (2D-TEE) and 47 patients underwent 3D-TEE in addition to 2D-TEE. The cardiac surgeons and physicians discussed the repair procedure preoperatively with the echocardiographic images. As a result, 18 patients of the 2D-TEE group and 37 patients of the 3D-TEE group underwent mitral valve repair by small thoracotomy including robotic approach. Simple repair was done in 21 with 2D-TEE and 21 with 3D-TEE and complex repair was done in 18 with 2D-TEE and 26 with 3D-TEE. Importantly, three patients with 2D-TEE before surgery had to undergo reoperation due to recurrent severe mitral regurgitation with dehiscence of the annuloplasty rings, although none with 3D-TEE did. CONCLUSIONS: These results demonstrate that 3D-TEE is helpful in assessing the morphology of mitral apparatus and complexity of mitral valve repair, particularly in minimally invasive cardiac surgery including robotic ones. We would suggest that sonographers, cardiologists, and cardiac surgeons should be familiar with 3D-TEE and work together throughout the perioperative period for better outcomes.