RyR2-targeting therapy prevents left ventricular remodeling and ventricular tachycardia in post-infarction heart failure.

BACKGROUND: Dantrolene binds to the Leu601-Cys620 region of the N-terminal domain of cardiac ryanodine receptor (RyR2), which corresponds to the Leu590-Cys609 region of the skeletal ryanodine receptor, and suppresses diastolic Ca2+ leakage through RyR2. OBJECTIVE: We investigated whether the chronic administration of dantrolene prevented left ventricular (LV) remodeling and ventricular tachycardia (VT) after myocardial infarction (MI) by the same mechanism with the mutation V3599K of RyR2, which indicated that the inhibition of diastolic Ca2+ leakage occurred by enhancing the binding affinity of calmodulin (CaM) to RyR2. METHODS AND RESULTS: A left anterior descending coronary artery ligation MI model was developed in mice. Wild-type (WT) were divided into four groups: sham-operated mice (WT-Sham), sham-operated mice treated with dantrolene (WT-Sham-DAN), MI mice (WT-MI), and MI mice treated with dantrolene (WT-MI-DAN). Homozygous V3599K RyR2 knock-in (KI) mice were divided into two groups: sham-operated mice (KI-Sham) and MI mice (KI-MI). The mice were followed for 12 weeks. Survival was significantly higher in the WT-MI-DAN (73%) and KI-MI groups (70%) than the WT-MI group (40%). Echocardiography, pathological tissue, and epinephrine-induced VT studies showed that LV remodeling and VT were prevented in the WT-MI-DAN and KI-MI groups compared to the WT-MI group. An increase in diastolic Ca2+ spark frequency and a decrease in the binding affinity of CaM to the RyR2 were observed at 12 weeks after MI in the WT-MI group, although significant improvements in these values were observed in the WT-MI-DAN and KI-MI groups. CONCLUSIONS: Pharmacological or genetic stabilization of RyR2 tetrameric structure improves survival after MI by suppressing LV remodeling and proarrhythmia.

Herpud1 modulates hypertrophic signals independently of calmodulin nuclear translocation in rat myocardium-derived H9C2 cells.

In this study, we aimed to analyze the role of the Homocysteine-responsive endoplasmic reticulum-resident ubiquitin-like domain member 1 (Herpud1) gene in the development of cardiomyocyte hypertrophy in association with Calmodulin (CaM) nuclear translocation and cytosolic Ca2+ levels. To observe the mobilization of CaM in cardiomyocytes, we stably expressed eGFP-CaM in rat myocardium-derived H9C2 cells. These cells were then treated with Angiotensin II (Ang II), which stimulates a cardiac hypertrophic response, or dantrolene (DAN), which blocks the release of intracellular Ca2+. To observe intracellular Ca2+ in the presence of eGFP fluorescence, a Rohd-3 Ca2+ sensing dye was used. To examine the effect of suppressing Herpud1 expression, Herpud1 small interfering RNA (siRNA) were transfected into H9C2 cells. To examine whether hypertrophy induced by Ang II could be suppressed by Herpud1 overexpression, a Herpud1-expressing vector was introduced into H9C2 cells. CaM translocation was observed using eGFP fluorescence. Nuclear translocation of Nuclear factor of activated T-cells, cytoplasmic 4 (NFATc4) and nuclear export of Histone deacetylase 4 (HDAC4) were also examined. First, Ang II induced H9C2 hypertrophy with nuclear translocation of CaM and elevation of cytosolic Ca2+, which were inhibited by DAN treatment. We also found that Herpud1 overexpression suppressed Ang II-induced cellular hypertrophy without preventing nuclear translocation of CaM or elevation of cytosolic Ca2+. Additionally, Herpud1 knockdown induced hypertrophy without the nuclear translocation of CaM, which was not inhibited by DAN treatment. Finally, Herpud1 overexpression suppressed Ang II-induced NFATc4 nuclear translocation but did not suppress Ang II-induced CaM nuclear translocation or HDAC4 nuclear export. Ultimately, this study lays the groundwork for elucidating the anti-hypertrophic effects of Herpud1 and the underlying mechanism of pathological hypertrophy.

Stabilizing cardiac ryanodine receptor with dantrolene treatment prevents left ventricular remodeling in pressure-overloaded heart failure mice.

Dantrolene (DAN) directly binds to cardiac ryanodine receptor 2 (RyR2) through Leu601-Cys620 in the N-terminal domain and subsequently inhibits diastolic Ca2+ leakage through RyR2. We previously reported that therapy using RyR2 V3599K mutation, which inhibits diastolic Ca2+ leakage by enhancing calmodulin (CaM) binding ability to RyR2, prevents left ventricular (LV) remodeling in transverse aortic constriction (TAC) heart failure. Here, we examined whether chronic administration of DAN prevents LV remodeling in TAC heart failure via the same mechanism as genetic therapy. A pressure-overloaded hypertrophy mouse model was developed using TAC. Wild-type (WT) mice were divided into three groups: sham-operated mice (Sham group), TAC mice (TAC group), and TAC mice treated with DAN (TAC-DAN group, 20 mg/kg/day, i.p.). They were then followed up for 8 weeks. The survival rate was higher in the TAC-DAN group (83%) than in the TAC group (49%), and serial echocardiography studies and pathological tissue analysis showed that LV remodeling was significantly prevented in the TAC-DAN group compared to the TAC group. An increase in the diastolic Ca2+ spark frequency and a decrease in the binding affinity of CaM to RyR2 were observed at 8 weeks in the TAC group but not in the TAC-DAN group. Stabilization of RyR2 with DAN prevented LV remodeling and improved survival after TAC by enhancing CaM binding to RyR2 and inhibiting RyR2-mediated diastolic Ca2+ leakage.

Usefulness of Simple Diffusion Kurtosis Imaging for Head and Neck Tumors: An Early Clinical Study.

Diffusion kurtosis (DK) imaging (DKI), a type of restricted diffusion-weighted imaging, has been reported to be useful for tumor diagnoses in clinical studies. We developed a software program to simultaneously create DK images with apparent diffusion coefficient (ADC) maps and conducted an initial clinical study. Multi-shot echo-planar diffusion-weighted images were obtained at b-values of 0, 400, and 800 sec/mm2 for simple DKI, and DK images were created simultaneously with the ADC map. The usefulness of the DK image and ADC map was evaluated using a pixel analysis of all pixels and a median analysis of the pixels of each case. Tumor and normal tissues differed significantly in both pixel and median analyses. In the pixel analysis, the area under the curve was 0.64 for the mean kurtosis (MK) value and 0.77 for the ADC value. In the median analysis, the MK value was 0.74, and the ADC value was 0.75. The MK and ADC values correlated moderately in the pixel analysis and strongly in the median analysis. Our simple DKI system created DK images simultaneously with ADC maps, and the obtained MK and ADC values were useful for differentiating head and neck tumors from normal tissue.

Dantrolene reduces platelet-derived growth factor (PDGF)-induced vascular smooth muscle cell proliferation and neointimal formation following vascular injury in mice.

Dantrolene is a ryanodine receptor blocker that is used clinically for treatment of malignant hyperthermia. This study was conducted using murine aortic vascular smooth muscle cells (MOVAS) and a mouse arterial injury model to investigate the inhibitory effect of dantrolene on smooth muscle cell proliferation and migration. We investigated whether dantrolene suppressed platelet-derived growth factor (PDGF)-induced vascular smooth muscle cell proliferation and migration in vitro. The effect of dantrolene on smooth muscle phenotype was evaluated using immunostaining. In addition, smooth muscle cell proliferation and phenotype switching were tested by applying dantrolene around blood vessels using a mouse arterial injury model. Dantrolene inhibited PDGF-induced cell proliferation and migration of MOVAS. Dantrolene also inhibited the switch from contractile to synthetic phenotype both in vitro and in vivo. Dantrolene is effective at inhibiting vascular smooth muscle cell proliferation, migration, and neointimal formation following arterial injury in mice.

Endoplasmic reticulum stress promotes nuclear translocation of calmodulin, which activates phenotypic switching of vascular smooth muscle cells.

BACKGROUND AND AIMS: Increased endoplasmic reticulum (ER) stress is strongly associated with the phenotypic switching of vascular smooth muscle cells (VSMCs) in atherosclerosis. Depletion of the ER Ca2+ content is one of the leading causes of increased ER stress in VSMCs. The ryanodine receptor (RyR) is a major Ca2+ release channel in the sarcoplasmic reticulum membrane. Calmodulin (CaM), which binds to RyR (CaM-RyR), stabilizes the closed state of RyR in the resting state in normal cells. Defective CaM-RyR interactions can cause abnormal Ca2+ leakage through RyR, resulting in decreased Ca2+ content, indicating that defective CaM-RyR interactions may be a cause of increased ER stress. Herein, we used a mouse VSMCs to assess whether CaM-RyR plays a pivotal role in VSMCs phenotypic switching, which is caused by ER stress, and whether dantrolene, which enhances the binding affinity of CaM to RyR, affects VSMCs phenotypic switching. METHODS AND RESULTS: Tunicamycin was used to mimic ER stress in vitro. Tunicamycin-induced ER stress caused CaM to dissociate from the RyR and translocate to the nucleus, which stimulated phenotypic switching through the activation of MEF2 and KLF5. Dantrolene suppressed tunicamycin-induced apoptosis, ER stress (restoring ER Ca2+ content), and phenotypic switching of VSMCs. Suramin, which directly unbinds CaM from RyR, promoted nuclear CaM accumulation with parallel VSMCs phenotypic switching, and dantrolene prevented these effects. CONCLUSIONS: We observed that ER stress causes CaM translocation to the nucleus and drives the phenotypic switching of VSMCs. Thus, restoration of the binding affinity of CaM to RyR may be a therapeutic target for atherosclerosis.

Asymptomatic latent Wolff-Parkinson-White syndrome detected during school heart screening: a case Report.

In latent Wolff-Parkinson-White syndrome, ventricular pre-excitation is inapparent during sinus rhythm but carries the same possibility of sudden cardiac death and palpitations as overt Wolff-Parkinson-White syndrome. It is difficult to diagnose latent Wolff-Parkinson-White syndrome when a patient does not have syncope or palpitations. We report the case of an asymptomatic patient with latent Wolff-Parkinson-White syndrome detected on school heart screening using subtle electrocardiography findings.

Dantrolene prevents ventricular tachycardia by stabilizing the ryanodine receptor in pressure- overload induced failing hearts.

Aberrant Ca2+ release from cardiac ryanodine receptors (RyR2) has been shown to be one of the most important causes of lethal arrhythmia in various types of failing hearts. We previously showed that dantrolene, a specific agent for the treatment of malignant hyperthermia, inhibits Ca2+ leakage from the RyR2 by correcting the defective inter-domain interaction between the N-terminal (1-619 amino acids) and central (2000-2500 amino acids) domains of the RyR2 and allosterically enhancing the binding affinity of calmodulin to the RyR2 in diseased hearts. In this study, we examined whether dantrolene inhibits this Ca2+ leakage, thereby preventing the pharmacologically inducible ventricular tachycardia in ventricular pressure-overloaded failing hearts. Ventricular tachycardia (VT) was easily induced after an injection of epinephrine in mice after 8 weeks of transverse aortic constriction-induced pressure-overload. Pretreatment with dantrolene almost completely inhibited the pharmacologically inducible VT. In the presence of dantrolene, the occurrence of both Ca2+ sparks and spontaneous Ca2+ transients was inhibited, which was associated with enhanced calmodulin binding affinity to the RyR2. These results suggest that dantrolene could be a new potent agent in the treatment of lethal arrhythmia in cases of acquired heart failure.

Nuclear translocation of calmodulin in pathological cardiac hypertrophy originates from ryanodine receptor bound calmodulin.

In cardiac myocytes Calmodulin (CaM) bound to the ryanodine receptor (RyR2) constitutes a large pool of total myocyte CaM, but the CaM-RyR2 affinity is reduced in pathological conditions. Knock-in mice expressing RyR2 unable to bind CaM also developed hypertrophy and early death. However, it is unknown whether CaM released from this RyR2-bound pool participates in pathological cardiac hypertrophy. We found that angiotensin II (AngII) or phenylephrine (PE) both cause CaM to dissociate from the RyR2 and translocate to the nucleus. To test whether this nuclear CaM accumulation depends on CaM released from RyR2, we enhanced CaM-RyR2 binding affinity (with dantrolene), or caused CaM dissociation from RyR2 (using suramin). Dantrolene dramatically reduced AngII- and PE-induced nuclear CaM accumulation. Conversely, suramin enhanced nuclear CaM accumulation. This is consistent with nuclear CaM accumulation coming largely from the CaM-RyR2 pool. CaM lacks a nuclear localization signal (NLS), but G-protein coupled receptor kinase 5 (GRK5) binds CaM, has a NLS and translocates like CaM in response to AngII or PE. Suramin also promoted GRK5 nuclear import, and caused nuclear export of histone deacetylase 5 (HDAC5). Dantrolene prevented these effects. After 2-8 weeks of pressure overload (TAC) CaM binding to RyR2 was reduced, nuclear CaM and GRK5 were both elevated and there was enhanced nuclear export of HDAC5. Stress (acute AngII or TAC) causes CaM dissociation from RyR2 and translocation to the nucleus with GRK5 with parallel HDAC5 nuclear export. Thus CaM dissociation from RyR2 may be an important step in driving pathological hypertrophic gene transcription.

Safety and Efficacy of Radiofrequency Catheter Ablation for Tachyarrhythmia in Children Weighing Less Than 10 kg.

An increasing number of children are undergoing radiofrequency catheter ablation (RFCA) for tachyarrhythmia. However, infants and toddlers undergoing RFCA are often resistant to medication or need to eliminate arrhythmia substrate, and the risks of RFCA complications are still high in infants and toddlers. From April 2008 and December 2016, 285 children who underwent radiofrequency catheter ablation (RFCA) were stratified according to body weight (group A, less than 10 kg, n = 22; group B, over 10 kg, n = 263) and the clinical features of RFCA were retrospectively reviewed in these groups. Indications for RFCA included drug-refractory tachyarrhythmia or symptomatic tachycardia and tachycardia-induced cardiomyopathy. The acute success rate in this group was 90.9%, with a relatively low recurrence rate (15.0%) after 7.0 ± 1.6 years follow-up. We performed RFCA using only 2-4 catheters in all cases. Major complications included complete right bundle branch block in one patient. No significant differences in rates of success, recurrence, or complications were noted between children weighing less and more than 10 kg. RFCA is safe and efficacious for tachyarrhythmia even in patients weighing less than 10 kg.

Feasibility and safety of transseptal puncture procedures for radiofrequency catheter ablation in small children weighing below 30 kg: single-centre experience.

AIMS: Transseptal puncture (TSP) has become a common approach in catheter ablation of arrhythmia originating from the left atrium. In paediatric patients, however, TSP can be a challenge due to narrower access vessels and small left atrial size, and the safety of TSP in smaller children is yet to be understood. The purpose of this study was to retrospectively evaluate the feasibility and safety of TSP in children weighing below 30 kg. METHODS AND RESULTS: Among 655 paediatric patients who underwent catheter ablation of arrhythmia between July 2009 and April 2015, 43 cases having structurally normal hearts, weighing <30 kg and requiring TSP were included in the study. Age, height, body weight, diagnosis, and complications during TSP and catheter ablation were evaluated. The median age, height, and body weight (range) were 7.0 years (0.3-11.1), 116.8 cm (54.0-138.4 cm) and 21.5 kg (4.3-29.6 kg), respectively. Diagnosis included manifest (n = 27; 62.8%) and concealed accessory pathway (n = 14; 32.6%) and atrial tachycardia (n = 2; 4.6%). In 10 cases (23.2%), TSP using radiofrequency energy was performed. None of the patients had major complications. Pericardial effusion was recorded as a minor complication in one patient (2.3%). CONCLUSION: TSP was feasible, safe, and of low risk of complications in children weighing <30 kg.

Early Postoperative Outcomes of Periprosthetic Femoral Fracture in Patients Over 90 Years of Age.

The number of total hip arthroplasty and bipolar hemiarthroplasty is increasing because of their good clinical outcomes and the aging population. Consequently, the incidence of periprosthetic femoral fractures (PFFs) is expected to increase in older patients with osteoporosis. Surgery is the first choice of treatment for PFF, except in Vancouver Type A fractures. However, surgical treatment of PFF, including open reduction and internal fixation (ORIF) and revision arthroplasty, is highly invasive, and high mortality rates have been reported. The indication for ORIF for PFF in very elderly patients at a high risk of complications remains controversial, and postoperative outcomes are uncertain. This study aimed to evaluate the postoperative outcomes of ORIF for PFF in elderly patients. We retrospectively analyzed four females with a mean age of 90.7 years (91-92 years) who underwent ORIF for PFF at our institution from September 2014 to January 2023. No cases of American Society of Anesthesiologists (ASA) grade 3 or higher were found. Three patients were classified as Vancouver Type B1, and one was classified as Vancouver Type C. Cementless stems were used in primary surgeries in all cases. To measure clinical outcomes, we investigated the patient's walking ability at 30 days, three months postoperatively, and the final follow-up. Mortality was assessed during the follow-up period. One patient could walk without walking aids preoperatively, two used a walking stick, and one used a walker. All patients remained hospitalized and underwent gait training with a walker at 30 days follow-up; however, at three months postoperatively and the final follow-up, no patient was unable to walk. No deaths occurred within one month of surgery. Three deaths occurred during follow-up: one within six months, one within one year, and one within five years of surgery. The postoperative ORIF results for PFF in patients aged > 90 years showed no fatal perioperative complications and low mortality within 30 days postoperatively. These results suggest that ORIF for PFF can be considered for elderly patients if the preoperative ASA grade is relatively low.

Manual on the proper use of the 211At-labeled PSMA ligand ([211At]PSMA-5) for clinical trials of targeted alpha therapy (1st edition).

Recently, an astatine-labeled prostate-specific membrane antigen (PSMA) ligand ([211At]PSMA-5) has been developed for the targeted alpha therapy of patients with prostate cancer. This manual delineates its physicochemical characteristics to assist healthcare professionals in understanding the α-ray-emitting drug of [211At]PSMA-5 when administered to patients. The safety considerations regarding the handling and use of this drug in clinical trials are outlined, based on the proper usage manual of previous studies. The dose limits, as defined by the guidelines of the International Commission on Radiological Protection (ICRP) and the International Atomic Energy Agency (IAEA), are assessed for patients' caregivers and the general public. According to the calculations provided in this manual, clinical trials involving [211At]PSMA-5 can be safely conducted for these populations even if patients are released after its administration. Moreover, this manual provides comprehensive guidance on the handling of [211At]PSMA-5 for healthcare facilities, and compiles a list of precautionary measures to be distributed among patients and their caregivers. While this manual was created by a research team supported by Ministry of Health, Labour, and Welfare in Japan and approved by Japanese Society of Nuclear Medicine, its applicability extends to healthcare providers in other countries. This manual aims to facilitate conducting clinical trials using [211At]PSMA-5 in patients with prostate cancer.

Enhancing Diagnostic Precision: Evaluation of Preprocessing Filters in Simple Diffusion Kurtosis Imaging for Head and Neck Tumors.

Background: Our initial clinical study using simple diffusion kurtosis imaging (SDI), which simultaneously produces a diffusion kurtosis image (DKI) and an apparent diffusion coefficient map, confirmed the usefulness of SDI for tumor diagnosis. However, the obtained DKI had noticeable variability in the mean kurtosis (MK) values, which is inherent to SDI. We aimed to improve this variability in SDI by preprocessing with three different filters (Gaussian [G], median [M], and nonlocal mean) of the diffusion-weighted images used for SDI. Methods: The usefulness of filter parameters for diagnosis was examined in basic and clinical studies involving 13 patients with head and neck tumors. Results: The filter parameters, which did not change the median MK value, but reduced the variability and significantly homogenized the MK values in tumor and normal tissues in both basic and clinical studies, were identified. In the receiver operating characteristic curve analysis for distinguishing tumors from normal tissues using MK values, the area under curve values significantly improved from 0.627 without filters to 0.641 with G (σ = 0.5) and 0.638 with M (radius = 0.5). Conclusions: Thus, image pretreatment with G and M for SDI was shown to be useful for improving tumor diagnosis in clinical practice.

Time elapsed from definitive diagnosis to surgery for osteonecrosis of the femoral head: a nationwide observational study in Japan.

OBJECTIVES: This study documents the time elapsed from the diagnosis of osteonecrosis of the femoral head (ONFH) to surgery, exploring the factors that influence ONFH severity. DESIGN: Retrospective observational study of a nationwide database. SETTING: The Kaplan-Meier method with log-rank tests was applied to examine the period from definitive diagnosis of ONFH to surgery using any surgery as the end point. For bilateral cases, the date of the first surgery was the endpoint. PARTICIPANTS: This study included 2074 ONFH cases registered in 34 university hospitals and highly specialised hospitals of the multicentre sentinel monitoring system of the Japanese Investigation Committee between 1997 and 2018. MAIN OUTCOME MEASURE: The primary outcome was the time from diagnosis to surgery. The secondary outcome was the proportion of subjects remaining without surgery at 3, 6 and 9 months, and at 1, 2 and 5 years after diagnosis. RESULTS: The median time to surgery was 9 months (IQR 4-22 months) after diagnosis of ONFH. The time to surgery was significantly shorter in the alcohol alone group and the combined corticosteroid and alcohol group than in the corticosteroid alone group (p=0.018 and p<0.001, respectively), in early stage ONFH with no or mild joint destruction (stages II and III, p<0.001), and with joint preserving surgery (p<0.001). The proportion without surgery was 75.8% at 3 months, 59.6% at 6 months, 48.2% at 9 months, 40.5% at 1 year, 22.2% at 2 years and 8.3% at 5 years. CONCLUSION: ONFH has been considered to be an intractable disease that often requires surgical treatment, but the fact that surgery was performed in more than half of the patients within 9 months from diagnosis suggests severe disease with a significant clinical impact. TRIAL REGISTRATION NUMBER: Chiba University ID1049.

Dantrolene improves left ventricular diastolic property in mineralcorticoid-salt-induced hypertensive rats.

Left ventricular (LV) diastolic dysfunction is increasingly common in heart failure with preserved ejection fraction (HFpEF), and new drug therapy is desired. We recently reported that dantrolene (DAN) attenuates pressure-overload induced hypertrophic signaling through stabilization of tetrameric structure of cardiac ryanodine receptor (RyR2). Because cardiac hypertrophy substantially affects LV diastolic properties, we investigated the effect of DAN on LV diastolic properties in mineralocorticoid-salt-induced hypertensive rat model exhibiting the HFpEF phenotype. Male Sprague-Dawley (SD) rats (8 weeks old) received an uninephrectomy (UNX), subcutaneous implantation of a 200 mg pellet of deoxycorticosterone acetate (DOCA), and 0.9% NaCl water (UNX + DOCA-salt). UNX, a control pellet, and water without NaCl served as controls (UNX control). The effect of oral administration of 100 mg/kg/d DAN was examined in UNX control and UNX + DOCA-salt groups (UNX + DAN and UNX + DOCA-salt + DAN). UNX + DOCA-salt treatment resulted in mild hypertension. Chronic administration of DAN to UNX + DOCA-salt rats (UNX + DOCA-salt + DAN) did not affect blood pressure. DAN treatment increased the mitral annular early relaxation velocity in the UNX + DOCA-salt group. The size of cardiomyocytes increased in the UNX + DOCA-salt group, whereas the increase was suppressed by DAN treatment. LV fibrotic area was significantly smaller in the UNX + DOCA-salt + DAN group than in the UNX + DOCA-salt group (2.0 ± 0.2% vs 4.0 ± 0.4%). The LV chamber stiffness significantly increased in the UNX + DOCA-salt group, whereas the increase was suppressed by DAN treatment. DAN treatment normalized the CaM-RyR2 interaction and inhibited aberrant Ca2+ release. DAN improved left ventricular diastolic properties with respect to both myocardial relaxation and chamber stiffness. DAN may be a new treatment option for HFpEF.

Characteristic Mean Kurtosis Values in Simple Diffusion Kurtosis Imaging of Dentigerous Cysts.

We evaluated the usefulness of simple diffusion kurtosis (SD) imaging, which was developed to generate diffusion kurtosis images simultaneously with an apparent diffusion coefficient (ADC) map for 27 cystic disease lesions in the head and neck region. The mean kurtosis (MK) and ADC values were calculated for the cystic space. The MK values were dentigerous cyst (DC): 0.74, odontogenic keratocyst (OKC): 0.86, ranula (R): 0.13, and mucous cyst (M): 0, and the ADC values were DC: 1364 × 10-6 mm2/s, OKC: 925 × 10-6 mm2/s, R: 2718 × 10-6 mm2/s, and M: 2686 × 10-6 mm2/s. The MK values of DC and OKC were significantly higher than those of R and M, whereas their ADC values were significantly lower. One reason for the characteristic signal values in diffusion-weighted images of DC may be related to content components such as fibrous tissue and exudate cells. When imaging cystic disease in the head and neck region using SD imaging, the maximum b-value setting at the time of imaging should be limited to approximately 1200 s/mm2 for accurate MK value calculation. This study is the first to show that the MK values of DC are characteristically higher than those of other cysts.

Treating to target matrix metalloproteinase 3 normalisation together with disease activity score below 2.6 yields better effects than each alone in rheumatoid arthritis patients: T-4 Study.

OBJECTIVES: To assess whether therapy to achieve both a disease activity score in 28 joints (DAS28) less than 2.6 and matrix metalloproteinase (MMP) 3 normalisation offers better outcomes than either target alone in early rheumatoid arthritis (RA) at 56 weeks: Treating to Twin Targets (T-4) Study. METHODS: 243 early RA patients were randomly allocated to one of four strategy groups: routine care (R group; n=62); DAS28-driven therapy (D group; n=60); MMP-3-driven therapy (M group; n=60); or both DAS28 and MMP-3-driven therapy group (twin; T group; n=61). Medication was started with sulfasalazine (1 g/day) in all intervention groups. Targets were DAS28 less than 2.6 for the D group, MMP-3 normalisation for the M group and both DAS28 less than 2.6 and MMP-3 normalisation for the T group. If the value in question did not fall below the previously measured level, medication was intensified, including methotrexate, other disease-modifying antirheumatic drugs and biological agents. Primary, secondary and outcome measures consisted of the proportions of patients showing clinical remission (DAS28 <2.6), radiographic non-progression (Δmodified total Sharp score ≤0.5), normal physical function (modified health assessment questionnaire score 0), or comprehensive disease remission defined as the combination of clinical remission, radiographic non-progression and normal physical function. RESULTS: Clinical remission at 56 weeks was achieved by more patients in the T group (56%) than in the R group (p<0.0005) or M group (p<0.0005). CONCLUSIONS: Results of the T-4 Study reveal that a twin target strategy can achieve a high clinical remission rate in early RA.

An infant with heart failure due to ventricular dyssynchrony and refractory tachycardia caused by a right anterolateral accessory pathway.

Wolff-Parkinson-White syndrome is associated with heart failure (HF) mainly via tachycardia. Several case report series have suggested dyssynchrony due to an accessory pathway as a possible cause of HF even in the absence of tachyarrhythmias. The role of cardiac resynchronization in the suppression of anterograde conduction of accessory pathways by catheter ablation or pharmacotherapy in such patients remains unclear, especially in the pediatric population. We describe an infant case with HF due to ventricular dyssynchrony and refractory tachycardia caused by a right anterolateral accessory pathway. Cardiac resynchronization either by catheter ablation or amiodarone appears to be of value in such cases.

Manual on the proper use of meta-[211At] astato-benzylguanidine ([211At] MABG) injections in clinical trials for targeted alpha therapy (1st edition).

In this manuscript, we present the guideline for use of meta-[211At] astatobenzylguanidine ([211At] MABG), a newly introduced alpha emitting radiopharmaceutical to the up-coming World's first clinical trial for targeted alpha therapy (TAT) at Fukushima Medical University in Japan, focusing on radiation safety issues in Japan. This guideline was prepared based on a study supported by the Ministry of Health, Labour, and Welfare, and approved by the Japanese Society of Nuclear Medicine on Oct. 5th, 2021. The study showed that patients receiving [211At] MABG do not need to be admitted to a radiotherapy room and that TAT using [211At] MABG is possible on an outpatient basis. The radiation exposure from the patient is within the safety standards of the ICRP and IAEA recommendations for the general public and caregivers or patient's family members. In this guideline, the following contents are also included: precautions for patients and their families, safety management associated with the use of [211At] MABG, education and training, and disposal of medical radioactive contaminants. TAT using [211At] MABG in Japan should be carried out according to this guideline. Although this guideline is based on the medical environment and laws and regulations in Japan, the issues for radiation protection and evaluation methodology presented in this guideline are useful and internationally acceptable as well.