Phase 3 immunogenicity and safety study of a tick-borne encephalitis vaccine in healthy Japanese participants 1 year of age and older.

BACKGROUND: Tick-borne encephalitis (TBE) virus infects the central nervous system and may lead to severe neurological complications or death. This study assessed immunogenicity, safety, and tolerability of TBE vaccine in Japanese participants 1 year of age and older. METHODS: This phase 3, multicenter, single-arm, open-label study was conducted in Japanese adult (≥ 16 years) and pediatric (1-< 16 years) populations. Participants received a single 0.5-mL (adult) or 0.25-mL (pediatric) dose of TBE vaccine at each of 3 visits. The primary endpoint was the proportion of participants who were seropositive (neutralization test [NT] titer ≥ 1:10) 4 weeks after Dose 3. Secondary and exploratory endpoints included NT seropositivity rates 4 weeks after Dose 2, immunoglobulin G (IgG) seropositivity 4 weeks after Doses 2 and 3, NT geometric mean titers (GMTs), IgG geometric mean concentrations (GMCs), and geometric mean fold rises. Primary safety endpoints were frequencies of local reactions, systemic events, adverse events (AEs), and serious AEs. RESULTS: Among 100 adult and 65 pediatric participants, 99.0 % and 100.0 % completed the study, respectively. NT seropositivity was achieved in 98.0 % adult and 100.0 % pediatric participants after Dose 3; seropositivity after Dose 2 was 93.0 % and 92.3 %, respectively. In both age groups, IgG seropositivity was ≥ 90.0 % and ≥ 96.0 % after Doses 2 and 3, respectively; GMTs and GMCs were highest 4 weeks after Dose 3. Reactogenicity events were generally mild to moderate in severity and short-lived. AEs were reported by 15.0 % (adult) and 43.1 % (pediatric) of participants. No life-threatening AEs, AEs leading to discontinuation, immediate AEs, related AEs, or deaths were reported. No serious AEs were considered related to TBE vaccine. CONCLUSIONS: TBE vaccine elicited robust immune responses in Japanese participants 1 year of age and older. The 3-dose regimen was safe and well tolerated, and findings were consistent with the known safety profile of this TBE vaccine. CLINICALTRIALS: gov: NCT04648241.

Transcatheter coil embolization for large pulmonary arteriovenous fistulae through an artificial tricuspid ball valve.

Pulmonary arteriovenous fistulae (PAFs) occur congenitally or are acquired. A PAF can cause hypoxemia, sudden death from rupture, abscess formation, and embolism. Treatment for PAF is transcatheter embolization or surgery. Transcatheter embolization is the first choice of treatment; however, this treatment is impossible to perform if a patient has had tricuspid or pulmonary valve replacement. In this paper, we describe a case of PAFs complicated with tricuspid valve replacement with a ball valve (which had been performed 40 years earlier) that was treated with transcatheter embolization. .

Multiple Synchronous Sporadic Gastrointestinal Stromal Tumors in the Stomach and Jejunum.

A 77-year-old patient was admitted to our hospital for the further examination of melena. A computed tomography scan detected two submucosal tumors (SMTs) in the stomach and jejunum. Double-balloon endoscopy revealed the presence of a delle on the jejunal SMT, suggesting that the SMT was the origin of the gastrointestinal bleeding. Both tumors were surgically resected and subsequently diagnosed via histology as gastrointestinal stromal tumors (GISTs). Furthermore, the two GISTs had different mutations in the c-kit gene, suggesting that they were derived from different clonal origins. This report depicts an extremely rare case of multiple synchronous sporadic GISTs in the stomach and jejunum.

Aortic Regurgitation Presenting with Recurrent Detachment of a Prosthetic Valve, as the First Presenting Symptom of Cardiovascular Behçet's Disease.

A 33-year-old man with severe aortic regurgitation underwent initial aortic valve replacement (AVR). During the 2 years after AVR, 3 reoperations for prosthetic valve detachment were required. During hospitalization, he had no typical clinical findings, with the exception of a persistent inflammatory reaction; a pseudo-aneurysm around the Bentall graft developed 27 days after the 4th operation. This unique clinical course suggested the possibility of Behçet's disease. In the 8 years of follow-up after the administration of prednisolone, the pseudo-aneurysm did not become enlarged and the detachment of the prosthetic valve was not observed. We herein present a case of cardiovascular Behçet's disease, with a review of the literature.

Failing Left Ventricles Have an Enhanced Post-Stimulation Potentiation Despite Their Impaired Force Frequency Relationship.

The left ventricular contractile force (LV dP/dtmax) of patients with left ventricular systolic dysfunction does not increase effectively with an increase in heart rate. In other words, their force-frequency relationship (FFR) is impaired. However, it is unknown whether a longer coupling interval subsequent to tachycardia causes a stronger contraction (poststimulation potentiation, PSP) in a rate-dependent manner.In 16 patients with idiopathic dilated cardiomyopathy (DCM) (48 ± 2 years old, LVEF 30 ± 10%) and 6 control patients (58 ± 4 years old, LVEF 70 ± 7%), FFR was assessed by right atrial pacing using a micro-manometer-tipped catheter. At each pacing rate, the increase of LV dP/dtmax over basal LV dP/dt (ΔFFR) and the increase of LV dP/dtmax of the first beat after pacing cessation over LV dP/dtmax during pacing (ΔPSP) were evaluated.Patients with DCM had smaller LV dP/dtmax at baseline (872 ± 251 versus 1370 ± 123 mmHg/second, P = 0.0002) and developed smaller ΔFFR (eg, at 120/minute, 77 ± 143 versus 331 ± 131 mmHg/second, P = 0.0011). In contrast, they showed a rate-dependent increase of LV dP/dtmax of PSP and had greater ΔPSP (eg, at 120/minute, 294 ± 173 versus -152 ± 131 mmHg/second, P < 0.0001).Failing left ventricles develop little contractile force during tachycardia despite their rate-dependent enhancement in post-stimulation potentiation, suggesting that refractoriness of contractile force underlies impaired FFR.

Elevated Endomyocardial Biopsy Macrophage-Related Markers in Intractable Myocardial Diseases.

Tissue macrophages can be activated by endogenous danger signals released from cells that are stressed or injured, leading to infiltration of inflammatory macrophages and neutrophils. We postulated that macrophage-related markers might be closely associated with the existence of endogenous danger signals, reflecting ongoing tissue injury in the absence of foreign substances. This study was designed to assess the ability of macrophage-related markers in endomyocardial biopsies to predict ongoing cardiac injury in non-inflammatory myocardial diseases. We examined levels of macrophage-related markers (CD68, CD163, CD45) in endomyocardial biopsies from patients (n = 86) with various myocardial diseases by quantitative reverse transcription-polymerase chain reaction (n = 78) and immunohistochemistry (n = 56). Thirty-three patients without inflammatory cardiac disease such as myocarditis and sarcoidosis were classified as "improved" or "non-improved" defined as a 10% increase in left ventricular ejection fraction by echocardiograph and a value greater than 30% at the time of follow-up. All macrophage-related (MacR) markers levels were not higher in non-improved dilated cardiomyopathy (DCM) patients than improved patients. However, patients with cardiac amyloidosis, cardiac Fabry disease, mitochondrial cardiomyopathy, and biventricular arrhythmogenic right ventricular cardiomyopathy (ARVC), which were categorized as "non-improvement diseases," had elevated macrophage-related markers compared to improved patients. Macrophage-related markers levels were increased in endomyocardial biopsy samples of patients with intractable myocardial diseases such as amyloidosis, mitochondrial disease, Fabry disease, and biventricular ARVC.

Liver congestion in heart failure contributes to inappropriately increased serum hepcidin despite anemia.

Hepcidin is a key regulator of mammalian iron metabolism and mainly produced by the liver. Hepcidin excess causes iron deficiency and anemia by inhibiting iron absorption from the intestine and iron release from macrophage stores. Anemia is frequently complicated with heart failure. In heart failure patients, the most frequent histologic appearance of liver is congestion. However, it remains unclear whether liver congestion associated with heart failure influences hepcidin production, thereby contributing to anemia and functional iron deficiency. In this study, we investigated this relationship in clinical and basic studies. In clinical studies of consecutive heart failure patients (n = 320), anemia was a common comorbidity (41%). In heart failure patients without active infection and ongoing cancer (n = 30), log-serum hepcidin concentration of patients with liver congestion was higher than those without liver congestion (p = 0.0316). Moreover, in heart failure patients with liver congestion (n = 19), the anemia was associated with the higher serum hepcidin concentrations, which is a type of anemia characterized by induction of hepcidin. Subsequently, we produced a rat model of heart failure with liver congestion by injecting monocrotaline that causes pulmonary hypertension. The monocrotaline-treated rats displayed liver congestion with increase of hepcidin expression at 4 weeks after monocrotaline injection, followed by anemia and functional iron deficiency observed at 5 weeks. We conclude that liver congestion induces hepcidin production, which may result in anemia and functional iron deficiency in some patients with heart failure.

Electrical transport properties of small diameter single-walled carbon nanotubes aligned on ST-cut quartz substrates.

A method is introduced to isolate and measure the electrical transport properties of individual single-walled carbon nanotubes (SWNTs) aligned on an ST-cut quartz, from room temperature down to 2 K. The diameter and chirality of the measured SWNTs are accurately defined from Raman spectroscopy and atomic force microscopy (AFM). A significant up-shift in the G-band of the resonance Raman spectra of the SWNTs is observed, which increases with increasing SWNTs diameter, and indicates a strong interaction with the quartz substrate. A semiconducting SWNT, with diameter 0.84 nm, shows Tomonaga-Luttinger liquid and Coulomb blockade behaviors at low temperatures. Another semiconducting SWNT, with a thinner diameter of 0.68 nm, exhibits a transition from the semiconducting state to an insulating state at low temperatures. These results elucidate some of the electrical properties of SWNTs in this unique configuration and help pave the way towards prospective device applications.

Relative refractoriness of left ventricular contraction underlies human tachycardia-induced mechanical and electrical alternans.

BACKGROUND: Mechanical alternans (MA) and electrical alternans (EA) are predictors of cardiac events. Experimental studies have suggested that refractoriness of calcium cycling underlies these cardiac alternans. However, refractoriness of left ventricular contraction has not been examined in patients with cardiac alternans. METHODS: In 51 patients with miscellaneous heart diseases, incremental right atrial pacing was performed to induce MA and EA. MA was quantified by alternans amplitude (AA: the difference between left ventricular dP/dt of a strong beat and that of a weak beat), and AA at 100/min (AA100) and maximal AA (AAmax) were measured. EA was defined as alternation of T wave morphology in 12-lead electrocardiogram. Relative refractoriness of left ventricular contraction was examined by drawing the mechanical restitution curve under a basal coupling interval (BCL) of 600 ms (100/min) and was assessed by the slope at BCL (Δmechanical restitution). Postextrasystolic potentiation (PESP) was also examined and the slope of PESP curve (ΔPESP) was assessed as a property to alternate strong and weak beats. RESULTS: MA and EA were induced in 19 patients and in none at 100/min or less, and at any heart rate in 32 and in 10, respectively. AA100 and AAmax correlated positively with Δmechanical restitution and negatively with ΔPESP. Patients with EA had a significantly larger Δmechanical restitution and a significantly larger absolute value of ΔPESP than those without. CONCLUSIONS: In patients with MA and EA, the left ventricular contractile force during tachycardia is under relative refractoriness and prone to cause large fluctuation of contractile force.

A mutant mRNA expression in an endomyocardial biopsy sample obtained from a patient with a cardiac variant of Fabry disease caused by a novel acceptor splice site mutation in the invariant AG of intron 5 of the α-galactosidase A gene.

We herein describe the case of a 58-year-old man who presented with dilated-phase hypertrophic cardiomyopathy (HCM) and required an implantable cardioverter defibrillator implant. Subsequently, the patient was diagnosed with Fabry disease (FD), which was suspected based on the results of an endomyocardial biopsy and diagnosed following demonstration of deficient α-galactosidase A (GLA) activity. Molecular studies showed a novel point mutation in the 3' splice site consensus sequence of intron 5 in the gene encoding GLA that created a new splicing site, resulting in the expression of mutant mRNA. FD should be considered a cause of HCM in patients with severe tachyarrhythmia without other remarkable manifestations of FD.

Effects of the tulobuterol patch on the treatment of acute asthma exacerbations in young children.

The tulobuterol patch (TP) is a beta(2)-adrenergic agonist with a favorable pharmacokinetic profile used for asthma management in Japan. Because it contains tulobuterol in a molecular, crystallized form that is gradually absorbed percutaneously, TP exerts a prolonged bronchodilator effect exceeding 24 hours. Although it is a well-established treatment for asthma and wheezing, few studies have investigated whether it can reduce or prevent the symptoms associated with upper respiratory tract infections (URTIs) in young children. This study evaluated the effect of TP on the long-term management of asthma in young children. In this 1-year, randomized, multicenter, double-blind, placebo-controlled study, children aged 0.5-3 years old with mild-to-moderate persistent asthma were treated with either TP or placebo patch. The parents/guardians applied the TP or placebo patch to their children after URTI symptoms appeared. Respiratory symptoms were recorded daily during the 1-year observation period. Overall, 86 patients were enrolled and 80 were treated and analyzed in this study. All patients had been treated with anti-inflammatory drugs before enrollment. The time to symptom resolution was significantly shorter (p = 0.001) and the total respiratory symptom score (p = 0.0457) was significantly lower in the TP group than in the placebo group. In young children with mild-to-moderate asthma who had been treated with anti-inflammatory drugs, using the TP soon after the appearance of URTI symptoms led to quicker resolution of respiratory symptoms and lower respiratory symptom scores.

Effects of the tulobuterol patch on the treatment of acute asthma exacerbations in young children.

The tulobuterol patch (TP) is a beta2-adrenergic agonist with a favorable pharmacokinetic profile used for asthma management in Japan. Because it contains tulobuterol in a molecular, crystallized form that is gradually absorbed percutaneously, TP exerts a prolonged bronchodilator effect exceeding 24 hours. Although it is a well-established treatment for asthma and wheezing, few studies have investigated whether it can reduce or prevent the symptoms associated with upper respiratory tract infections (URTIs) in young children. This study evaluated the effect of TP on the long-term management of asthma in young children. In this 1-year, randomized, multicenter, double-blind, placebo-controlled study, children aged 0.5-3 years old with mild-to-moderate persistent asthma were treated with either TP or placebo patch. The parents/guardians applied the TP or placebo patch to their children after URTI symptoms appeared. Respiratory symptoms were recorded daily during the 1-year observation period. Overall, 86 patients were enrolled and 80 were treated and analyzed in this study. All patients had been treated with anti-inflammatory drugs before enrollment. The time to symptom resolution was significantly shorter (p = 0.001) and the total respiratory symptom score (p = 0.0457) was significantly lower in the TP group than in the placebo group. In young children with mild-to-moderate asthma who had been treated with anti-inflammatory drugs, using the TP soon after the appearance of URTI symptoms led to quicker resolution of respiratory symptoms and lower respiratory symptom scores.

Effects of nutritional supplementation combined with low-intensity exercise in malnourished patients with COPD.

STUDY OBJECTIVES: The first aim of this study was to investigate the effects of nutritional supplementation combined with low-intensity exercise on body components, exercise tolerance, and health-related quality of life (HRQOL) in malnourished patients with COPD. The second aim of this study was to examine the degree of systemic inflammation and the actual changes in levels of systemic CRP, TNFα, IL-6 and IL-8 actual changes after a combination of nutritional supplementation and low-intensity exercise in these patients. DESIGN: A prospective randomized trial. PATIENTS: Thirty-two moderate to severe, clinically stable malnourished COPD patients. METHODS: Patients were randomly divided into a nutritional supplementation with low-intensity exercise group and a control group. Lung function, maximum inspiratory and expiratory muscle force, the Chronic Respiratory Disease Questionnaire (CRQ), the 6-min walking distance (6MWD), and the Borg scale were measured at baseline and were re-assessed at 3 months after intervention. The degree of systemic inflammation and the changes in levels of systemic CRP, TNFα, IL-6 and IL-8 were assessed before and after a combination nutritional supplementation with low-intensity exercise. RESULTS: Body weight and FFM increased significantly after 12 weeks of nutritional supplementation therapy in patients with COPD. The dietary intake energy increased and the REE:REEpred ratio decreased significantly in the nutrition with low-intensity exercise group. PI(max), Quadriceps muscle force and the 6-min walking distance (6MWD) increased significantly from baseline through week 12. Health status, as assessed by CRQ, improved in the domains of dyspnea and total sores significantly in the nutrition with low-intensity exercise group after intervention. In this group, hsCRP, IL-6, IL-8, and TNFα, decreased significantly after intervention compared with the control group. CONCLUSIONS: The combination of nutritional supplementation with low-intensity exercise training was successful in increasing weight and energy intake as well as exercise capacity and health-related QOL in our patients. Moreover, REE and major inflammatory cytokines decreased significantly after nutritional supplementation with low-intensity exercise training. The present study results suggest a potential role for the combination of nutritional supplementation and low-intensity exercise in the management of malnourished patients with COPD.

Clustering trend of components of metabolic syndrome.

Hereby we report our observations derived from the study of a huge cross-sectional sample of the general population that metabolic risk factors (RFs) tend to cluster into metabolic syndrome (MS). The clustering trend was considered to be intensified with 4-5 RFs.

Cardiovascular risk factors are really linked in the metabolic syndrome: this phenomenon suggests clustering rather than coincidence.

BACKGROUND: The accumulation of cardiovascular risk factors can be seen in a single person but it needs to be determined if this occurs more frequently than might be explained by mere coincidence. METHODS: This study involved 119,412 adults: 41,819 males and 77,593 females, who were 40 years of age or older and who underwent an annual health examination. From the clinical and biochemical data, the actual prevalence of a combination of 3 or more factors: abnormal body mass index (> or =25.0), hypertension, high triglyceride (> or =150 mg/dl), low HDL cholesterol (<40 mg/dl) and abnormal fasting glucose metabolism (fasting blood sugar > or =110 mg/dl or HbA1c. > or =5.5%) was determined. Then, the prevalence of a corresponding combination of 3-5 factors was predicted from the prevalence of each factor on the assumption that their combination occurs as a result of coincidence. RESULTS: The criteria of metabolic syndrome (> or =3 risk factors) was met in 17,842 (14.9%) of the examinees. The actual prevalence of any combination of 3-5 factors of metabolic syndrome was more frequent than those expected to occur by coincidence (P < 0.001). When compared with the prevalence of the total examinees, the prevalence of obesity and insulin resistance was 2.5 and 2.9 times higher in metabolic syndrome compared to that in the total examinees but it was 1.7 to 2.1 times higher in hypertension and high triglyceride. The former two were clustering more than hypertension or high triglyceride in metabolic syndrome. Abnormal levels of serum creatinine and total cholesterol were found more often in metabolic syndrome. CONCLUSION: Combinations of risk factors of metabolic syndrome were found more frequently than coincidental phenomenon in the subjects from the general population. These finding suggest that these risk factors do cluster and obesity and insulin resistance were suggested to be linked with metabolic syndrome more than hypertension or high triglyceride.

Bovine 5-oxo-L-prolinase: simple assay method, purification, cDNA cloning, and detection of mRNA in the coronary artery.

RS-7897 is a novel antianginal nitrate containing an L-2-oxothiazolidine-4-carboxylic acid (OTCA) and unlike other organic nitrates does not induce nitrate tolerance. OTCA is known to be converted to L-cysteine (L-Cys) by rat 5-oxo-prolinase (5-OPase) and was detected in the plasma of RS-7897-treated dogs. Nitrate tolerance is considered to develop mainly through sulfhydryl depletion. We hypothesized that RS-7897-derived OTCA was converted into L-Cys by 5-OPase and supplied sulfhydryl groups in vascular smooth muscle cells, the targets of the nitrate. As the initial step for clarifying the presumed role of 5-OPase in RS-7897 metabolism, we established a non-radiochemical assay method highly specific for 5-OPase. Using this assay method, we purified 5-OPase from bovine kidney cytosol until homogeneous results were obtained in sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The catalytic activity of bovine 5-OPase to convert OTCA to L-Cys was confirmed, as was the case for the rat enzyme. Then the cDNA encoding bovine 5-OPase was cloned. The deduced amino acid sequence revealed that bovine 5-OPase was highly homologous to rat 5-OPase. Based on the bovine cDNA sequence, oligonucleotide primers were synthesized and used for RT-PCR. 5-OPase mRNA was significantly detected in the RT-PCR product of the bovine coronary artery, a major target organ of RS-7897. These results suggest that OTCA may be converted to L-Cys by 5-OPase in the mammalian coronary artery when treated with RS-7897, and thus generated L-Cys may reduce sulfhydryl depletion and contribute to the prevention of the development of nitrate tolerance.

Roles of FcgammaRIIB in nasal eosinophilia and IgE production in murine allergic rhinitis.

The low-affinity IgG Fc receptor, FcgammaRIIB, displays inhibitory potential in experimental models such as autoimmune diseases. However, whether this receptor is involved in the onset of allergic diseases remains unknown. This study examines the role of FcgammaRIIB in the initiation of allergic rhinitis in mice. Repeated intranasal sensitization with Schistosoma mansoni egg antigen (SEA) induced SEA-specific IgE and marked nasal eosinophilia in high-responder BALB/c mice. FcgammaRIIB gene-deficient (-/-) BALB/c mice displayed severe eosinophilia compared with that of wild-type counterparts. However, FcgammaRIIB -/- mice conversely produced less SEA-specific IgE. The production of interleukin (IL)-4 but not of IL-5 or IFN-gamma by nasal mononuclear cells was also decreased in FcgammaRIIB -/- mice, suggesting that the exacerbation of nasal eosinophila in FcgammaRIIB -/- mice is independent of the local IL-5 levels. The findings in low responder C57BL/6 mice were similar. In addition, nasal eosinophilia in FcgammaRIIB -/- mice passively sensitized with SEA was exacerbated, and conversely, specific IgE production was inhibited after a nasal challenge. These results suggest that FcgammaRIIB plays a regulatory role in the initiation of allergic rhinitis that is independent of either mouse strain or type of sensitization.

Clear cell carcinoma arising in a cesarean section scar. Report of a case with fine needle aspiration cytology.

BACKGROUND: Clear cell carcinoma arising in a cesarean section scar is an extremely rare disease. To the best of our knowledge, there is no published report on the aspiration cytology. CASE: A 56-year-old woman presented with a mass in a cesarean section scar. Initially an abdominal desmoid was considered, but the features of fine needle aspiration (FNA) cytology suggested an adenocarcinoma. The resected tumor was histologically composed of clear cell carcinoma showing cystic, solid and papillary patterns. CONCLUSION: FNA cytology of masses arising in a surgical scar can be a useful tool in obtaining an accurate pathologic diagnosis of a malignant neoplasm.