Decreased Stroke Volume and Venous Return in School Children with Postural Tachycardia Syndrome.

In postural tachycardia syndrome (POTS), a subtype of orthostatic intolerance, the changes in hemodynamics due to postural changes are poorly understood. We speculated that inappropriate venous return, which may occur in the upright position in patients with school-aged POTS, could be detected by echocardiography. Our prospective study was conducted with 100 POTS patients (45 boys and 55 girls), aged 13.1 ± 1.5 years and 52 age- and sex-matched healthy subjects (control). Echocardiography was performed in the supine and sitting positions. Cardiac parameters [stroke volume index, cardiac index, heart rate, and the maximum inferior vena cava diameter (max IVC)] were evaluated in addition to pulse pressure. Unlike the control subjects, POTS patients demonstrated decreased stroke volume index (P = 0.02) and max IVC (P < 0.01) irrespective of posture. The rates of max IVC change did not differ between control and POTS groups. The enrolled POTS patients were divided into two subgroups [dilatation (n = 57) and contraction (n = 43)] based on whether the change rate of max IVC was less than zero or not. The contraction group showed a significantly higher heart rate than the dilatation group with respect to posture (P = 0.03), indicating the poor response of peripheral vessels in the lower limbs only in the contraction group. In conclusion, echocardiographic assessment detected decreased stroke volume and venous return in POTS. The changes in max IVC in response to postural changes may indicate an underlying pathophysiology in POTS.

Effect of liraglutide on lipids in patients with type 2 diabetes: a pilot study.

The mechanism for the cholesterol-lowering effect of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) remains unknown in patients with type 2 diabetes. We evaluated the effect of liraglutide on serum lipid profiles, including cholesterol synthesis and absorption markers, during daily clinical practice in Japanese patients with type 2 diabetes. We enrolled 38 patients with type 2 diabetes mellitus who were not treated with a GLP-1 RA (≥20 years of age, HbA1c ≥6.5%). Liraglutide, a GLP-1 RA, was administered subcutaneously once a day for three months to these patients. Blood samples and body weights were collected at 0, 1, and 3 months. Total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) at 1 month, and non-high-density lipoprotein cholesterol (non-HDL-C) and calculated TC at 1 and 3 months, were decreased, while the cholesterol synthesis and cholesterol absorption markers were unchanged by this treatment. In patients with LDL-C levels over 100 mg/dL, LDL-C, non-HDL-C, TC, and calculated TC levels were decreased significantly by the treatment at 1 and 3 months, and the cholesterol absorption marker, campesterol, was decreased at 3 months. The administration of liraglutide for 3 months decreased non-HDL-C and calculated TC significantly, while the cholesterol synthesis and absorption markers were not changed by this treatment.

Improved cognitive apprenticeship clinical teaching after a faculty development program.

BACKGROUND: While it is well known that the cognitive apprenticeship is an effective workplace-based teaching approach for clinical teachers, the effects of faculty development (FD) have not been analyzed from that perspective. The purpose of this study was to investigate self-assessment by clinical teachers of their educational perceptions and behaviors after a FD program using the cognitive apprenticeship model. METHODS: Board-certified pediatricians who participated in a 3-day FD program on practical clinical teaching were asked to complete questionnaires. Fifty participants completed two questionnaires prior to and 3 and 6 months after the FD program: the first was on the participants' general perceptions and behaviors in relation to their own clinical education and the second was a self-assessment using the Maastricht Clinical Teaching Questionnaire (MCTQ) that was developed based on the cognitive apprenticeship model. RESULTS: The general survey demonstrated that 78% of the participants experienced positive changes in their educational perceptions 6 months after FD. Self-assessment using the MCTQ showed that the scores in the categories of "articulation," "exploration," and "safe learning environment" remained significantly improved 6 months after the FD program. CONCLUSIONS: The participants' self-perceived improvement in behaviors was sustainable for 6 months after participation the FD program. The results of the MCTQ show that through their experiences in the FD program, the participants seemingly transformed their clinical teaching to become interactive facilitators, encouraging self-directed learning. Our results also suggest that the MCTQ can be used for self-assessment of clinical teachers and to enhance the effectiveness of the FD program.

Selective degradation of splicing factor CAPERα by anticancer sulfonamides.

Target-protein degradation is an emerging field in drug discovery and development. In particular, the substrate-receptor proteins of the cullin-ubiquitin ligase system play a key role in selective protein degradation, which is an essential component of the anti-myeloma activity of immunomodulatory drugs (IMiDs), such as lenalidomide. Here, we demonstrate that a series of anticancer sulfonamides NSC 719239 (E7820), indisulam, and NSC 339004 (chloroquinoxaline sulfonamide, CQS) induce proteasomal degradation of the U2AF-related splicing factor coactivator of activating protein-1 and estrogen receptors (CAPERα) via CRL4DCAF15 mediated ubiquitination in human cancer cell lines. Both CRISPR-Cas9-based knockout of DCAF15 and a single amino acid substitution of CAPERα conferred resistance against sulfonamide-induced CAPERα degradation and cell-growth inhibition. Thus, these sulfonamides represent selective chemical probes for disrupting CAPERα function and designate DCAFs as promising drug targets for promoting selective protein degradation in cancer therapy.

Predictable Value of Functional Independence Measure Differs between Anterior and Posterior Circulation Ischemic Strokes.

BACKGROUND: The functional independence measure (FIM) is a standard tool to provide a detailed evaluation of ADL of patients with disabilities. This study aimed to show the differences in FIM scores as an outcome predictor between patients with anterior circulation (AC) and posterior circulation (PC) strokes. METHODS: Consecutive patients with acute ischemic stroke hospitalized within 7 days after onset were investigated. Baseline NIHSS scores, 1st-FIM (< 72 h after -admission to stroke unit), 2nd-FIM (< 72 h before discharge), and modified Rankin Scale (mRS) scores were collected. Logistic regression analyses were used to identify predictors of a favorable outcome (mRS 0-2) at 3-month after stroke. RESULTS: Three hundred eighty-five patients (median age, 78 years; male, 59%; median length of stroke unit stay, 20 days) were included. The median baseline NIHSS, 1st- and 2nd-FIM scores were 4 (interquartile range 2-9), 65 (33-91), and 98 (54-122) respectively. Baseline NIHSS (3 vs. 4, p = 0.01) and mRS score at 3-month (1 vs. 2, p = 0.01) were lower, and 1st-FIM (75 vs. 64, p < 0.01) and 2nd-FIM (113 vs. 95, p = 0.01) were higher in 82 patients with PC than 303 patients with AC strokes. On multivariate logistic regression analysis, 2nd-FIM score was an independent predictor of favorable outcomes in both PC (OR 1.18, 95% CI 1.04-1.48, p < 0.01) and AC (OR 1.12, 95% CI 1.06-1.20, p < 0.01) strokes. The optimal cutoff scores of 2nd-FIM for predicting favorable outcome were 104 for PC (sensitivity 0.82, specificity 0.88) and 93 for AC (0.88-0.90) strokes. CONCLUSIONS: The differences in outcome predictability by FIM score between AC and PC strokes should be considered, although FIM scores at discharge from stroke unit were useful to predict a favorable outcome.

Health-care transition after Kawasaki disease in patients with coronary artery lesion.

BACKGROUND: Discussion of health-care transition (HCT) for adults with a childhood history of coronary artery lesions (CAL) after Kawasaki disease (KD) is important. A nationwide questionnaire survey was performed with support by the Japanese Society of Kawasaki Disease. The purpose of this study was to clarify the reality of HCT and loss to follow-up in patients with CAL after KD. METHODS: The survey was emailed to 48 members of the Japanese Society of Kawasaki Disease from May to July 2014. RESULTS: Forty surveys were collected, giving a response rate of 83.3%. Sixty-five percent of the respondents belonged to a university hospital. Approximately 90% of the respondents dealt with patients who needed HCT, and 55% had patients who completed HCT. Approximately 70% of the respondents considered that pediatricians should continue sharing HCT information with cardiologists. More than 95% of the respondents had a favorable or average impression of HCT care provided by cardiologists. The percentage of respondents who had loss to follow up for HCT was >40%. CONCLUSION: Adult cardiologists began managing patients with CAL after KD in more than half of the institutes in this study. Pediatricians should construct a support program for better management of these patients and for cooperation with cardiologists to prevent loss to follow up.

Cardiac function on 3-D speckle tracking imaging and cytokines in Kawasaki disease.

BACKGROUND: Serum N-terminal pro-brain natriuretic peptide (NT-proBNP) tends to rise in acute phase Kawasaki disease (KD), but the cause of NT-proBNP elevation has not been clarified. In a previous study, cardiac function evaluated on 2-D echocardiography (2D-E) such as ejection fraction was normal, but this does not reflect subtle changes in cardiac dysfunction, and hence the association between cardiac function and NT-proBNP elevation is still controversial. The aim of this study was therefore to elucidate the influence of cardiac function on NT-proBNP elevation, by evaluating cardiac function via strain on 3-D speckle tracking imaging (3D-STI), in acute and subacute KD patients. Given that cytokines are also thought to induce NT-proBNP in acute phase KD, serum cytokines and cytokine receptors were measured at the same time. METHODS: Laboratory data and echocardiography in 52 KD patients in the acute and subacute phases were reviewed. RESULTS: Median NT-proBNP was significantly elevated in the acute phase compared with the subacute phase (356.5 pg/mL; IQR, 145-904 pg/mL vs 103.5 pg/mL; IQR, 59-150 pg/mL, P < 0.01). All cytokines were also significantly elevated in the acute phase compared with the subacute phase. Tumor necrosis factor (TNF)-α, soluble TNF receptor (sTNFR)1, and sTNFR2 concentration were all significantly higher in the acute phase. Indices of cardiac function were not significant different between phases. NT-proBNP in the acute and subacute phases correlated with sTNFR1 (r = 0.63/0.43, P < 0.01), sTNFR2 (r = 0.50/0.31, P < 0.05), and interleukin-6 (r = 0.58/0.43, P < 0.01). NT-proBNP did not correlate with global longitudinal strain (GLS) on 3D-STI. CONCLUSION: Although no correlation was seen between NT-proBNP and GLS on 3D-STI, correlations between NT-proBNP and cytokines were clear. NT-proBNP might be a marker of inflammation in KD, but is not a marker of cardiac function.

Appropriate use of a beta-blocker in paediatric coronary CT angiography.

BACKGROUND: There is no standard dose or protocol for beta-blocker administration as preconditioning in children undergoing coronary CT angiography. METHODS: A total of 63 consecutive patients, with a mean age of 10.0±3.1 years, who underwent coronary CT angiography to assess possible coronary complications were enrolled in a single-centre, retrospective study. All patients were given an oral beta-blocker 1 hour before coronary CT angiography. Additional oral beta-blocker or intravenous beta-blocker was given to those with a high heart rate. We compared image quality, radiation exposure, and adverse events among the patients without additional beta-blocker, with additional oral beta-blocker, and with additional intravenous beta-blocker. RESULTS: There were no significant differences in image quality or radiation exposure among the groups. The heart rate just before scanning was significantly correlated with image quality (p<0.001, r=-0.533) but was not correlated with radiation exposure (p=0.45, r=0.096). There were no adverse events related to any allergic reaction, thereby showing the effectiveness of the beta-blocker. CONCLUSION: Initial oral beta-blocker administration (0.8 mg/kg/dose) should be administered to all children undergoing coronary CT angiography. Additional intravenous beta-blocker should be given to those with poor heart rate control to improve image quality without increasing radiation exposure or allowing adverse events.

Factors affecting N-terminal pro-brain natriuretic peptide elevation in the acute phase of Kawasaki disease.

BACKGROUND: The aim of this study was to investigate the clinical significance and factors that affect N-terminal pro-brain natriuretic peptide (NT-proBNP) elevation in the acute phase of Kawasaki disease (KD) despite the absence of apparent cardiac complications. METHODS: The laboratory and echocardiography results of 44 KD patients in the acute and subacute phases were reviewed. RESULTS: With preserved cardiac function, median NT-proBNP was significantly elevated in the acute phase compared with the subacute phase (343 pg/mL, IQR, 162-1182 pg/mL vs 98 pg/mL, IQR, 61-205 pg/mL, respectively; P < 0.0001). The respective levels of tumor necrosis factor (TNF)-α, soluble TNF receptor (sTNFR)1, and sTNFR2 were also significantly elevated in the acute phase compared with the subacute phase: TNF-α, 3.3 pg/mL (IQR, 2.6-4.8 pg/mL) versus 2.4 pg/mL (IQR 1.9-4.0 pg/mL; P < 0.01), sTNFR1, 2741 pg/mL (IQR, 2080-3183 pg/mL) versus 976 pg/mL (IQR, 814-1247 pg/mL; P < 0.0001), sTNFR2, 5644 pg/mL (IQR, 4693-7520 pg/mL) versus 3169 pg/mL (IQR, 2132-3878 pg/mL; P < 0.0001). Log-transformed NT-proBNP was correlated with TNF-α (r = 0.29, P = 0.056), sTNFR1 (r = 0.60, P < 0.0001), and sTNFR2 (r = 0.65, P < 0.0001). TNF-α was correlated with sTNFR1 (r = 0.35, P = 0.02) and sTNFR2 (r = 0.51, P < 0.001). CONCLUSION: Tumor necrosis factor-α may cause NT-proBNP elevation in the acute phase of KD, and NT-proBNP level may be an indicator of TNF-α activity.

Idiopathic pulmonary hemosiderosis complicated by Down syndrome.

We report the case of a 9-year-old girl with Down syndrome (DS) diagnosed with idiopathic pulmonary hemosiderosis (IPH). Although acute pneumonia complicated by hemolytic anemia was suspected, IPH was finally diagnosed on bronchoscopy. Treatment with prednisolone achieved good clinical response. An association between IPH and DS was not able to be identified, but immunological issues in DS may contribute to the onset of IPH. Recurrent and intractable respiratory symptoms with marked infiltrative shadows in the bilateral lungs and complicated by severe anemia in patients with DS should suggest IPH.

[Current status of clinical development of novel anti-diabetic drugs].

Clinical development of novel antidiabetic drugs, such as GK activator, GPR40 agonist, GPR119 agonist, 11ß-HSD1 inhibitor and trelagliptin, has been progressing over the world. Especially, GK activator, GPR40 agonist, GPR119 agonist and 112-HSD1 inhibitor have unique action mechanism compared to existing drugs. GK activator potentiates glucose-stimulated insulin secretion from ß cells and stimulates glucose uptake into the liver. GPR40 agonists and GPR119 agonist stimulate glucose-dependent insulin secretion from ß cells. 11ß-HSD1 inhibitor reduces the conversion of cortisone to cortisol. Trelagliptin is a long acting dipeptidyl peptidase-4(DPP-4) inhibitor and a once-weekly treatment by trelagliptin would improve the drug adherence of patients. This article focuses on these new and emerging diabetes agents.

Successful control of life-threatening polymorphic ventricular tachycardia by radiofrequency catheter ablation in an infant.

We present a case of a 9-month-old girl in whom malignant polymorphic ventricular tachycardia (VT) was successfully controlled by radiofrequency catheter ablation under guidance with a three-dimensional mapping system. The VTs originated from the left ventricular lateral wall, left ventricular anterior wall, and left ventricular apex. At least six types of VTs were documented during the electrophysiology study. All VTs were successfully controlled after two sessions of radiofrequency catheter ablation, and she was discharged from our hospital on propranolol, mexiletine, flecainide, and aprindine.

Effects of miglitol, vildagliptin, or their combination on serum insulin and peptide YY levels and plasma glucose, cholecystokinin, ghrelin, and obestatin levels.

We previously reported that combination therapy with an α-glucosidase inhibitor (αGI) and a dipeptidyl peptidase-4 (DPP-4) inhibitor increased active glucagon-like peptide-1 (GLP-1) levels and decreased total glucose-dependent insulinotropic polypeptide (GIP) levels, compared with monotherapy, in non-diabetic men. However, the peptide YY (PYY), cholecystokinin (CCK), ghrelin, and obestatin levels in patients receiving a combination of αGIs and DPP-4 inhibitors have not been previously reported. We evaluated the effect of miglitol, vildagliptin, or their combination on these parameters. Miglitol and/or vildagliptin were administered according to four different intake schedules in eleven non-diabetic men (C: no drug, M: miglitol; V: vildagliptin, M+V: miglitol+vildagliptin). Blood samples were collected at 0, 30, 60, and 120 min after the start of breakfast. The plasma glucose, serum insulin, serum total PYY (PYY1-36 and PYY3-36), plasma CCK, plasma active ghrelin, and plasma obestatin levels were measured. The area under the curve (AUC) of the serum total PYY level in the M group was significantly greater than that in the C group, and the AUC of the serum total PYY level in the M+V group was significantly lower than that in the M group. The combination therapy did not change the AUC of the plasma CCK, plasma active ghrelin, plasma obestatin, and ghrelin/obestatin levels, compared with the control. The results of our study suggested that combination therapy with miglitol and vildagliptin had no effect on appetite regulation hormones, such as total PYY, CCK, active ghrelin, and obestatin, compared with the levels in the control group.

Asymmetrical changes in cerebral blood oxygenation induced by an active standing test in children with postural tachycardia syndrome.

Near-infrared spectroscopy enables recognition of various brain conditions based on certain factors, such as oxygenated hemoglobin (oxy-Hb). Since July 2012, we have been trying to determine the mechanisms of autonomic function in Japanese children with orthostatic intolerance (also called orthostatic dysregulation) in Nihon University Itabashi Hospital in Tokyo, Japan. A total of 23 children aged 7-16 years diagnosed with postural tachycardia syndrome (POTS), a subtype of orthostatic dysregulation, were enrolled in the study. We evaluated the relation between asymmetry in frontal cortex activity and the automatic nervous system and compared oxy-Hb changes in the right and left frontal cortices during an active standing test. We observed that during active standing oxy-Hb decreased in the frontal cortex. The oxy-Hb changes were asymmetrical, with a significantly larger decrease in the left frontal cortex than in the right frontal cortex, suggesting that tachycardia during active standing in POTS patients might be caused by activation of the right frontal cortex, which induces sympathetic nervous system activity.

[Cardiac scintigraphy-Pharmacological stress and appropriate management of pediatric radiopharmaceutical administration in patients after Kawasaki disease].

Cardiac scintigraphy accounted for 2.5 % of all 3,884 patients based on a survey ques- tionnaire of pediatric nuclear medicine examinations performed at 14 Japanese institutes in 2011. Myocardial perfusion imaging, classified as cardiac scintigraphy, is essential to detect myocardial ischemia in patients after Kawasaki disease (KD), although its less frequent performance is reported. Adenosine is widely noticed as a medication for pharma- cological stress testing in coronary arterial lesions after KD. We describe characteristics of adenosine including newly-devised administration protocol and pathway making of intravenous injection for stress testing. We comment on optimal radiopharmaceutical administered doses proposed in Japanese consensus guidelines for pediatric nuclear medi- cine. Their proposal doses approximate that calculated by Pediatric Dosage Card of Euro- pean Association of Nuclear Medicine. We hope myocardial perfusion imaging is performed under appropriate management of pediatric radiopharmaceutical administration.

Improvement in non-tachycardia-induced cardiac failure after radiofrequency catheter ablation in a child with a right-sided accessory pathway.

A 6-year-old boy was referred for an evaluation of intolerance to physical activity at his elementary school. The patient had no episodes of palpitations. He was diagnosed as Wolff-Parkinson-White syndrome with a right-sided accessory pathway (AP) and dilated cardiomyopathy (DCM). Ventricular dyskinesis was detected mostly in the ventricular septum. Because the asynchronous septal motion caused by pre-excitation through a right-sided AP might deteriorate his cardiac function, he underwent an AP ablation, after which the asynchronous ventricular wall motion disappeared and the wall thickness improved. We suggest that an AP ablation may be the treatment of first priority in patients who have DCM-like dyskinesis even without sustained tachyarrhythmias.

Mosapride citrate, a 5-HT4 receptor agonist, increased the plasma active and total glucagon-like peptide-1 levels in non-diabetic men.

Mosapride citrate, a selective agonist of the 5-hydroxytryptaine (5-HT)4 receptor, is typically used to treat heartburn, nausea, and vomiting associated with chronic gastritis or to prepare for a barium enema X-ray examination. Mosapride citrate reportedly improves insulin sensitivity in patients with type 2 diabetes. As mosapride citrate activates the motility of the gastrointestinal tract, we hypothesized that mosapride citrate affects incretin secretion. We examined the effect of the administration of mosapride citrate on the plasma glucose, serum insulin, plasma glucagon, and plasma incretin levels before breakfast and at 60, 120, and 180 min after breakfast in men with normal glucose tolerance (NGT) or impaired glucose tolerance (IGT) to exclude gastropathy. Mosapride citrate was administered according to two different intake schedules (C: control (no drug), M: mosapride citrate 20 mg) in each of the subject groups. The area under the curve (AUC) of the plasma glucose levels was smaller in the M group than in the C group. The time profiles for the serum insulin levels at 60 and 120 min after treatment with mosapride citrate tended to be higher, although the difference was not statistically significant. The AUCs of the plasma active and total glucagon-like peptide-1 (GLP-1) levels were significantly larger in the M group than in the C group. No significant difference in the AUC of the plasma glucose-dependent insulinotropic polypeptide (GIP) level was observed between the two groups. Our results suggest that mosapride citrate may have an antidiabetic effect by increasing GLP-1 secretion.

[Survey questionnaire of pediatric nuclear medicine examinations in 14 Japanese institutes].

Under the auspices of the Japanese Society of Pediatric Nuclear Medicine, an annual aggregate from a 5-year period, 2007 to 2011, of a survey questionnaire of pediatric nuclear medicine examinations performed at 14 institutes in the Kanto region was conducted. The subjects were pediatric patients 15 years old or younger. The survey questions included the determination method for administered dose of radiopharmaceuticals, the items examined and number of examinations. Of 14 institutes, 11 determined administered doses using the formula: adult dose X (age +1) / (age+7), while the remaining 3 used the adult dose as the maximum dose and used a conversion formula based on age and physical condition. In 2011, in a total of 3,884 pediatric patients, renoscintigraphy accounted for 41.5%, brain 14.4%, pulmonary scintigraphy 12.9%, oncology 9.0%, hepatobiliary scintigraphy 6.3%, gastrointestinal scintigraphy 4.8%, musculoskeletal scintigraphy 4.3%, cardiology 2.5%, and other 4.9% of all nuclear medicine examinations. Pediatric nuclear medicine examinations in general hospitals accounted for only 3.4% of all examinations. A similar trend was observed in previous years. Since pediatric patients have a longer reproductive term and higher sensitivity to radiation exposure, pediatric nuclear medicine requires a strict selection of appropriate studies and administered dose. These results show the current practice and would warrant further consideration.