Combination of TS-021 with metformin improves hyperglycemia and synergistically increases pancreatic ß-cell mass in a mouse model of type 2 diabetes.

AIMS: The objectives of this study were to elucidate the effects of a potent dipeptidyl peptidase (DPP)-IV inhibitor, TS-021, combined with/without metformin on glycemic control and pathological changes in pancreatic islets in high-fat diet and streptozotocin-induced (HFD-STZ) diabetic mice. MAIN METHODS: The anti-diabetic effects of TS-021 and/or metformin in HFD-STZ mice were examined in both acute and chronic treatment studies. In addition, we performed immunohistochemical analysis after repeated administration of TS-021 and/or metformin to HFD-STZ mice twice a day for 5 weeks. KEY FINDINGS: In the acute treatment study, TS-021 and/or metformin significantly improved glucose tolerance and glucagon-like peptide-1 (GLP-1) level, and TS-021 alone or in combination with metformin significantly increased the plasma insulin level after nutrient ingestion. In the chronic treatment study, TS-021 in combination with metformin significantly lowered the glycosylated hemoglobin level, plasma insulin level, and α-cell-to-ß-cell area ratio in pancreatic islets. In particular, the combined treatment synergistically increased the insulin-positive area in pancreatic islets from 32.3% in diabetic mice treated with the vehicle to 51.1% (TS-021 alone, 35.3%; metformin alone, 30.6%). SIGNIFICANCE: The present study demonstrated that the coadministration of TS-021 and metformin synergistically improved the islet morphology by increasing the circulating level of biologically active GLP-1, which is thought to result from two different mechanisms (namely, an increase in GLP-1 secretion and DPP-IV inhibition). These findings strongly support the rationale for combined treatment with DPP-IV inhibitors plus metformin in clinical practice by clearly demonstrating an anti-diabetic effect associated with the remarkable improvement in pancreatic ß-cell morphology.

Electrophysiological characteristics of idiopathic ventricular tachycardia in children.

BACKGROUND: Idiopathic ventricular tachycardia (VT) has been reported to have a good prognosis, but there still might be the potential risk of sudden death. METHODS AND RESULTS: The 46 consecutive children (mean age 11.7 ± 3.4 years) with idiopathic VT were enrolled in this study. Monomorphic VT was detected in 39 patients and polymorphic VT in 7 patients. The VT originated from the right ventricle (RV) in 22 patients, and left ventricle (LV) in 17 patients. The VT was induced by exercise in 68% of the RVVT, 41% of the LVVT, and 100% of the polymorphic VT. The VT was induced by programmed ventricular stimulation in 41% of the RVVT, 35% of the LVVT, and none of the polymorphic VT. Adenosine tri-phosphate terminated the VT in 9 of 15 patients (60%). The mechanism of the VT was suspected to be triggered by activity in 36.4%, automaticity in 40.9%, and re-entry in 22.7% of the RVVT, whereas it was 52.9%, 5.9%, and 41.2% of the LVVT, respectively. CONCLUSIONS: The exercise inducibility was higher in polymorphic VT than the RVVT and LVVT, but no difference in the programmed stimulation. The sensitivity to adenosine tri-phosphate was not different between the RVVT and LVVT. In some patients with idiopathic VT, a non-verapamil sensitive re-entry was documented, which was more common in patients with ischemic heart disease or cardiomyopathy.

Dual myocardial scintigraphy mismatch in an infant with Bland-White-Garland syndrome.

Bland-White-Garland syndrome (BWG) is a rare disorder that includes abnormalities of the coronary arteries that cause severe myocardial ischemia or infarction in infancy. In this case report, we describe an infant with BWG evaluated by dual single photon emission computed tomography using thallium-201 and I-123 beta-methyl-p-iodophenyl-pentadecanoic acid before and after surgery.

Association of sinus node dysfunction, atrioventricular node conduction abnormality and ventricular arrhythmia in patients with Kawasaki disease and coronary involvement.

BACKGROUND: This study was performed to investigate the incidence of arrhythmias in patients with Kawasaki disease (KD). METHODS AND RESULTS: Electrophysiologic studies (EPS) were performed in 40 patients (mean age: 10.3+/-5.1 years; 30 males, 10 females) with KD who had severe to moderate coronary artery disease. Clinical arrhythmias were documented in 4 patients (premature ventricular contractions, ventricular tachycardia, atrioventricular block, and ventricular fibrillation). Dual atrioventricular nodal pathways were demonstrated in 3 patients. Nonsustained atrial fibrillation was induced in 1 patient. The AH interval was prolonged in 2 patients. The Wenckebach rate was 164+/-37 beats/min, and 4 of the patients had a decreased Wenckebach rate. The maximum and corrected sinus node recovery times were 997+/-257 ms and 281+/-130 ms, respectively, and 7 patients were thought to be abnormal. The sino-atrial conduction time was 108+/-64 ms, and 2 patients had prolonged conduction times. CONCLUSIONS: Although there was no relationship between coronary stenosis or obstruction and the EPS parameters, the incidence of abnormal sinus node and atrioventricular node function is apparently higher in KD patients than in the normal population. These functional abnormalities may possibly be caused by myocarditis or an abnormal microcirculation in the sinus node and atrioventricular node artery. In some patients, myocardial ischemia may provoke malignant ventricular arrhythmia.

[Advantages of multislice spiral computed tomography for evaluation of serious coronary complications after Kawasaki disease].

OBJECTIVES: Novel multislice spiral computed tomography (MSCT) findings were identified in patients after Kawasaki disease that could not be detected by coronary angiography (CAG). METHODS: Eighteen patients had suffered from serious coronary arterial lesions after Kawasaki disease (mean age 21.7 years, range 13-34 years). Seventeen patients had stenotic lesions, and all of them had coronary aneurysms. MSCT was performed using a Siemens SOMATOM Volume Zoom (4-detector row) or a Toshiba Aquillion 16 (16-detector row). Findings of coronary calcification, stenotic lesion, and intimal hypertrophy in all coronary arteries were compared to those of CAG. RESULTS: Eleven of the 18 patients (61%) had novel findings detected by MSCT. Coronary calcifications were found in 11 of the 18 patients (61%). Five patients had concentric calcified aneurysms, four had eccentric calcified aneurysms, and two had mixed calcified aneurysms. Coronary stenotic lesions were present in 6 of the 18 patients (33%) with calcified aneurysms. Two patients had intimal hypertrophy (11%). One patient had intimal hypertrophy along the left main trunk with a giant calcified aneurysm along the left anterior descending artery. Two patients had severe stenoses just distal to giant calcified aneurysms that were regarded as false positive findings, and were identified as mild stenoses by CAG. CONCLUSIONS: MSCT offers advantages over CAG in the evaluation of calcified aneurysms and intimal hypertrophy, and is a potential diagnostic modality for coronary intervention in patients after Kawasaki disease.

The role of histidine residues conserved in the putative ATP-binding region of macrolide 2'-phosphotransferase II.

Macrolide 2'-phosphotransferase (MPH(2')) catalyzes the transfer of the gamma-phosphate of ATP to the 2'-hydroxyl group of macrolide antibiotics. In this study, H198 and H205, conserved in the ATP-binding region motif 1 in the putative amino acid sequence of MPH(2')II, were replaced by Ala to investigate their role. H205 was also subsequently replaced by Asn. H198A and H205N mutant enzymes retained more than 50% of the specific activity of the original enzyme to substrate oleandomycin. On the other hand, the specific activity of the H205A mutant enzyme was reduced to less than 1% of that of the wild enzyme. The results suggested that H205 is crucial for maintaining the catalytic activity of MPH(2')II, and Asn can substitute for His at this position.