Bradycardia-induced abnormal QT prolongation in patients with complete atrioventricular block with torsades de pointes.

Fourteen patients with complete atrioventricular block with or without torsades de pointes (TdP) were included in this study. They were divided into 2 groups, 6 patients with TdP (TdP[+] group) and 8 patients without TdP (TdP[-] group). The patients were evaluated at 2 different periods, before (acute period) and after (chronic period) pacemaker implantation. In the acute period, the QRS and heart rate during the escape rhythm were not significantly different between the 2 groups; however, the QT and QTc intervals were significantly longer in the TdP(+) group than in the TdP(-) group: 753 +/- 57.5 vs 635 +/- 78.4 ms (p less than 0.01) and 585 +/- 44.8 vs 476 +/- 58.3 ms (p less than 0.01). In the chronic period (greater than 2 months after pacemaker implantation), we changed the pacemaker rate from 90 or 100 beats/min to 50 beats/min and examined the QT interval changes in relation to the heart rate. The QT interval in the TdP(+) group was significantly prolonged compared with the TdP(-) group when the pacing rate was decreased less than or equal to 60 beats/min: 551 +/- 40 vs 503 +/- 36 ms at 60 beats/min (p less than 0.05), and 700 +/- 46 vs 529 +/- 43 ms at 50 beats/min (p less than 0.001). Patients with complete atrioventricular block with TdP had a bradycardia-sensitive repolarization abnormality and this characteristic remained after pacemaker implantation. The critical heart rate that induced abnormal QT prolongation in the TdP(+) group was less than or equal to 60 beats/min.     

Association of (-)786T-C mutation of endothelial nitric oxide synthase gene with insulin resistance

AIMS/HYPOTHESIS: Endothelial derived nitric oxide synthase ( eNOS) gene polymorphisms affect eNOS activity and are associated with abnormal vasomotility and impaired local blood flow. A decrease in local blood flow has been reported to cause insulin resistance. The aim of this study was to examine a possible association of two eNOS polymorphisms, Glu298Asp (G894T) in exon 7 and (-)786T-C mutation with insulin resistance. METHODS: Genotypes of both Glu298Asp and (-)786T-C mutation were examined by the PCR-RFLP method. Plasma nitrate and nitrite concentrations were also measured. RESULTS: The allele frequencies of both polymorphisms showed no considerable differences in 233 non-diabetic subjects and 301 patients with Type II (non-insulin-dependent) diabetes mellitus. Non-diabetic subjects with the (-)786C allele had (p<0.05) higher fasting plasma insulin and homeostasis model assessment of insulin resistance than those with the (-)786T/ (-)786T genotype. Diabetic subjects with (-)786C allele showed higher HbA(1c) than those with the (-)786T/(-)786T genotype. A euglycaemic hyperinsulinemic clamp study done on 71 of the 301 patients showed a lower glucose infusion rate in diabetic patients with the (-)786C allele than those without it. In diabetic patients with the (-)786C allele, plasma nitrate and nitrite concentrations were lower than in subjects without it (p=0.026). No differences were observed between mutant carriers of Glu298Asp and non-carriers among both non-diabetic subjects and Type II diabetic patients. CONCLUSIONS/INTERPRETATION: The (-)786T-C mutation of the eNOS gene is associated with insulin resistance in both Japanese non-diabetic subjects and Type II diabetic patients.     

Urinary adiponectin excretion is an early predictive marker of the decline of the renal function in patients with diabetes mellitus

AimsSince diabetes-associated kidney complication changes from diabetic nephropathy to diabetic kidney disease (DKD), more suitable biomarkers than urinary albumin are required. It has been hypothesized that urinary adiponectin (u-ADPN) is associated with the progression of DKD. We therefore evaluated the effectiveness of u-ADPN in predicting the decline of the renal function in patients with diabetes prior to end-stage renal disease.MethodsAn ultrasensitive immune complex transfer enzyme immunoassay (ICT-EIA) was used to measure total and high molecular weight (HMW) adiponectin separately. We evaluated the relationships between the creatinine-adjusted urinary total-ADPN and HMW-ADPN, albumin (UACR) and liver-type fatty acid binding protein (L-FABP) at baseline and the 2-year change of the estimated glomerular filtration rate (ΔeGFR).ResultsThis 2-year prospective observational study included 201 patients with diabetes. These patients were divided into three groups according to their ΔeGFR: ≤?10 mL/min/1.73m², >?10 and ≤0 mL/min/1.73m², and >0 mL/min/1.73m². Jonckheere-Terpstra test showed that lower ΔeGFR was associated with higher u-HMW-ADPN (p = 0.045). In logistic regression analysis, u-HMW-ADPN was associated with ΔeGFR after adjusted age, sex, and basal eGFR.ConclusionUrinary HMW-ADPN could predict a declining renal function in patients with diabetes.     

Possible novel index determined by the glucose clamp test for selection of a suitable therapy for each type 2 diabetic patient

The hallmark of type 2 diabetes is insulin resistance and insufficient insulin secretion, and appropriate therapy should be selected for each patient. In this study, to establish some index to select suitable therapy for each patient, we evaluated insulin sensitivity and insulin secretion with euglycemic hyperinsulinemic clamp and hyperglycemic clamp tests, respectively, and found that specific GIR index (GIRxIRI (90)) could be a useful marker to select suitable therapy for each type 2 diabetic patient (GIR: glucose infusion rate in euglycemic hyperinsulinemic clamp test; IRI (90): plasma insulin level 90 min after starting the hyperglycemic clamp test).     

Electrocardiographic and electrophysiologic studies in patients with torsades de pointe--role of monophasic action potentials

The study group consisted of 26 patients with a history of documented Torsade de Pointes (TdP) who were divides into 3 groups according to the causes of TdP. Group I consisted of 5 patients with congenital long QT syndrome. Group II consisted of 15 patients with TdP caused by antiarrhythmic drugs. Group III consisted of 6 patients with TdP caused by bradycardia resulting from third degree atrioventricular block. The QT interval was determined from a 12-lead electrocardiogram. Monophasic Action Potential (MAP) was recorded by a 6 F USCI electrode catheter. Isoproterenol infusion resulted in TU abnormality in all patients in Group I and induced a hump at phase 3 slope of MAP in all 3 patients tested. The QT interval change before and after IA administration was significantly larger in Group II patients compared to those without TdP (0.132 +/- 0.062 vs 0.029 +/- 0.31 sec, less than 0.005). Injection of 100 mg. of disopyramide in 2 patients in Group II resulted a hump at phase 3 slope of the MAP in both of them. The QT prolongation associated with decreasing the pacing rate from 70 to 50/min was significantly larger in patients with Group III compared to patients with bradycardia but without TdP (0.02 +/- 0.04 vs 0.07 +/- 0.05 sec, p less than 0.005). The results suggests: 1) different approaches are necessary for evaluation of TU abnormalities in patients with TdP according to the causes of TdP, 2) MAP might be a useful method for evaluating TU abnormality in patients with TdP.     

YM155, a novel small-molecule survivin suppressant, induces regression of established human hormone-refractory prostate tumor xenografts

Various accumulating evidence suggests that survivin, a member of the inhibitor of apoptosis (IAP) family, plays an important role in drug resistance and cancer cell survival in many types of cancer, including hormone-refractory prostate cancer (HRPC). Here, we characterized YM155, a novel small-molecule survivin suppressant, using a survivin gene promoter activity assay. YM155 suppressed expression of survivin and induced apoptosis in PC-3 and PPC-1 human HRPC cell lines at 10 nmol/L. In contrast, YM155 up to 100 nmol/L showed little effect on expression levels of other IAP- or Bcl-2-related proteins. In a s.c. xenografted PC-3 tumor model in mice, 3-day continuous infusions of YM155 at 3 to 10 mg/kg induced massive tumor regression accompanied by suppression of intratumoral survivin. YM155 also completely inhibited the growth of orthotopically xenografted PC-3 tumors. No significant decreases in body weight were observed in mice treated with YM155 during the experimental period. Pharmacokinetic analyses indicated that YM155 is highly distributed to tumors and at concentrations approximately 20-fold higher than those in plasma. Our findings represent the first attempt to show tumor regression and suppression of survivin in p53-deficient human HRPC cells by a single small molecular compound treatment. Further extensive investigation of YM155 in many types of cancer, including HRPC, seems to be worthwhile to develop this novel therapeutic approach.     

Continuous hemodiafiltration during cardiopulmonary bypass in infants

The homologous blood prime in cardiopulmonary bypass circuits contributes a significant electrolyte and metabolite load in small infants. The efficacy of hemofiltration and continuous hemodiafiltration of the blood prime in preventing metabolic disturbances in small infants was compared in two groups of 60 patients each. Blood pH, base excess, and calcium concentrations decreased during cardiopulmonary bypass in the hemofiltration group. The acid-base balance was well preserved during cardiopulmonary bypass by continuous hemodiafiltration. This therapeutic strategy may confer an advantage in maintaining more physiological conditions during cardiopulmonary bypass in small infants.     

Helicobacter pylori infection in combination with the serum pepsinogen I/II ratio and interleukin-1β-511 polymorphisms are independent risk factors for gastric cancer in Thais

Background Thailand has the lowest incidence of gastric cancer in the world. Helicobacter pylori infection, a low serum pepsinogen I/II ratio, and interleukin (IL)-1β-511 polymorphisms are suspected to be risk factors for gastric cancer. Methods A total of 167 Thais, comprising 56 cancer patients and 111 volunteers without cancer, underwent an esophagogastroduodenoscopic examination and three fixed-point biopsies; a cancer tissue biopsy was also done, and blood samples were collected. The subjects without cancer were divided into normal subjects and chronic gastritis patients. IL-1β-511 polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism, and the serum levels of pepsinogen I and II were determined by a radioimmunoassay. Helicobacter pylori IgG antibody and tissue pathology were tested in all groups. Results The pepsinogen I/II ratio was significantly lower in the gastric cancer group than in the normal and chronic gastritis groups [odds ratio (OR), 2.3; 95% confidence interval (CI), 1.10–4.80; P = 0.025]. Gastric cancer patients were positive for the H. pylori IgG antibody more frequently than negative (OR, 2.946; 95% CI, 1.4–6.39; P = 0.005). However, only 15 (27%) cancer patients were both positive for H. pylori IgG antibody and had low serum pepsinogen I/II. The C/C genotype was found more frequently in the gastric cancer group than in the group with a normal gastric mucosa (OR, 0.64; 95% CI, 0.50–0.81; P = 0.014). Conclusions A low serum pepsinogen I/II ratio combined with positivity for H. pylori IgG, and a IL-1β-511 C/C genotype may be independent risk factors for gastric cancer in Thais. Presented at the 19th World Congress of the International Society of Digestive Surgery, Pacifico Yokohama, Japan, December 8–11, 2004 (Helicobacter pylori Symposium)