Heart rate response during dipyridamole stress as a predictor of mortality in patients with normal myocardial perfusion and normal electrocardiograms

Although it is well established that a blunted chronotropic response to exercise is associated with a higher risk of death, recent data suggest a similar association between mortality risk and blunted heart rate response to vasodilatory stress. We investigated the heart rate response to dipyridamole-induced stress as a predictor of death in the setting of normal myocardial perfusion and a normal electrocardiogram. We followed 1,087 patients for 8 years (range 5.7 to 11.8) who underwent dipyridamole vasodilator stress and had normal perfusion scans and electrocardiograms. None had heart failure, known left ventricular systolic dysfunction, pacemaker implantation, or valve disease. Heart rate response was assessed as the ratio of heart rate at peak stress to heart rate at rest. The primary end point was all-cause mortality. Quartile values for the peak-to-rest heart rate ratio were <1.19, 1.19 to 1.30, 1.31 to 1.44, and >1.44. There were 246 deaths. Death rates according to quartiles of heart rate ratio were 103 of 271 (38%), 64 of 272 (24%), 52 of 272 (19%), and 27 of 272 (10%). After adjusting for age, gender, heart rate at rest, blood pressure response, standard cardiovascular risk factors, and other confounders, a blunted heart rate response remained predictive of death (adjusted hazard ratio for lowest vs highest quartile 3.3, 95% confidence interval 2.1 to 5.1, p <0.0001). When considered as a continuous variable, the logarithm of the heart rate ratio was the strongest predictor of death, aside from age. Thus, among patients who have normal myocardial perfusion and normal electrocardiograms, a blunted heart rate response to vasodilator stress is predictive of a marked increase in risk of death.     

Rotavirus P[8] Infections in Persons with Secretor and Nonsecretor Phenotypes,Tunisia

To determine whether rotavirus infections are linked to secretor status, we studied samples from children in Tunisia with gastroenteritis. We phenotyped saliva for human blood group antigens and tested feces for rotavirus. Rotavirus was detected in 32/114 patients. Secretor genotyping showed that P[8] rotavirus infected secretors and nonsecretors, and infection correlated with presence of Lewis antigen.     

Metabolic Effects of Bariatric Surgery in Patients With Moderate Obesity and Type 2 Diabetes: Analysis of a randomized control trial comparing surgery with intensive medical treatment

OBJECTIVE

To evaluate the effects of two bariatric procedures versus intensive medical therapy (IMT) on β-cell function and body composition.

RESEARCH DESIGN AND METHODS

This was a prospective, randomized, controlled trial of 60 subjects with uncontrolled type 2 diabetes (HbA_1c 9.7 ± 1%) and moderate obesity (BMI 36 ± 2 kg/m²) randomized to IMT alone, IMT plus Roux-en-Y gastric bypass, or IMT plus sleeve gastrectomy. Assessment of β-cell function (mixed-meal tolerance testing) and body composition was performed at baseline and 12 and 24 months.

RESULTS

Glycemic control improved in all three groups at 24 months (N = 54), with a mean HbA_1c of 6.7 ± 1.2% for gastric bypass, 7.1 ± 0.8% for sleeve gastrectomy, and 8.4 ± 2.3% for IMT (P < 0.05 for each surgical group versus IMT). Reduction in body fat was similar for both surgery groups, with greater absolute reduction in truncal fat in gastric bypass versus sleeve gastrectomy (−16 vs. −10%; P = 0.04). Insulin sensitivity increased significantly from baseline in gastric bypass (2.7-fold; P = 0.004) and did not change in sleeve gastrectomy or IMT. β-Cell function (oral disposition index) increased 5.8-fold in gastric bypass from baseline, was markedly greater than IMT (P = 0.001), and was not different between sleeve gastrectomy versus IMT (P = 0.30). At 24 months, β-cell function inversely correlated with truncal fat and prandial free fatty acid levels.

CONCLUSIONS

Bariatric surgery provides durable glycemic control compared with intensive medical therapy at 2 years. Despite similar weight loss as sleeve gastrectomy, gastric bypass uniquely restores pancreatic β-cell function and reduces truncal fat, thus reversing the core defects in diabetes.Type 2 diabetes mellitus and obesity are closely interrelated chronic conditions growing in incidence worldwide, with diabetes-related deaths projected to double between 2005 and 2030 (1). The development of both insulin resistance and insulin secretory defects is the hallmark of type 2 diabetes, resulting in progressive hyperglycemia, subsequent microvascular complications, and macrovascular complications. Although lifestyle modifications and oral hypoglycemic agents improve glycemic control, the majority of patients do not achieve the optimal glycohemoglobin (HbA_1c) levels recommended by current guidelines (≤7.0%). The disease inexorably progresses in the majority of patients, ultimately requiring insulin replacement therapy. Most patients with type 2 diabetes are overweight or obese (BMI ≥30 kg/m²), and abdominal adiposity, particularly, is tightly linked to induction of insulin resistance, metabolic syndrome, and increased cardiovascular risk. Many hypoglycemic agents, especially insulin, exacerbate weight gain and thwart lifestyle efforts, potentially contributing to the underlying pathophysiologic disorder.Because of the limitations to medical therapy, surgical approaches for the treatment of obesity have increased 10-fold in the past decade. Roux-en-Y gastric bypass surgery is the most commonly performed in the United States, followed closely by the sleeve gastrectomy (2). Recently, two randomized controlled trials (3,4) demonstrated improved glycemic control in patients undergoing bariatric surgery compared with intensive medical therapy, resulting in the ability to withdraw or reduce glucose-lowering medications. The rapid rate of glucose lowering, disproportionate to degree of weight loss, suggests that bariatric surgery reverses the fundamental pathophysiological defects of type 2 diabetes. Animal studies suggest that bariatric surgery increases insulin secretion or improves enteroinsulinar responses, specifically, the main incretin hormones glucagon like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP) (5–7). Previous small-scale studies from matched case-control and observational studies in severely obese diabetic individuals have reported that weight loss improves insulin sensitivity, reduces hyperinsulinemia, and improves pancreatic β-cell function by weight-independent mechanisms related to an incretin effect (8–10). However, there are no data from a randomized controlled trial examining the prolonged metabolic adaptations in conjunction with clinical efficacy outcomes after bariatric surgery relative to the effects of intensive medical therapy in moderately obese subjects with poorly controlled type 2 diabetes.The STAMPEDE trial evaluated the efficacy and safety of intensive medical therapy (IMT) alone or intensive medical therapy combined with Roux-en-Y gastric bypass or sleeve gastrectomy to achieve a primary end point of HbA_1c level of ≤6% (with or without medications) after 1 year of follow-up (11). The current report is a 2-year extension of a metabolic substudy of the STAMPEDE trial designed to thoroughly evaluate the effects of the three treatments on glucose regulation, pancreatic β-cell function (insulin secretion/sensitivity), and body composition in a subset of 60 subjects.     

Rabbit blastocoelic fluid regulation of tumor-cell proliferation in vitro

To determine whether rabbit blastocoelic fluid could inhibit tumor-cell proliferation, day-9 and day-12 embryonic fluids, together with autologous and homologous sera, were collected from pregnant or pseudopregnant rabbits and tested against 13 different cell lines and on human carcinoma cells in primary culture. An inhibitory effect on cell proliferation was observed in the presence of blastocoelic fluids, but not with homologous or heterologous sera. This suppression was higher with samples collected at day 12 than at day 9 of pregnancy. No such inhibition could be detected on one-cell rabbit embryos or on freshly prepared uterine stromal or myometrial cells. In addition, the inhibitory activity on tumor cells was completely reversible upon removal of the fluids. Incorporation of 3H-thymidine, 3H-uridine and 35S-methionine revealed that, in the presence of blastocoelic fluids, both DNA and RNA syntheses were rapidly inhibited. Inhibition of protein synthesis did not occur before 24 hr of treatment. We conclude that rabbit blastocoelic fluid suppresses the proliferation of tumor cells via inhibition of RNA and DNA synthesis by a process which may involve the expression of growth-suppression gene(s).     

RNA interference in vitro and in vivo using DsiRNA targeting the nucleocapsid N mRNA of human metapneumovirus

Human metapneumovirus causes respiratory diseases with outcomes that can be severe in children, the immunocompromised, and the elderly. Synthetic small interfering RNAs (siRNAs) that silence targeted genes can be used as therapeutic agents. Currently, there is no specific therapy for hMPV. In this study, we designed Dicer-substrate siRNAs (DsiRNAs) that target metapneumovirus sequences on the mRNAs of the N, P, and L genes. In vitro, six DsiRNAs were shown to inhibit virus replication using cell proliferation tests. Of those, the DsiRNA that targets the most conserved mRNA sequence was then resynthesized in Evader? format with heavy 2′-O-methyl modification of the guide strand. In a murine model, the prophylactic administration of this Evader? DsiRNA was effective at partially inhibiting viral replication of hMPV (13 × 10³ vs. 29 × 10³ PFU/g of lung; p < 0.01), which was not the case for the control, a mismatched DsiRNA. Inhibition was achieved without inducing cytokines or off-target effects. Moreover, the specificity of the siRNA mechanism of action was demonstrated in vitro and in vivo using 5′-RACE methodology. This in vivo approach of using a DsiRNA against hMPV is an important step in the development of synthetic siRNA as a therapeutic agent for this virus.