Antibody-Dependent Enhancement of Severe Disease Is Mediated by Serum Viral Load in Pediatric Dengue Virus Infections.

BACKGROUND: Low preexisting anti-dengue virus (DENV) antibody levels are associated with elevated disease severity. While antibody-dependent enhancement of dengue is thought to be driven by viral load, this has not been conclusively shown. We evaluated the association between preinfection anti-DENV antibody titers, viral load, and disease severity among 133 dengue cases in a Nicaraguan pediatric cohort study. METHODS: Viral load was quantified in acute-phase serum by real-time reverse transcription polymerase chain reaction and analyzed in relation to preinfection antibody titer (measured by inhibition enzyme-linked immunosorbent assay) and dengue severity, categorized using 3 definitions. RESULTS: Higher viral load was significantly associated with dengue severity; for each increase of 1.0 log10 copies/mL, the odds of severe dengue increased approximately 50%, regardless of severity definition. Viral load at presentation and the odds of severe disease were highest among patients with low to intermediate preinfection antibody titers and lowest among those with the highest antibody titers. We showed the effect of preinfection antibody titer on disease severity was mediated by viral load for each of 3 dengue severity outcomes. CONCLUSIONS: This study demonstrates the association between preinfection anti-DENV antibody titer, serum viral load, and disease severity, and provides evidence for the mechanism of antibody-dependent enhancement in dengue cases.

GLP-1 plays a limited role in improved glycemia shortly after Roux-en-Y gastric bypass: a comparison with intensive lifestyle modification.

Rapid glycemic improvements following Roux-en-Y gastric bypass (RYGB) are frequently attributed to the enhanced GLP-1 response, but causality remains unclear. To determine the role of GLP-1 in improved glucose tolerance after surgery, we compared glucose and hormonal responses to a liquid meal test in 20 obese participants with type 2 diabetes mellitus who underwent RYGB or nonsurgical intensive lifestyle modification (ILM) (n = 10 per group) before and after equivalent short-term weight reduction. The GLP-1 receptor antagonist exendin(9-39)-amide (Ex-9) was administered, in random order and in double-blinded fashion, with saline during two separate visits after equivalent weight loss. Despite the markedly exaggerated GLP-1 response after RYGB, changes in postprandial glucose and insulin responses did not significantly differ between groups, and glucagon secretion was paradoxically augmented after RYGB. Hepatic insulin sensitivity also increased significantly after RYGB. With Ex-9, glucose tolerance deteriorated similarly from the saline condition in both groups, but postprandial insulin release was markedly attenuated after RYGB compared with ILM. GLP-1 exerts important insulinotropic effects after RYGB and ILM, but the enhanced incretin response plays a limited role in improved glycemia shortly after surgery. Instead, enhanced hepatic metabolism, independent of GLP-1 receptor activation, may be more important for early postsurgical glycemic improvements.

Threshold for improvement in insulin sensitivity with adolescent weight loss.

OBJECTIVES: To assess the association of weight loss and insulin sensitivity, glucose tolerance, and metabolic syndrome (MS) in obese adolescents following weight loss treatment, and to determine the threshold amount of weight loss required to observe improvements in these measures. STUDY DESIGN: A randomized, controlled behavioral weight loss trial was conducted with 113 obese adolescents. Changes in fasting insulin, homeostasis model assessment of insulin resistance, whole body insulin sensitivity index (WBISI), body mass index (BMI), and MS criteria were assessed at baseline and at month 4. RESULTS: There was significant improvement in all measures of insulin sensitivity at month 4. Mean fasting insulin dropped from 22.3 to 16.6 µU/mL (P < .0001). Homeostasis model assessment of insulin resistance decreased significantly from 4.9 to 3.7 (P = .001) and WBISI increased significantly from 2.87 to 3.98 (P < .0001). An 8% reduction in BMI led to a significant improvement in WBISI (P = .03) and was the optimal threshold. Fewer individuals met criteria for MS after weight loss (P = .0038), although there were no significant changes in the individual features of the syndrome. CONCLUSIONS: In this trial, weight loss at month 4 was associated with improved insulin sensitivity in obese adolescents. An approximate decrease in BMI of 8% was the threshold level at which insulin sensitivity improved. As more weight loss programs are designed for obese adolescents, it will be important to have reasonable weight loss goals that will yield improvements in metabolic and cardiovascular disease risk factors.

Transcranial Doppler ultrasonography and prophylactic transfusion program is effective in preventing overt stroke in children with sickle cell disease.

OBJECTIVE: To assess the impact of our transcranial Doppler ultrasonography (TCD) program on the incidence of first stroke and the rate of transfusion for stroke prevention in children with sickle cell disease. STUDY DESIGN: In this single-institution, retrospective study, we compared the incidence of stroke and of transfusion for stroke prevention in 475 patients observed in the 8-year period before instituting TCD screening with the rate in 530 children in the 8-year period after. RESULTS: The incidence of overt stroke in the pre-TCD period was 0.67 per 100 patient-years, compared with 0.06 per 100 patient-years in the post-TCD period (P<.0001). Of the 2 strokes in the post-TCD period, 1 occurred in a child too young for the screening protocol, and 1 occurred in a child with high velocities solely in the anterior cerebral arteries. The rate of transfusion therapy for stroke prevention increased from 0.67 per 100 patient-years to 1.12 per 100 patient-years since instituting our program (P=.008). CONCLUSIONS: Our program has been successful in reducing the rate of first overt stroke, but with increased use of transfusion. Additional modifications to screening might further reduce the risk of first stroke, and studies of alternative treatments may be beneficial.