Rationale: Obstructive lung disease, the major cause of mortality in cystic fibrosis (CF), is poorly correlated with mutations in the diseasecausing gene, indicating that other factors determine severity of lung disease. Objectives: To quantify the contribution of modifier genes to variation in CF lung disease severity. Methods: Pulmonary function data from patients with CF living with their affected twin or sibling were converted into reference values based on both healthy and CF populations. The best measure of FEV 1 within the last year was used for cross-sectional analysis. FEV 1 measures collected over at least 4 years were used for longitudinal analysis. Genetic contribution to disease variation (i.e., heritability) was estimated in two ways: by comparing similarity of lung function in monozygous (MZ) twins ‫ف(‬ 100% gene sharing) with that of dizygous (DZ) twins/siblings ‫ف(‬ 50% gene sharing), and by comparing similarity of lung function measures for related siblings to similarity for all study subjects. Measurements and Main Results

Background & Aims-Neonatal intestinal obstruction (meconium ileus or MI) occurs in 15% of patients with cystic fibrosis (CF). Our aim was to determine the relative contribution of genetic and non-genetic modifiers to the development of this major complication of CF.

This is the first study to correlate live cell imaging with quantitative genetic and histologic techniques. Noninvasive molecular imaging tracked delivered cells and will permit the evaluation of new and improved delivery platforms designed to increase cell homing, retention, and engraftment.

Diabetes is characterized by hyperglycemia due partly to increased hepatic glucose production. The hypothalamus regulates hepatic glucose production in rodents. However, it is currently unknown whether other regions of the brain are sufficient in glucose production regulation. The N-methyl-D-aspartate (NMDA) receptor is composed of NR1 and NR2 subunits, which are activated by co-agonist glycine and glutamate or aspartate, respectively. Here we report that direct administration of either co-agonist glycine or NMDA into the dorsal vagal complex (DVC), targeting the nucleus of the solitary tract, lowered glucose production in vivo. Direct infusion of the NMDA receptor blocker MK-801 into the DVC negated the metabolic effect of glycine. To evaluate whether NR1 subunit of the NMDA receptor mediates the effect of glycine, NR1 in the DVC was inhibited by DVC NR1 antagonist 7-chlorokynurenic acid or DVC shRNA-NR1. Pharmacological and molecular inhibition of DVC NR1 negated the metabolic effect of glycine. To evaluate whether the NMDA receptors mediate the effects of NR2 agonist NMDA, DVC NMDA receptors were inhibited by antagonist D-2-amino-5-phosphonovaleric acid (D-APV). DVC D-APV fully negated the ability of DVC NMDA to lower glucose production. Finally, hepatic vagotomy negated the DVC glycine ability to lower glucose production. These findings demonstrate that activation of NR1 and NR2 subunits of the NMDA receptors in the DVC is sufficient to trigger a brain-liver axis to lower glucose production, and suggest that DVC NMDA receptors serve as a therapeutic target for diabetes and obesity.Diabetes and obesity are partly characterized by a disruption in glucose homeostasis. An elevation of glucose production and/or a decrease in glucose uptake lead to a rise in plasma glucose levels and the breakdown of gluco-regulatory homeostatic mechanisms. In fact, an increased production of glucose by the liver is determined to be the major contributing factor to fasting hyperglycemia in type 2 diabetes (1).To date, the mechanisms underlying the regulation of hepatic glucose production and homeostasis in healthy and obese/diabetic conditions remain to be elucidated. In this regard, the hypothalamus detects a rise in nutrients and hormones to regulate peripheral glucose homeostasis and specifically lower glucose production (2-14). However, the neuronal network that controls glucose homeostasis remains unclear.The N-methyl-D-aspartate (NMDA) 5 receptor is composed of NR1 and NR2 subunits, which are activated by co-agonist glycine and glutamate or aspartate, respectively (15). NMDA is a selective agonist of NMDA receptors and NMDA receptors are fundamental to excitatory neurotransmission (Fig. 1a). In the CNS, the NMDA receptors have important roles in synaptic plasticity and neuronal development (16). In addition, direct administration of NMDA receptor blocker into the DVC negates the ability of lipid/cholecystokinin-sensing mechanisms in the gut to regulate glucose production (17, 18). However, it remains unknown whether direct a...