Faculty Bibliography

á…ŸRefractory GERD is very common, and while many different underlying mechanisms have been identified, the main focus has remained on residual reflux (acidic or non-acidic). Recently, Rome IV introduced two new concepts with important impact on patients with refractory GERD. They include the introduction of the reflux hypersensitivity group and the proposal that GERD can overlap with a functional esophageal disorder. Recent studies have demonstrated that the latter affects approximately three quarters of the GERD patients who failed PPI once daily.

The progression of genetically inherited cardiomyopathies from an altered protein structure to clinical presentation of disease is not well understood. One of the main roadblocks to mechanistic insight remains a lack of high-resolution structural information about multiprotein complexes within the cardiac sarcomere. One example is the tropomyosin (Tm) overlap region of the thin filament that is crucial for the function of the cardiac sarcomere. To address this central question, we devised coupled experimental and computational modalities to characterize the baseline function and structure of the Tm overlap, as well as the effects of mutations causing divergent patterns of ventricular remodeling on both structure and function. Because the Tm overlap contributes to the cooperativity of myofilament activation, we hypothesized that mutations that enhance the interactions between overlap proteins result in more cooperativity, and conversely, those that weaken interaction between these elements lower cooperativity. Our results suggest that the Tm overlap region is affected differentially by dilated cardiomyopathy-associated Tm D230N and hypertrophic cardiomyopathy-associated human cardiac troponin T (cTnT) R92L. The Tm D230N mutation compacts the Tm overlap region, increasing the cooperativity of the Tm filament, contributing to a dilated cardiomyopathy phenotype. The cTnT R92L mutation causes weakened interactions closer to the N-terminal end of the overlap, resulting in decreased cooperativity. These studies demonstrate that mutations with differential phenotypes exert opposite effects on the Tm-Tn overlap, and that these effects can be directly correlated to a molecular level understanding of the structure and dynamics of the component proteins.

BACKGROUND:Heartburn is commonly associated with the presence of acid in the oesophageal lumen. However, in patients with nonerosive reflux disease (NERD), the mechanism by which acid traverses the mucosa is not clear. We hypothesized that the luminal acid signal traverses the oesophageal epithelium in the form of the highly permeant gas CO(2) , which then is reconverted to H(+) in the submucosa. MATERIALS AND METHODS/METHODS:  Ten patients with heartburn, normal upper endoscopy and increased oesophageal acid exposure (NERD patients) and 10 healthy subjects were enrolled. Perceptual responses to intraoesophageal acid (0·1 N HCl solution) and a high PCO(2) solution were determined using a randomized cross over design. Stimulus-response functions to perfusions were quantified by three parameters: lag time to symptom perception, intensity rating and perfusion sensitivity score. RESULTS: In NERD patients, the difference in lag time to typical symptom perception, intensity rating and perfusion sensitivity score between high PCO(2) and acid perfusions was statistically significant (P = 0·02, 0·01 and 0·02, respectively). However, the difference in the same perfusion parameters between acid and high PCO(2) perfusions was nonsignificant in healthy controls. When NERD and controls were compared, the difference between the different perfusion variables was nonsignificant (adjusted to age). CONCLUSIONS:In NERD subjects, acid perfusion reliably evoked heartburn symptoms of greater intensity than in healthy controls. Nevertheless, a high PCO(2) perfusion failed to produce symptoms in either group.