Characteristics of Consecutive Esophageal Motility Diagnoses After a Decade of Change

BACKGROUND AND AIMS Combined multichannel intraluminal impedance and esophageal manometry (MII-EM) measures concomitantly bolus transit and pressure changes allowing determination of the functional impact of esophageal motility abnormalities. Ten years ago our laboratory reported MII-EM results in 350 consecutive patients. Since then high-resolution impedance manometry (HRIM) became available and the definitions of ineffective esophageal motility (IEM) and nutcracker esophagus were revised. The aim of this study was to assess the impact of these developments on esophageal function testing. METHODS From August 2012 through May 2013, HRIM was performed in 350 patients referred for esophageal function testing. Each patient received 10 liquid and 10 viscous swallows. While taking advantage of the new technology and revised criteria, HRIM findings were classified according to the conventional criteria to allow more appropriate comparison with our earlier analysis. RESULTS Compared with the study performed 10 years ago, the prevalence of normal manometry (36% vs. 35%), achalasia (7% vs. 8%), scleroderma (1% vs. 1%), hypertensive lower esophageal sphincter (LES) (7% vs. 7%), and hypotensive LES (1% vs. 2%) remained the same, whereas the prevalence of distal esophageal spasm (9% vs. 3%), nutcracker esophagus (9% vs. 3%), and poorly relaxing LES (10% vs. 3%) decreased and the prevalence of IEM increased (20% vs. 31%) significantly. Compared with the early study, normal liquid bolus transit was significantly different in patients with hypertensive LES (96% vs. 57%) and poorly relaxing LES (55% vs. 100%). CONCLUSIONS This study brings to light the increase in prevalence of IEM. In addition, it suggests that the hypertensive LES and poorly relaxing LES may each affect bolus transit in about half of these patients.

Prevalence of gastro esophageal reflux disease following the Montreal Consensus and its association with Helicobacter pylori infection and obesity in a random sample of adults of Ciudad Juarez, Mexico, 2004.

Gastroesophageal reflux disease is a common condition affecting 25 to 40% of the population and causes significant morbidity in the U.S., accounting for at least 9 million office visits to physicians with estimated annual costs of $10 billion. Previous research has not clearly established whether infection with Helicobacter pylori, a known cause of peptic ulcer, atrophic gastritis and non cardia adenocarcinoma of the stomach, is associated with gastroesophageal reflux disease. This study is a secondary analysis of data collected in a cross-sectional study of a random sample of adult residents of Ciudad Juarez, Mexico, that was conducted in 2004 (Prevalence and Determinants of Chronic Atrophic Gastritis Study or CAG study, Dr. Victor M. Cardenas, Principal Investigator). In this study, the presence of gastroesophageal reflux disease was based on responses to the previously validated Spanish Language Dyspepsia Questionnaire. Responses to this questionnaire indicating the presence of gastroesophageal reflux symptoms and disease were compared with the presence of H. pylori infection as measured by culture, histology and rapid urease test, and with findings of upper endoscopy (i.e., hiatus hernia and erosive and atrophic esophagitis). The prevalence ratio was calculated using bivariate, stratified and multivariate negative binomial logistic regression analyses in order to assess the relation between active H. pylori infection and the prevalence of gastroesophageal reflux typical syndrome and disease, while controlling for known risk factors of gastroesophageal reflux disease such as obesity. In a random sample of 174 adults 48 (27.6%) of the study participants had typical reflux syndrome and only 5% (or 9/174) had gastroesophageal reflux disease per se according to the Montreal consensus, which defines reflux syndromes and disease based on whether the symptoms are perceived as troublesome by the subject. There was no association between H. pylori infection and typical reflux syndrome or gastroesophageal reflux disease. However, we found that in this Northern Mexican population, there was a moderate association (Prevalence Ratio=2.5; 95% CI=1.3, 4.7) between obesity (≥30 kg/m2) and typical reflux syndrome. Management and prevention of obesity will significantly curb the growing numbers of persons affected by gastroesophageal reflux symptoms and disease in Northern Mexico. ^

A novel amplicon at 8p22–23 results in overexpression of cathepsin B in esophageal adenocarcinoma

Cathepsin B (CTSB) is overexpressed in tumors of the lung, prostate, colon, breast, and stomach. However, evidence of primary genomic alterations in the CTSB gene during tumor initiation or progression has been lacking. We have found a novel amplicon at 8p22–23 that results in CTSB overexpression in esophageal adenocarcinoma. Amplified genomic NotI–HinfI fragments were identified by two-dimensional DNA electrophoresis. Two amplified fragments (D4 and D5) were cloned and yielded unique sequences. Using bacterial artificial chromosome clones containing either D4 or D5, fluorescent in situ hybridization defined a single region of amplification involving chromosome bands 8p22–23. We investigated the candidate cancer-related gene CTSB, and potential coamplified genes from this region including farnesyl-diphosphate farnesyltransferase (FDFT1), arylamine N-acetyltransferase (NAT-1), lipoprotein lipase (LPL), and an uncharacterized expressed sequence tag (D8S503). Southern blot analysis of 66 esophageal adenocarcinomas demonstrated only CTSB and FDFT1 were consistently amplified in eight (12.1%) of the tumors. Neither NAT-1 nor LPL were amplified. Northern blot analysis showed overexpression of CTSB and FDFT1 mRNA in all six of the amplified esophageal adenocarcinomas analyzed. CTSB mRNA overexpression also was present in two of six nonamplified tumors analyzed. However, FDFT1 mRNA overexpression without amplification was not observed. Western blot analysis confirmed CTSB protein overexpression in tumor specimens with CTSB mRNA overexpression compared with either normal controls or tumors without mRNA overexpression. Abundant extracellular expression of CTSB protein was found in 29 of 40 (72.5%) of esophageal adenocarcinoma specimens by using immunohistochemical analysis. The finding of an amplicon at 8p22–23 resulting in CTSB gene amplification and overexpression supports an important role for CTSB in esophageal adenocarcinoma and possibly in other tumors.

Caldesmon Inhibits Nonmuscle Cell Contractility and Interferes with the Formation of Focal Adhesions

Caldesmon is known to inhibit the ATPase activity of actomyosin in a Ca2+–calmodulin-regulated manner. Although a nonmuscle isoform of caldesmon is widely expressed, its functional role has not yet been elucidated. We studied the effects of nonmuscle caldesmon on cellular contractility, actin cytoskeletal organization, and the formation of focal adhesions in fibroblasts. Transient transfection of nonmuscle caldesmon prevents myosin II-dependent cell contractility and induces a decrease in the number and size of tyrosine-phosphorylated focal adhesions. Expression of caldesmon interferes with Rho A-V14-mediated formation of focal adhesions and stress fibers as well as with formation of focal adhesions induced by microtubule disruption. This inhibitory effect depends on the actin- and myosin-binding regions of caldesmon, because a truncated variant lacking both of these regions is inactive. The effects of caldesmon are blocked by the ionophore A23187, thapsigargin, and membrane depolarization, presumably because of the ability of Ca2+–calmodulin or Ca2+–S100 proteins to antagonize the inhibitory function of caldesmon on actomyosin contraction. These results indicate a role for nonmuscle caldesmon in the physiological regulation of actomyosin contractility and adhesion-dependent signaling and further demonstrate the involvement of contractility in focal adhesion formation.

Rho-stimulated Contractility Contributes to the Fibroblastic Phenotype of Ras-transformed Epithelial Cells

Oncogenic transformation of cells alters their morphology, cytoskeletal organization, and adhesive interactions. When the mammary epithelial cell line MCF10A is transformed by activated H-Ras, the cells display a mesenchymal/fibroblastic morphology with decreased cell–cell junctions but increased focal adhesions and stress fibers. We have investigated whether the transformed phenotype is due to Rho activation. The Ras-transformed MCF10A cells have elevated levels of myosin light chain phosphorylation and are more contractile than their normal counterparts, consistent with the activation of Rho. Furthermore, inhibitors of contractility restore a more normal epithelial phenotype to the Ras-transformed MCF10A cells. However, inhibiting Rho by microinjection of C3 exotransferase or dominant negative RhoA only partially restores the normal phenotype, in that it fails to restore normal junctional organization. This result prompted us to examine the effect that inhibiting Rho would have on the junctions of normal MCF10A cells. We have found that inhibiting Rho by C3 microinjection leads to a disruption of E-cadherin cytoskeletal links in adherens junctions and blocks the assembly of new adherens junctions. The introduction of constitutively active Rho into normal MCF10A cells did not mimic the Ras-transformed phenotype. Thus, these results lead us to conclude that some, but not all, characteristics of Ras-transformed epithelial cells are due to activated Rho. Whereas Rho is needed for the assembly of adherens junctions, high levels of activated Rho in Ras-transformed cells contribute to their altered cytoskeletal organization. However, additional events triggered by Ras must also be required for the disruption of adherens junctions and the full development of the transformed epithelial phenotype.

Membrane healing and restoration of contractility after mechanical injury in isolated skeletal muscle fibers of the frog.

In single isolated skeletal muscle fibers of the frog, we studied (i) the recovery from large sarcolemmal mechanical injuries of the response to electric stimulation and (ii) the integrity of the sarcolemma under the light microscope. In Ringer's solution, the damaged cells stopped contracting and deteriorated completely within 1 hr. In the presence of phosphatidylcholine (0.025 g/ml in Ringer's solution), the injured cells initially responded with local twitches. Within 0.5 hr, contractility and membrane integrity started to recover and both were back to control levels within 3 hr. When these cells were placed back in normal Ringer's solution, they remained viable and active for several hours. Our results suggest that phosphatidylcholine can protect muscle fibers from the effects of sarcolemmal injury.

Markers for silent atrial fibrillation in esophageal long-term electrocardiography.

PURPOSE Paroxysmal atrial fibrillation (PAF) often remains undiagnosed. Long-term surface ECG is used for screening, but has limitations. Esophageal ECG (eECG) allows recording high quality atrial signals, which were used to identify markers for PAF. METHODS In 50 patients (25 patients with PAF; 25 controls) an eECG and surface ECG was recorded simultaneously. Partially A-V blocked atrial runs (PBARs) were quantified, atrial signal duration in eECG was measured. RESULTS eECG revealed 1.8‰ of atrial premature beats in patients with known PAF to be PBARs with a median duration of 853ms (interquartile range (IQR) 813-1836ms) and a median atrial cycle length of 366ms (IQR 282-432ms). Even during a short recording duration of 2.1h (IQR 1.2-17.2h), PBARs occurred in 20% of PAF patients but not in controls (p=0.05). Left atrial signal duration was predictive for PAF (72% sensitivity, 80% specificity). CONCLUSIONS eECG reveals partially blocked atrial runs and prolonged left atrial signal duration - two novel surrogate markers for PAF.

Current cancer research on etiology, epidemilogy and related biology of gastrointestinal, oral, esophageal and pancreatic cancers.

Includes index.

Irritability and Contractility of Muscle

The student is determining the effect of after-load on the work done on a frog's muscle (source: Not Just Any Medical School by Horace W. Davenport)

Relationship between longitudinal and radial contractility in subclinical diabetic heart disease

Subclinical left ventricular (W) dysfunction may be identified by reduced longitudinal contraction. We sought to define the effects of subclinical LV dysfunction on radial contractility in 53 patients with diabetes mellitus with no LV hypertrophy, normal ejection fraction and no ischaemia as assessed by dobutamine echocardiography, in comparison with age-matched controls. Radial peak myocardial systolic velocity (S-m) and early diastolic velocity (E-m), strain and strain rate were measured in the mid-posterior and mid-anteroseptal walls in parasternal views and each variable was averaged for individual patients (radial contractility). These variables were also measured in the mid-posterior and mid-anteroseptal walls in the apical long-axis view and each variable was averaged for individual patients (longitudinal contractility). Mean radial S-m, strain and strain rate were significantly increased in diabetic patients (2.9+/-0.6 cm/s, 28+/-5% and 1.8+/-0.4 s(-1) respectively) compared with controls (2.4+/-0.7 cm/s, 23+/-4% and 1.6+/-0.3 s(-1) respectively; all P<0.001), but there was no difference in E-m (3.3&PLUSMN;1.2 compared with 3.1&PLUSMN;1.1 cm/s, P=not significant). In contrast, longitudinal S-m, E-m, strain and strain rate were significantly lower in diabetic patients (3.6&PLUSMN;1.1 cm/s, 4.3&PLUSMN;1.6 cm/s, 21&PLUSMN;4% and 1.6&PLUSMN;0.3 s(-1) respectively) than in controls (4.3&PLUSMN;1.0 cm/s, 5.7&PLUSMN;2.3 cm/s, 26&PLUSMN;4% and 1.9&PLUSMN;0.3 s(-1) respectively; all P<0.00 1). Thus radial contractility appears to compensate for reduced longitudinal contractility in subclinical LV dysfunction occurring in the absence of ischaemia or LV hypertrophy.