Larry D. Scott

Effect of pregnancy on gastrointestinal transit.

In order to evaluate the possible effects of pregnancy-associated sex steroids on gastrointestinal function, we determined gastrointestinal transit times and sex steroid levels in 15 women during the third trimester of their pregnancies and again 4–6 weeks following delivery when gastrointestinal function had symptomatically returned to normal. Gastrointestinal transit time from ingestion of a liquid lactulose meal to its delivery to the cecum was determined by monitoring breath hydrogen concentrations at 10-min intervals. Gastrointestinal transit times were significantly prolonged in the third trimester of pregnancy, when progesterone and estradiol levels were increased, compared to the postpartum period. This study supports previous findings which suggest that increasing levels of progesterone and estradiol affect gastrointestinal function and therefore may contribute to gastrointestinal symptoms that often occur in pregnant women.

Artificial Nutrition and Hydration: The Evolution of Ethics, Evidence, and Policy

IntroductionThe debate over use of artificial nutrition and hydration (ANH) in terminal illness, including advanced dementia, remains contentious despite extensive ethical and empirical investigation.MethodsFor this narrative review we undertook a focused, selective review of literature reflecting ethical analysis, empirical assessment of outcomes, legal responses, and thinking within the Roman Catholic religious tradition.ResultsThe history of the debate over the past 60 years results from a complex interplay of ethical concerns, a growing empirical database, legal changes, public opinion, and financial as well as institutional concerns. Discussions of ANH today are often conducted without any understanding of this historical context.DiscussionPatients’ interests could be better protected through remedial action at both the individual and the policy levels.

Pregnancy-Related Changes in Small Intestinal Myoelectric Activity in the Rat

To determine if changes in intestinal motility occur during pregnancy, we studied small intestinal myoelectric activity, using monopolar electrodes, in fasted pregnant rats from day 12 to day 18 of the 22-day gestation period. We also studied fasting myoelectric activity in postpartum, nonpregnant, and castrate females. In all rats, the interdigestive myoelectric complex was invariably present with recurring activity fronts appearing at the proximal electrode and moving slowly abroad. Intervals between fronts were similar in all four groups, ranging from 12.61 min to 14.58 min. In pregnant rats, however, there was loss of the periodicity characteristic of activity fronts in the other groups; intervals up to 43 min in length were occasionally noted. Unorganized, randomly occurring spike potentials characterized these intervals. The average coefficient of variation of interval length was significantly (p less than 0.05) greater in pregnant rats (0.401) than in castrate (0.197) and nonpregnant rats (0.248). These studies confirm the presence in rats of pregnancy-related changes in small intestinal myoelectric activity.

Esophageal adenocarcinoma in a patient with surgically treated achalasia.

SummaryAlthough squamous cell carcinoma of the esophagus occurs with increased incidence in primary achalasia, esophageal adenocarcinoma has been considered rare in this condition. We report a patient with long-standing achalasia in whom adenocarcinoma of the esophagus occurred many years after Heller esophagomyotomy, presumably related to Barretts esophagus complicating gastroesophageal reflux disease.

Improved Angiogenesis in Response to Localized Delivery of Macrophage-Recruiting Molecules

Successful engineering of complex organs requires improved methods to promote rapid and stable vascularization of artificial tissue scaffolds. Toward this goal, tissue engineering strategies utilize the release of pro-angiogenic growth factors, alone or in combination, from biomaterials to induce angiogenesis. In this study we have used intravital microscopy to define key, dynamic cellular changes induced by the release of pro-angiogenic factors from polyethylene glycol diacrylate hydrogels transplanted in vivo. Our data show robust macrophage recruitment when the potent and synergistic angiogenic factors, PDGFBB and FGF2 were used as compared with VEGF alone and intravital imaging suggested roles for macrophages in endothelial tip cell migration and anastomosis, as well as pericyte-like behavior. Further data from in vivo experiments show that delivery of CSF1 with VEGF can dramatically improve the poor angiogenic response seen with VEGF alone. These studies show that incorporating macrophage-recruiting factors into the design of pro-angiogenic biomaterial scaffolds is a key strategy likely to be necessary for stable vascularization and survival of implanted artificial tissues.

Research‐Related Injury: Problems and Solutions

he highly publicized deaths of research participants Ellen Roche and Jesse Gelsinger are stark T reminders that risk is inherent in medical research and while untoward outcomes are infrequent when compared to individual and societal benefits, injury and even death will happen.’ Who is responsible for the welfare of research subjects and what are they owed? Why were they put at risk to begin with? Are obligations, if any, to research subjects dependent on the type of study in which they participate, in recognition that there may be personal benefit from participation in some studies? The issue of injury resulting from participation in research and answers to questions such as those just posed were last considered in depth nearly 20 years ago by the President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research.* The Commission concluded that while the likelihood of injury was small, there was nonetheless an obligation to provide some kind of compensation. It thus proposed an experiment, to be conducted with federal funding at a small number of institutions, to define need and to evaluate compensation of injured subjects on a no-fault basis. This proposal was never implemented, although it was endorsed in 1335 by the Advisory Committee on Human Radiation E~periments,~ and in 2001 by the National Bioethics Advisory Commission (NBAC), just prior to its decommi~sion.~ The research enterprise has expanded significantly since 1982 and the sophistication and complexity of studies has markedly increased. The private domain has assumed a larger proportion of sponsorship of investigation involving human subjects.5 In the development of new drugs, there has been an emphasis on a more timely approval process.

The PEG "consult".

The patient is a 70-yr-old Asian male admitted to the hospital 1 day previously because of suspected dehydration. A highly educated man, he had obtained two Ph.D. degrees when younger, and had had a productive professional life; however, over the prior few years he had developed dementia which was thought to be multi-infarct in origin. He had no close relatives and his personal and medical affairs were managed by an attorney who resided in another city. Despite these circumstances, he had remained reasonably functional, living in an assisted-living facility, up until 2 wk prior to admission. At that time, the chart noted, he had suffered a “massive stroke.” Any details about his neurological state at that time were not available. His other medical problems were diabetes and hypertension, for which he was on medication. Following admission to the hospital he was managed with intravenous fluids. He was noted to drool continually and there was concern that he might not be able to swallow. The consultation was called for placement of a percutaneous endoscopic gastrostomy (PEG). Upon entering the room, the patient was actually sitting in a chair, with a restraining vest keeping him from getting up. He appeared alert, but was noncommunicative. He was able to shake hands, but had no facial expression and seemed unaware of what was going on around him. He could not squeeze fingers or nod in response to simple questions. There seemed to be excessive oral secretions, but he would not drink fluids either through a straw or with assistance. The remainder of his physical exam uncovered no abnormalities. His lungs were clear. Heart rate and rhythm were normal; no murmur was heard. The abdomen was soft and nondistended. No surgical scars were noted. There was no tenderness, mass, or organomegaly, and bowel sounds were normal. Apart from mild prerenal azotemia, no significant laboratory abnormalities were found. On further discussion with the patient’s nurse, it was learned that the patient had an out-of-hospital DNR and within this document a number of life-sustaining interventions were declined. However, no advance directive was noted. COMMENT

Enhanced Cardiomyocyte NLRP3 Inflammasome Signaling Promotes Atrial Fibrillation

Background: Atrial fibrillation (AF) is frequently associated with enhanced inflammatory response. The NLRP3 (NACHT, LRR, and PYD domain containing protein 3) inflammasome mediates caspase-1 activation and interleukin-1&bgr; release in immune cells but is not known to play a role in cardiomyocytes (CMs). Here, we assessed the role of CM NLRP3 inflammasome in AF. Methods: NLRP3 inflammasome activation was assessed by immunoblot in atrial whole-tissue lysates and CMs from patients with paroxysmal AF or long-standing persistent (chronic) AF. To determine whether CM-specific activation of NLPR3 is sufficient to promote AF, a CM-specific knockin mouse model expressing constitutively active NLRP3 (CM-KI) was established. In vivo electrophysiology was used to assess atrial arrhythmia vulnerability. To evaluate the mechanism of AF, electric activation pattern, Ca2+ spark frequency, atrial effective refractory period, and morphology of atria were evaluated in CM-KI mice and wild-type littermates. Results: NLRP3 inflammasome activity was increased in the atrial CMs of patients with paroxysmal AF and chronic AF. CM-KI mice developed spontaneous premature atrial contractions and inducible AF, which was attenuated by a specific NLRP3 inflammasome inhibitor, MCC950. CM-KI mice exhibited ectopic activity, abnormal sarcoplasmic reticulum Ca2+ release, atrial effective refractory period shortening, and atrial hypertrophy. Adeno-associated virus subtype-9–mediated CM-specific knockdown of Nlrp3 suppressed AF development in CM-KI mice. Finally, genetic inhibition of Nlrp3 prevented AF development in CREM transgenic mice, a well-characterized mouse model of spontaneous AF. Conclusions: Our study establishes a novel pathophysiological role for CM NLRP3 inflammasome signaling, with a mechanistic link to the pathogenesis of AF, and establishes the inhibition of NLRP3 as a potential novel AF therapy approach.

Treatment of catecholaminergic polymorphic ventricular tachycardia in mice using novel RyR2-modifying drugs

RATIONALE Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal arrhythmic disorder caused by mutations in the type-2 ryanodine receptor (RyR2). Mutant RyR2 cause abnormal Ca2+ leak from the sarcoplasmic reticulum (SR), which is associated with the development of arrhythmias. OBJECTIVE To determine whether derivatives of tetracaine, a local anesthetic drug with known RyR2 inhibiting action, could prevent CPVT induction by suppression of RyR2-mediated SR Ca2+ leak. METHODS AND RESULTS Confocal microscopy was used to assess the effects of tetracaine and 9 derivatives (EL1-EL9) on spontaneous Ca2+ sparks in ventricular myocytes isolated from RyR2-R176Q/+ mice with CPVT. Whereas each derivative suppressed the Ca2+ spark frequency, derivative EL9 was most effective at the screening dose of 500nmol/L. At this high dose, the Ca2+ transient amplitude was not affected in myocytes from WT or R176Q/+ mice. The IC50 of EL9 was determined to be 13nmol/L, which is about 400× time lower than known RyR2 stabilizer K201. EL9 prevented the induction of ventricular tachycardia observed in placebo-treated R176Q/+ mice, without affecting heart rate or cardiac contractility. CONCLUSIONS Tetracaine derivatives represent a novel class of RyR2 stabilizing drugs that could be used for the treatment of the potentially fatal disorder catecholaminergic polymorphic ventricular tachycardia.

Gastritis cystica profunda: Endoscopic ultrasound findings and review of the literature

Gastritis cystica profunda (GCP) is a rare pseudotumor of the stomach characterized by benign growths of deep gastric glands through the muscularis mucosae into the submucosa. We review a case of GCP in a 61-year-old patient with GCP, with emphasis on endoscopic ultrasound findings and present review of the current literature.