Objective. To determine if DNA methylation inhibitors make T cells autoreactive by inducing lymphocyte function-associated antigen type 1 (LFA-1) ( C D l l d CD18) overexpression.Methods. T cell clones were treated with 3 distinct DNA methylation inhibitors or were stably transfected with a CD18 cDNA in a mammalian expression vector, and the effects on LFA-1 expression and activation requirements were examined.Results. LFA-1 overexpression, caused by DNA methylation inhibitors or by transfection, correlates with the development of autoreactivity.Conclusion. LFA-1 overexpression may contribute to T cell autoreactivity.

Tricyclic antidepressants treat chronic pain both in patients with somatic illness and with functional bowel disorders. We compared the effects of amitriptyline on perception of cutaneous and gastrointestinal stimulation to assess differential analgesic effects of tricyclics on somatic and visceral pain. Cutaneous electrical stimulation and rectal and esophageal distension were performed before and after 21 days of double-blind 50 mg amitriptyline vs. placebo in healthy volunteers. Amitriptyline increased currents that elicited cutaneous threshold, moderate discomfort, and moderate pain compared with basal ( P < 0.05), whereas placebo had no effect. Amitriptyline had no effect on perception of rectal and esophageal distension and did not alter luminal compliance; thus the lack of effect on perception is not due to altered visceral elastic wall properties. In conclusion, amitriptyline reduces perception of cutaneous stimulation but does not alter visceral perception or compliance. This investigation demonstrates differential effects of tricyclics on somatic and visceral afferent function in healthy humans and provides insight into mechanisms of action in chronic pain both from somatic disease and from functional bowel disorders.

Colonic motor function is modulated by extended and local neural reflexes involving unknown mediators. To test the role of serotonin (5-HT3) pathways, increases in colonic tone during antral distension and duodenal lipid perfusion (gastrocolonic responses) and changes in orad and caudad colonic tone in response to local colonic distension (peristaltic reflex) were measured after double-blind granisetron (10 μg/kg) or placebo infusion in healthy human volunteers. Antral distension evoked increases in colonic tone, which were blunted by granisetron ( P < 0.05) without effects on antral compliance. Intraduodenal lipid perfusion also evoked increased colonic tone, which was reduced by granisetron ( P < 0.05). In contrast, orad colonic contractions and caudad relaxations and contractions during colonic distension were unaffected by granisetron. In conclusion, 5-HT3 receptor antagonism blunts both the mechano- and chemoreceptor components of the human gastrocolonic response without altering antral compliance. In contrast, 5-HT3 pathways play no role in the ascending or descending components of the colonic peristaltic reflex. These findings demonstrate different roles for 5-HT3 receptors in the control of colonic motor function by the proximal gastrointestinal tract and by local neural reflexes.

Nausea and gastric dysrhythmias occur in conditions associated with gastric distension. The roles of distal and proximal gastric mechanoreceptors in these responses are unexplored. Because antral distension induces vomiting in animals and antral and fundic vagal afferent discharges differ, we hypothesized that distal gastric distension in humans leads to greater symptomatic and dysrhythmic responses than proximal distension. Symptoms and electrogastrograms were recorded in healthy humans during distal and proximal gastric distension with a barostat. Distal but not proximal distension induced nausea and a 747 ± 250% increase in dysrhythmic power ( P < 0.05), responses not affected by granisetron, indomethacin, or atropine, agents that block dysrhythmias in other settings. In the distal stomach, bloating and pain developed at lower pressures ( P < 0.05) not modified by granisetron, and compliance was significantly lower ( P < 0.05). In conclusion, gastric mechanoreceptor activation in the less-compliant distal stomach produces nausea and dysrhythmias via non-5-hydroxytryptamine3(5-HT3), non-prostaglandin-dependent, and noncholinergic pathways. Distal mechanoreceptor activation induces greater bloating and pain than proximal mechanoreceptor activation via 5-HT3-independent pathways.

First trimester nausea is associated with gastric slow wave dysrhythmias (tachygastria, bradygastria). We tested the roles of meal composition and caloric content on nausea and slow wave rhythm in 14 nauseated pregnant women. Electrogastrography quantified dysrhythmic activity and signal power responses to meals. Symptomatic women reported mild to moderate nausea and exhibited increased dysrhythmias during fasting (P < 0.05). Protein-predominant meals reduced nausea and dysrhythmic activity to greater degrees than equicaloric carbohydrate and fat meals and noncaloric meals (P < 0.05). Meal consistency did not affect symptom responses, although liquid meals decreased dysrhythmias more than solids (P < 0.05). Carbohydrates and fats increased electrogastrographic power to similar degrees as proteins, whereas responses to noncaloric meals were less. In conclusion, protein meals selectively reduce nausea and gastric slow wave dysrhythmias in first trimester pregnancy. Meal consistency is a limited factor in the favorable effects of protein. Electrogastrographic power changes do not explain the symptom response to protein. Thus dietary modulation of gastric myoelectric rhythm with protein supplementation may provide symptomatic benefit in nausea of pregnancy.