The Cooperative Study of Sickle Cell Disease

genetic variation within this enhancer is associated with modest impact on TF binding, BCL11A expression, and HbF level. Relatively small effect sizes associated with individual variants may not be surprising given that most single-nucleotide substitutions, even within critical motifs, result in only modest loss of enhancer activity Challenges to inhibiting BCL11A for mechanismbased reactivation of HbF include the supposedly "undruggable" nature of transcription factors (34) and its important nonerythroid functions (20

A placebo-controlled trial of itopride in functional dyspepsia

Dyspepsia remains a common and costly problem in primary care and gastroenterology practice; in most patients who are examined, no structural lesions causing these symptoms are found.1 Dyspepsia in the absence of a clinically identifiable structural lesion is referred to as functional dyspepsia,2,3 in part because disturbed gastrointestinal function is believed to play a role in the development of symptoms.4 Pharmacologic treatments for patients with functional dyspepsia remain unsatisfactory.5 The results of controlled trials have generally been disappointing, and only small benefits relative to placebo have been found with histamine H 2 -receptor antagonists,6 proton-pump inhibitors,7 and Helicobacter pylori eradication.8 Although several randomized, controlled trials and metaanalyses have demonstrated the superiority of cisapride over placebo,9-11 the use of cisapride is now restricted in most countries because of cardiac side effects. In Japan, itopride, which is a dopamine D2 antagonist with acetylcholinesterase inhibitory actions, is often prescribed for patients with functional dyspepsia. Although this drug has been shown to stimulate gastric motility,12 large, properly designed, randomized, controlled trials in patients with functional dyspepsia are lacking. In Japan, administration of 50 mg three times daily is standard practice. However, little is known regarding the dose response in other populations. For this reason, we aimed to study the efficacy of itopride in patients with functional dyspepsia in terms of symptom improvement and to compare various doses of itopride in terms of efficacy and safety in a white population. Methods Study Design and Patient Population Patients Outpatients who were considered to have functional dyspepsia on the basis of the Rome II criteria3 were eligible for the trial. Functional dyspepsia was diagnosed if persistent or recurrent upper abdominal pain or discomfort was present. Discomfort was characterized by the presence of one or more symptoms that included early satiety, postprandial fullness, bloating, and nausea