SUMMARYBackground: Irritable bowel syndrome is a common functional gastrointestinal disorder which affects up to 20% of the population, with a predominance in females. Aim: To evaluate the efficacy and safety of tegaserod in female patients with irritable bowel syndrome characterized by symptoms of abdominal pain ⁄ discomfort and constipation. Methods: In a randomized, double-blind, multicentre study, 1519 women received either tegaserod, 6 mg b.d. (n ¼ 767), or placebo (n ¼ 752) for 12 weeks, preceded by a 4-week baseline period without treatment and followed by a 4-week open withdrawal period. The primary efficacy evaluation was the patient's sympto-

The maximum size of organisms has increased enormously since the initial appearance of life >3.5 billion years ago (Gya), but the pattern and timing of this size increase is poorly known. Consequently, controls underlying the size spectrum of the global biota have been difficult to evaluate. Our period-level compilation of the largest known fossil organisms demonstrates that maximum size increased by 16 orders of magnitude since life first appeared in the fossil record. The great majority of the increase is accounted for by 2 discrete steps of approximately equal magnitude: the first in the middle of the Paleoproterozoic Era (Ϸ1.9 Gya) and the second during the late Neoproterozoic and early Paleozoic eras (0.6 -0.45 Gya). Each size step required a major innovation in organismal complexity-first the eukaryotic cell and later eukaryotic multicellularity. These size steps coincide with, or slightly postdate, increases in the concentration of atmospheric oxygen, suggesting latent evolutionary potential was realized soon after environmental limitations were removed.body size ͉ Cambrian ͉ oxygen ͉ Precambrian ͉ trend D espite widespread scientific and popular fascination with the largest and smallest organisms and numerous studies of body size evolution within individual taxonomic groups (1-9), the first-order pattern of body size evolution through the history of life has not been quantified rigorously. Because size influences (and may be limited by) a broad spectrum of physiological, ecological, and evolutionary processes (10-16), detailed documentation of size trends may shed light on the constraints and innovations that have shaped life's size spectrum over evolutionary time as well as the role of the body size spectrum in structuring global ecosystems. Bonner (17) presented a figure portraying a gradual, monotonic increase in the overall maximum size of living organisms over the past 3.5 billion years. The pattern appears consistent with a simple, continuous underlying process such as diffusion (18), but could also reflect a more complex process. Bonner, for example, proposed that lineages evolve toward larger sizes to exploit unoccupied ecological niches. For decades, Bonner's has been the only attempt to quantify body size evolution over the entire history of life on Earth, but the data he presented were not tied to particular fossil specimens and were plotted without consistent controls on taxonomic scale against a nonlinear timescale. Hence, we have lacked sufficient data on the tempo and mode of maximum size change to evaluate potential first-order biotic and abiotic controls on organism size through the history of life.Here, we document the evolutionary history of body size on Earth, focusing on the upper limit to size. Use of maximum size allows us to assess constraints on the evolution of large body size and avoids the more substantial empirical difficulties in determining mean, median, or minimum size for all life or even for many individual taxa. For each era within the Archean Eon (4,000-2,500 Mya) and ...

SUMMARY Background Gluten-free diet (GFD) is the only management available for celiac disease (CeD), a permanent immune intolerance to gluten. Nexvax2® is the first therapeutic vaccine designed to treat CeD. The adjuvant-free formulation of peptides is intended to engage and render gluten-specific CD4+ T cells unresponsive to further antigenic stimulation. We have assessed safety and pharmacodynamics of Nexvax2® in patients with CeD on GFD. Methods In two randomized, double-blind, placebo-controlled, phase 1 studies at 12 community sites in Australia, New Zealand and the United States, we screened for HLA-DQ2·5+ CeD patients (aged 18–70 years) on GFD. The screening and post-treatment periods included either a crossover, placebo-controlled, oral gluten challenge (OGC) to mobilize and assess T cells responsive to Nexvax2 or, for the final cohort in each study, endoscopy and duodenal histology without OGC. Participants and study staff were masked to the gluten content of food provided for each interval of the OGCs. One of two sequences of active and placebo challenges was assigned (1:1) by central randomization using a simple block method. The sequence of challenges was active/placebo then active/placebo, or placebo/active then active/placebo for the OGCs in the screening and post-treatment periods, respectively. Participants with a negative interferon (IFN)-γ release assay (IGRA) to Nexvax2 peptides after the screening OGC, or Marsh score >1 were discontinued before dosing. There was temporal allocation of participants to sequential cohorts assessing multiple fixed intradermal doses of Nexvax2 (60µg, 90µg, or 150µg weekly in the 3-dose study; or 150µg, or 300µg two-times weekly in the 16-dose study) in 0.1 mL 0.9% sodium chloride. A maximum tolerated dose (MTD) was administered in the final biopsy cohort in each study. Participants within each cohort were assigned to receive Nexvax2 or placebo by central randomization (2:1, respectively) using simple block method in SAS software Version 9·2. Participants, investigators, and study staff were masked to the treatment assignment, except for the study pharmacist. The primary endpoint was the number and percentage of adverse events in the treatment period. Other safety outcomes included duodenal histology, gastrointestinal symptoms, plasma cytokines, and immune cell frequencies. The main pharmacodynamic endpoint was IGRA to Nexvax2 peptides. All participants who received Nexvax2 or placebo, the safety population, were included in an intention to treat analysis for the primary endpoint. Additional post hoc analyses were also performed. Both trials were completed and closed before data analysis. Trials were registered with Australian New Zealand Clinical Trials Registry, numbers ACTRN12612000355875 and ACTRN12613001331729. Findings Participants were screened from November 28, 2012 to August 14, 2014, and August 3, 2012 to September 10, 2013, for the 3-dose and 16-dose studies respectively. Across both studies, 136 (80%) of 169 volunteers met initial eligibility crite...

Alosetron 0.5 mg and 1 mg once daily as well as 1 mg twice daily are effective in providing global improvement in IBS symptoms, adequate relief of IBS pain and discomfort, and improvement in bowel symptoms in women with severe d-IBS. Lower dosing regimens resulted in a decreased constipation rate.