A randomized trial of a transglutaminase 2 inhibitor for celiac disease

BACKGROUND In celiac disease, small intestinal transglutaminase 2 causes deamidation of glutamine residues in gluten peptides, which enhances stimulation of T cells and leads to mucosal injury. Inhibition of transglutaminase 2 is a potential treatment for celiac disease. METHODS In a proof-of-concept trial, we assessed the efficacy and safety of a 6-week treatment with ZED1227, a selective oral transglutaminase 2 inhibitor, at three dose levels as compared with placebo, in adults with well-controlled celiac disease who underwent a daily gluten challenge. The primary end point was the attenuation of gluten-induced mucosal damage, as measured by the ratio of villus height to crypt depth. Secondary end points included intraepithelial lymphocyte density, the Celiac Symptom Index score, and the Celiac Disease Questionnaire score (for assessment of health-related quality of life). RESULTS Of the 41 patients assigned to the 10-mg ZED1227 group, the 41 assigned to the 50-mg group, the 41 assigned to the 100-mg group, and the 40 assigned to the placebo group, 35, 39, 38, and 30 patients, respectively, had adequate duodenal-biopsy samples for the assessment of the primary end point. Treatment with ZED1227 at all three dose levels attenuated gluten-induced duodenal mucosal injury. The estimated difference from placebo in the change in the mean ratio of villus height to crypt depth from baseline to week 6 was 0.44 (95% confidence interval [CI], 0.15 to 0.73) in the 10-mg group (P=0.001), 0.49 (95% CI, 0.20 to 0.77) in the 50-mg group (P<0.001), and 0.48 (95% CI, 0.20 to 0.77) in the 100-mg group (P<0.001). The estimated differences from placebo in the change in intraepithelial lymphocyte density were -2.7 cells per 100 epithelial cells (95% CI, -7.6 to 2.2) in the 10-mg group, -4.2 cells per 100 epithelial cells (95% CI, -8.9 to 0.6) in the 50-mg group, and -9.6 cells per 100 epithelial cells (95% CI, -14.4 to -4.8) in the 100-mg group. Use of the 100-mg dose may have improved symptom and quality-of-life scores. The most common adverse events, the incidences of which were similar across all groups, were headache, nausea, diarrhea, vomiting, and abdominal pain. Rash developed in 3 of 40 patients (8%) in the 100-mg group. CONCLUSIONS In this preliminary trial, treatment with ZED1227 attenuated gluten-induced duodenal mucosal damage in patients with celiac disease.publishedVersionPeer reviewe

The Art of the Modernist Body

The Art of the Modernist Body explores the fraught relationship between corporeality and the genesis of new language in modernist literature. The dissertation argues that the history of disability in the early twentieth century facilitates a revised account of Anglo-American modernism; specifically, the modernists' formal preoccupation with loss, deficiency, and absence, long regarded as a vital aspect of the movement, can be re-imagined productively through the heuristic of disability theory. The project likewise reveals that many of modernism's signature novelties, including free verse, Imagism, and the embrace of ordinary speech, are influenced by artists' attempts to represent physical deviance. Each text in question is generated out of repeated encounters with extraordinary figures or forms, and the artists openly challenge the conceptual, social, and political parameters that delimit the ideal human body. Their literature also reminds us that the modernist period is a remarkably inchoate time in terms of how the body is imagined. Two World Wars, the rise of the machine age, and advances in prosthetic and rehabilitative medicine are just a few of the phenomena that brought the human form to the forefront of British and American culture, with politicians, cultural critics, industrial scions, workers, artists, and soldiers all tussling over the social and economic value of imperfect bodies. Accordingly, many accounts from the period resist any entrenched, discrete notions of normality and abnormality, and acts of corporeal discipline, normalization, and rehabilitation are neither roundly condemned nor applauded. The confluence of multiple visions of corporeality not only alters the cultural landscape, but it also affects the very language through which the experience of physical difference is articulated. The novelists and poets herein record both processes, namely by producing what might be called a "contingency of corporeality:" they define the superlative modernist body as a hybrid entity, a form that registers the dueling forces of normalization and destabilization

Not all men are sexually coercive: A preliminary investigation of the moderating effect of mate desirability on the relationship between female infidelity and male sexual coercion

Previous research has demonstrated the utility of men’s perceptions of their partner’s infidelity as a predictor of male sexual coercion in the context of an intimate relationship (Goetz and Shackelford, 2006 and Starratt, in press). Not all men who suspect partner infidelity are sexually coercive, however. Using reports secured from 280 men in a committed, sexual relationship with a woman, the current research provides preliminary evidence of a moderating effect of relative mate desirability in the relationship between perceptions of female infidelity and male sexual coercion. Specifically, men’s perceptions of their partner’s infidelity are positively related to men’s sexual coercion only in those relationships in which the man perceives that he is of equal or greater desirability than his partner. Men’s perceptions of their partner’s infidelity are not related to sexual coercion by men who perceive that they are less desirable than their partners. The discussion addresses interpretations of these findings, limitations of the current study, and directions for future research

Male mate retention mediates the relationship between female sexual infidelity and female-directed violence

Previous research has documented relationships between (1) female sexual infidelity and men’s non-violent mate retention behaviors, and (2) men’s non-violent mate retention behaviors and partner-directed violence. In the two studies, we examined two additional relationships: (1) the relationship between accusations of female sexual infidelity and men’s partner-directed violence and (2) whether men’s direct guarding mate retention behaviors mediates the relationship between accusations of female sexual infidelity and men’s partner-directed violence. The results indicate that (1) accusations of female sexual infidelity predict men’s partner-directed violence, (2) men’s reports of direct guarding mediates the relationship between accusations of partner sexual infidelity and partner-directed violence (Study 1, N = 165) and (3) women’s reports of men’s direct guarding partially mediates the same relationship (Study 2, N = 306). The discussion addresses sex differences identified in the mediation analyses, notes limitations of the research, and highlights directions for future research

cGMP Analogues with Opposing Actions on CNG Channels Selectively Modulate Rod or Cone Photoreceptor Function

The vertebrate retina harbors rod and cone photoreceptors. Human vision critically depends on cone photoreceptor function. In the phototransduction cascade, cGMP activates distinct rod and cone isoforms of the cyclic nucleotide-gated (CNG) channel. Excessive cGMP levels initiate a pathophysiological rollercoaster, which starts with CNG channel over-activation, typically in rod photoreceptors. This triggers cell death of rods first, and then cones, and is the root cause of many blinding retinal diseases, including Retinitis pigmentosa. While targeting of CNG channels has been proposed for therapeutic purposes, thus far, it has not been possible to inhibit rod CNG channels without compromising cone function. Here, we present a novel strategy, based on cGMP analogues with opposing actions on CNG channels, which enables the selective modulation of either rod or cone photoreceptor activity. The combined treatment with the weak rod-selective CNG-channel inhibitor (Rp-8-Br-PET-cGMPS) and the cone-selective CNG-channel activator (8-pCPT-cGMP) essentially normalized rod CNG-channel function while preserving cone functionality at physiological and pathological cGMP levels. Hence, combinations of cGMP analogues with desired properties may elegantly address the isoform-specificity problem in future pharmacological therapies. Moreover, this strategy may allow for improvements in visual performance in certain light environments

Energieflexibilitätspotenziale in der Produktionsinfrastruktur

Dieser Beitrag gibt einen Überblick über die im vom BMBF geförderten Kopernikus-Vorhaben SynErgie verfolgte Strategie zur Energieflexibilitätsbefähigung der Produktionsinfrastruktur. Diese umfasst die Analyse bestehender Flexibilitätspotenziale, die technische Anlagenbefähigung sowie den standardisierten Lösungstransfer in die industrielle Praxis. In diesem Beitrag wird vorgestellt, wie relevante Anlagen identifiziert werden und wie sich die Energieflexibilität in einem Datenmodell beschreiben lässt.*