Blockade of the complement C5a receptor reduces incisional allodynia, edema, and cytokine expression

BACKGROUND: Activation of the complement system is one component of the inflammatory response. Various components of the complement system participate in killing foreign organisms, recruiting immune cells, enhancing edema, and stimulating cytokine formation. Complement-mediated enhancement of the inflammation surrounding surgical incisions may increase pain. METHODS: In these studies, the authors used a murine hind paw incisional model to study the role of the complement C5a receptor in supporting incisional inflammation. At baseline and at various time points after incision, they measured the effects of a highly selective C5a receptor antagonist on nociceptive thresholds, edema formation, and cytokine production in the skin surrounding the incision. They also measured changes in C5a receptor expression near the incisions. RESULTS: The once-daily injection of the C5a receptor antagonist AcF-[OPdChaWR] reduced mechanical allodynia and edema in the incised hind paw. A multiplexed cytokine assay revealed that 8 of the 18 cytokines examined showed significant increases in skin tissue abundance after incision. Distinct time courses for the patterns of elevation were seen, though some degree of resolution occurred for all cytokines within 96 h. For 7 of these 8 cytokines, the C5a receptor antagonist reduced the enhancement of expression. In addition, the authors found that the C5a receptor messenger RNA level increased 15-fold in the skin surrounding the incisions within 24 h and then slowly declined. CONCLUSIONS: The tissue directly surrounding incisions in mouse hind paws undergoes large changes in the content of specific cytokines in addition to demonstrating edema and nociceptive sensitization. By blocking the receptor for one component of the complement system, C5a, all of these changes can be reduced. Complement receptor inhibitors may constitute a novel group of compounds useful in reducing the pain and swelling of surgical incisions.     

Small intestinal malabsorption of vitamin B(12) in iron-deficient rats.

Rats were rendered iron deficient by a combination of diet and bleeding to study its effects on vitamin B(12) absorption. Small intestinal loops were isolated in vivo and the absorption of -57Co-vitamin B(12) bound to a known quantity of intrinsic factor was measured. Iron deficiency resulted in the impairment of both uptake and transport of B(12). This malabsorption was corrected within 5 days by parenteral iron repletion. The findings were not due to a non-specific effect of anaemia since no correlation existed between haemoglobin levels and B(12) absorption in rats anaemic as a result of acute blood loss. No evidence was found for an altered small-intestinal microflora, bacterial counts being similar in iron-deficient and control rats. It is concluded that iron deficiency in the rat results in impaired absorption of B(12) by the small intestine, probably as a result of some defect produced in the enterocyte.     

Quantitative analysis of neuropeptide Y receptor association with ��-arrestin2 measured by bimolecular fluorescence complementation

Background and purpose:

β-Arrestins are critical scaffold proteins that shape spatiotemporal signalling from seven transmembrane domain receptors (7TMRs). Here, we study the association between neuropeptide Y (NPY) receptors and β-arrestin2, using bimolecular fluorescence complementation (BiFC) to directly report underlying protein–protein interactions.

Experimental approach:

Y1 receptors were tagged with a C-terminal fragment, Yc, of yellow fluorescent protein (YFP), and β-arrestin2 fused with the complementary N-terminal fragment, Yn. After Y receptor–β-arrestin association, YFP fragment refolding to regenerate fluorescence (BiFC) was examined by confocal microscopy in transfected HEK293 cells. Y receptor/β-arrestin2 BiFC responses were also quantified by automated imaging and granularity analysis.

Key results:

NPY stimulation promoted association between Y1–Yc and β-arrestin2–Yn, and the specific development of BiFC in intracellular compartments, eliminated when using non-interacting receptor and arrestin mutants. Responses developed irreversibly and were slower than for downstream Y1 receptor–YFP internalization, a consequence of delayed maturation and stability of complemented YFP. However, β-arrestin2 BiFC measurements delivered appropriate ligand pharmacology for both Y1 and Y2 receptors, and demonstrated higher affinity of Y1 compared to Y2 receptors for β-arrestin2. Receptor mutagenesis combined with β-arrestin2 BiFC revealed that alternative arrangements of Ser/Thr residues in the Y1 receptor C tail could support β-arrestin2 association, and that Y2 receptor–β-arrestin2 interaction was enhanced by the intracellular loop mutation H155P.

Conclusions and implications:

The BiFC approach quantifies Y receptor ligand pharmacology focused on the β-arrestin2 pathway, and provides insight into mechanisms of β-arrestin2 recruitment by activated and phosphorylated 7TMRs, at the level of protein–protein interaction.     

New Year,New You: a qualitative study of Dry January,self-formation and positive regulation

Abstract

In the last 5 years, giving up alcohol for January has become a common social practice in UK. Inspired by Alcohol Concern’s Dry January initiative and other related campaigns, an estimated 5 million UK adults attempted to abstain from alcohol in January 2017. Moreover, evaluative research has suggested that a 1-month spell of abstinence is an effective way of reducing average, longer-term drinking. However, the popularity and apparent effectiveness of Dry January are not well-understood. This article presents the first qualitative analysis of the meaning and significance of this important new cultural phenomenon. Based on analysis of media and social media content, it examines both how Dry January is managed by Alcohol Concern and how it is experienced by participants. The burgeoning popularity of Dry January is found to result from how this process of temporary abstinence is underpinned by positive regulatory techniques and the salience of embodiment. Consequently, rather than being a simple regime of bodily abstinence and self-control, Dry January should instead be understood as an embodied experience of ethical self-formation. The article also reflects on the implications of this finding for alcohol regulation more widely.     

Acquired flavor acceptance and intake facilitated by monosodium glutamate in humans

Monosodium glutamate (MSG) is known to enhance liking for the flavor of savory foods, but whether associations between flavors and effects of MSG lead to changes in subsequent liking and intake for the flavor alone is unclear. To test this, 32 volunteers evaluated and consumed a novel savory soup with no added MSG before and after four training sessions where the same soup was consumed either unchanged (Control) or with added MSG. The addition of MSG during training increased both pleasantness and savory character of the soup and resulted in a larger increase in rated pleasantness of the soup in the MSG-trained relative to control condition when the soup was re-evaluated Post-training without MSG. There was also a significant increase in voluntary soup intake Post-training after the soup had been paired with MSG but not in the Control condition, and rated hunger increased more after tasting the soup Post-training in the MSG-trained but not Control condition. These findings demonstrate that co-experience of a savory flavor and MSG can result in increased subsequent liking and intake for the flavor in the absence of MSG, and possible explanations for how MSG reinforces learning are discussed.     

Asia-Pacific Working Group consensus on non-variceal upper gastrointestinal bleeding

Upper gastrointestinal bleeding (UGIB), especially peptic ulcer bleeding, remains one of the most important cause of hospitalisation and mortality world wide. In Asia, with a high prevalence of Helicobacter pylori infection, a potential difference in drug metabolism, and a difference in clinical management of UGIB due to variable socioeconomic environments, it is considered necessary to re-examine the International Consensus of Non-variceal Upper Gastrointestinal Bleeding with emphasis on data generated from the region. The working group, which comprised experts from 12 countries from Asia, recommended the use of the Blatchford score for selection of patients who require endoscopic intervention and which would allow early discharge of patients at low risk. Patients' comorbid conditions should be included in risk assessment. A pre-endoscopy proton pump inhibitor (PPI) is recommended as a stop-gap treatment when endoscopy within 24 h is not available. An adherent clot on a peptic ulcer should be treated with endoscopy combined with a PPI if the clot cannot be removed. Routine repeated endoscopy is not recommended. High-dose intravenous and oral PPIs are recommended but low-dose intravenous PPIs should be avoided. COX-2 selective non-steroidal anti-inflammatory drugs combined with a PPI are recommended for patients with very high risk of UGIB. Aspirin should be resumed soon after stabilisation and clopidogrel alone is no safer than aspirin plus a PPI. When dual antiplatelet agents are used, prophylactic use of a PPI reduces the risk of adverse gastrointestinal events.     

Abnormal patterns of cerebral lateralisation as revealed by the universal chimeric faces task in individuals with autistic disorder

A previous study by Workman, Chilvers, Yeomans, and Taylor (2006), using the "Universal" Chimeric Faces Task (UCFT) for six emotional expressions, demonstrated that an overall left hemispatial/right hemisphere (RH) advantage has begun to develop by the age of 7-8. Moreover, the development of this left hemispatial advantage was observed to correlate positively with the ability to read emotions in the faces of others. Adopting the UCFT, the current study compared autistic children (11-15) with unimpaired children of two age groups (5-6 and 7-8) from this previous study. The autistic children showed a left hemispatial/RH advantage only for the two emotional expressions of "happiness" and "anger". Results for the autistic children revealed a similar overall pattern of lateralisation to the 5-6-year-olds and one that is less lateralised than the pattern for the 7-8-year-olds. Autistic children appear to show a developmental deficit for left hemispatial/RH advantage for emotional expression with the exception of "happiness" and "anger." The findings are discussed in terms of role hemisphericity and an approach-avoidance model.