Visceral hyperalgesia and intestinal dysmotility in a mouse model of postinfective gut dysfunction

BACKGROUND & AIMS: We established the concept that transient enteric infection may lead to persistent gut dysfunction, evident in vitro, in nematode-infected mice. The present study determined whether gut dysfunction in this model involves motor and sensory changes reminiscent of changes found in patients with postinfective irritable bowel syndrome (PI-IBS) and investigated underlying mechanisms. METHODS: Mice infected up to 70 days previously with Trichinella spiralis (Tsp) underwent videofluoroscopy with image analysis to assess upper gastrointestinal motility. Pseudoaffective responses to colorectal distention (CRD) were assessed using a barostat and validated by single fiber recordings from spinal nerves during CRD. Tissues were examined at different time points for histology, immunohistochemistry, and cytokine analysis. Some mice received dexamethasone intraperitoneally on days 23-25 PI or Tsp antigen orally on days 29, 43, and 57 PI. RESULTS: From day 28 PI, no discernible inflammation was present in the gut. Frequency and propagation velocity of intestinal contractions decreased, and retroperistalsis increased at days 28 to 42 PI. CRD induced an allodynic and hyperalgesic response in PI mice, which was accompanied by increased single unit discharge. Gavage of Tsp antigen induced T-cell responses and sustained gut dysfunction for 70 days PI. Administration of dexamethasone postinfection normalized dysmotility and visceral hyperalgesia. CONCLUSIONS: Long-lasting gut dysmotility and hyperalgesia develop in mice after transient intestinal inflammation. These changes are maintained by luminal exposure to antigen and reversed by corticosteroid treatment. The findings prompt consideration of this as a model of PI-IBS.     

Evaluation of serum IgE in peach-allergic patients with systemic reaction by using recombinant Pru p 7 (gibberellin-regulated protein)

Background

Lipid transfer protein (LTP) is a major fruit allergen. It has, however, recently been revealed that the systemic reaction in peach-allergic patients is related not only to LTP (Pru p 3) but also to gibberellin-regulated protein (Pru p 7). We investigated recombinant Pru p 7 (rPru p 7) for its potential use in worldwide standardization for the diagnosis of peach allergy.

MACVIA-LR,Reference site of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) in Languedoc Roussillon

The Région Languedoc-Roussillon is the umbrella organisation for an interconnected and integrated project on AHA covering the 3 pillars of the European Innovation Partnership on Active and Healthy Ageing. All sub-activities (A1: electronic pharmaceutical file, A2: falls prevention initiative, A3: frailty, B3: chronic respiratory diseases, chronic diseases with comorbidities, oral health and hepatitis virus C chronic infection, C2 and D4 active and independent living and handicap) are included in MACVIA-LR that has a strong political commitment and includes all stakeholders (public, private, patients, policy makers). It is one of the Reference Sites of the European Innovation Partnership on Active and Healthy Ageing built around chronic diseases, ageing and handicap. The framework of MACVIA-LR has the vision that the prevention and management of CDs is essential for AHA promotion and for the reduction of handicap. The main objective of MACVIA-LR is to develop innovative solutions for a network of Living Labs in order to improve the care of patients affected by CDs in the Languedoc-Roussillon area and to disseminate the innovation.     

调督解郁法针刺治疗肿瘤相关性抑郁:随机对照研究

目的:观察调督解郁法针刺联合盐酸舍曲林片与单纯盐酸舍曲林片对肿瘤相关性抑郁患者的影响,探讨其作用机制。方法:将120例肿瘤相关性抑郁患者随机分为观察组和对照组,各60例。在肿瘤内科常规治疗基础上,对照组予盐酸舍曲林片口服,每次50 mg,每日1次;观察组在对照组治疗基础上加用调督解郁法针刺治疗,穴取中脘、百会、神庭、心俞、肝俞、脾俞、神门、太冲、太溪,治疗20~40 min,每日1次,每周5次,均治疗6周。观察治疗前,治疗2、4、6周后两组患者抑郁自评量表(SDS)和汉密尔顿抑郁量表(HAMD)评分及治疗前后外周血血清白细胞介素(IL)-2、IL-4、IL-10、γ干扰素(IFN-γ)、转化生长因子β(TGF-β)水平。结果:治疗2、4、6周后,两组患者SDS、HAMD评分均较治疗前降低(P<0.05),且观察组低于对照组(P<0.05)。治疗后,两组患者外周血血清IL-4、IL-10、TGF-β水平均较治疗前降低(P<0.05),且观察组低于对照组(P<0.05);外周血血清IL-2、IFN-γ水平均较治疗前升高(P<0.05),且观察组高于对照组(P<0.05)。结论:调督解郁法针刺联合盐酸舍曲林片可有效缓解肿瘤相关性抑郁患者的抑郁状态,疗效优于单纯盐酸舍曲林片,其作用机制可能与调节机体免疫相关细胞因子表达有关。     

Interaction of metal oxide nanoparticles with lung surfactant protein A

The alveolar lining fluid (ALF) covering the respiratory epithelium of the deep lung is the first biological barrier encountered by nanoparticles after inhalation. We here report for the first time significant differences for metal oxide nanoparticles to the binding of surfactant protein A (SP-A), the predominant protein component of ALF. SP-A is a physiologically most relevant protein and provides important biological signals. Also, it is involved in the lung’s immune defence, controlling e.g. particle binding, uptake or transcytosis by epithelial cells and macrophages. In our study, we could prove different particle-protein interaction for eight different nanoparticles, whereas particles of the same bulk material revealed different adsorption patterns. In contrast to other proteins as bovine serum albumin (BSA), SP-A does not seem to significantly deagglomerate large agglomerates of particles, indicating different adsorption mechanisms as in the well-investigated model protein BSA. These findings may have important consequences for biological fate and toxicological effects of inhaled nanomaterials.     

Antinociceptive interactions of mu- and kappa-opioid agonists in the colorectal distension assay in rats

Interactions of opioid agonists, fentanyl and oxymorphone (mu-selective) and spiradoline and enadoline (kappa-selective), were examined for additive, sub-additive, or supra-additive antinociception in the colorectal distension (CRD) assay. Single-dose values (mg/kg, 0.006-0.016 for fentanyl, 0.25-1.26 for spiradoline, etc.) were summed to formulate theoretical additive-dose plots for comparison with actual combined-dose effects. Combined fentanyl and spiradoline yielded additive (low-dose levels) or supra-additive (high-dose levels) effects. Single and combined doses of fentanyl (0.012 mg/kg) and spiradoline (0.3 mg/kg) were tested after pretreatment with saline, beta-funaltrexamine (b-FNA, mu-selective antagonist), or nor-binaltorphimine (n-BNI, kappa-selective antagonist). Supra-additive effects of combined agonists were attenuated by either antagonist (greater with n-BNI). But paradoxical patterns of antagonism of single-dose effects occurred: the fentanyl antinociception was not antagonized by b-FNA, whereas the spiradoline antinociception was. The results indicate complex interactions of agonists in this visceral pain model and potential for combined agonists to improve pain relief with decreased side effects.     

Invertebrate immune diversity

The arms race between hosts and pathogens (and other non-self) drives the molecular diversification of immune response genes in the host. Over long periods of evolutionary time, many different defense strategies have been employed by a wide variety of invertebrates. We review here penaeidins and crustins in crustaceans, the allorecognition system encoded by fuhc, fester and Uncle fester in a colonial tunicate, Dscam and PGRPs in arthropods, FREPs in snails, VCBPs in protochordates, and the Sp185/333 system in the purple sea urchin. Comparisons among immune systems, including those reviewed here have not identified an immune specific regulatory “genetic toolkit”, however, repeatedly identified sequences (or “building materials” on which the tools act) are present in a broad range of immune systems. These include a Toll/TLR system, a primitive complement system, an LPS binding protein, and a RAG core/Transib element. Repeatedly identified domains and motifs that function in immune proteins include NACHT, LRR, Ig, death, TIR, lectin domains, and a thioester motif. In addition, there are repeatedly identified mechanisms (or “construction methods”) that generate sequence diversity in genes with immune function. These include genomic instability, duplications and/or deletions of sequences and the generation of clusters of similar genes or exons that appear as families, gene recombination, gene conversion, retrotransposition, alternative splicing, multiple alleles for single copy genes, and RNA editing. These commonly employed “materials and methods” for building and maintaining an effective immune system that might have been part of that ancestral system appear now as a fragmented and likely incomplete set, likely due to the rapid evolutionary change (or loss) of host genes that are under pressure to keep pace with pathogen diversity.     

Regulation of lipid raft proteins by glimepiride- and insulin-induced glycosylphosphatidylinositol-specific phospholipase C in rat adipocytes

The insulin receptor-independent insulin-mimetic signalling provoked by the antidiabetic sulfonylurea drug, glimepiride, is accompanied by the redistribution and concomitant activation of lipid raft-associated signalling components, such as the acylated tyrosine kinase, pp59(Lyn), and some glycosylphosphatidylinositol-anchored proteins (GPI-proteins). We now found that impairment of glimepiride-induced lipolytic cleavage of GPI-proteins in rat adipocytes by the novel inhibitor of glycosylphosphatidylinositol-specific phospholipase C (GPI-PLC), GPI-2350, caused almost complete blockade of (i) dissociation from caveolin-1 of pp59(Lyn) and GPI-proteins, (ii) their redistribution from high cholesterol- (hcDIGs) to low cholesterol-containing (lcDIGs) lipid rafts, (iii) tyrosine phosphorylation of pp59(Lyn) and insulin receptor substrate-1 protein (IRS-1) and (iv) stimulation of glucose transport as well as (v) inhibition of isoproterenol-induced lipolysis in response to glimepiride. In contrast, blockade of the moderate insulin activation of the GPI-PLC and of lipid raft protein redistribution by GPI-2350 slightly reduced insulin signalling and metabolic action, only. Importantly, in response to both insulin and glimepiride, lipolytically cleaved hydrophilic GPI-proteins remain associated with hcDIGs rather than redistribute to lcDIGs as do their uncleaved amphiphilic versions. In conclusion, GPI-PLC controls the localization within lipid rafts and thereby the activity of certain GPI-anchored and acylated signalling proteins. Its stimulation is required and may even be sufficient for insulin-mimetic cross-talking to IRS-1 in response to glimepiride via redistributed and activated pp59(Lyn).