Intravenous tolerance effectively overcomes enhanced pro-inflammatory responses and EAE severity in the absence of IL-12 receptor signaling

Intravenous (i.v.) administration of autoantigen effectively induces Ag-specific tolerance against experimental autoimmune encephalomyelitis (EAE). We and others have shown enhanced EAE severity in mice lacking IL-12 or its receptor, strongly suggesting an immunoregulatory effect of IL-12 signaling. To examine the role of IL-12 responsiveness in autoantigen-induced tolerance in EAE, we administered autoantigen i.v. in two distinct treatment regimes to wildtype and IL-12Rβ2(-/-) mice, immunized to develop EAE. Administration at the induction phase suppressed EAE in wildtype and IL-12Rβ2(-/-) mice however the effect was somewhat less potent in the absence of IL-12Rβ2. Expression of pro-inflammatory cytokines such as IFN-γ, IL-17 and IL-2, was inhibited in wild-type tolerized mice but less so in IL-12Rβ2(-/-) mice. I.v. antigen was also effective in suppressing disease in both genotypes when given during the clinical phase of disease with similar CNS inflammation, demyelination and peripheral inflammatory cytokine profiles observed in both genotypes. There was however a mild impact of a lack of IL-12 signaling on Treg induction during tolerance induction compared to WT mice in this treatment regime. These findings show that the enhanced severity of EAE that occurs in the absence of IL-12 signaling can be effectively overcome by i.v. autoantigen, indicating that this therapeutic effect is not primarily mediated by IL-12 and that i.v. tolerance could be a powerful approach in suppressing severe and aggressive MS.

Cough hypersensitivity syndrome is an important clinical concept:a pro/con debate

The major etiologies of chronic cough are generally accepted to consist of upper airway cough syndrome (formerly postnasal drip syndrome), eosinophilic airway inflammation (asthma, nonasthmatic eosinophilic bronchitis), and gastroesophageal reflux disease (GERD). However, only a small percentage of patients with these very common conditions suffers from chronic cough. Furthermore, acute cough due to viral upper respiratory tract infection (URI) is almost always a transient, self-limited condition, yet in a small subgroup of patients, URI heralds the onset of chronic, refractory cough. The cough hypersensitivity syndrome has been proposed to explain the occurrence of chronic cough in a subgroup of patients exposed to the same putative triggers as the vast majority of the population in whom chronic cough does not result. Although conceptually the cough hypersensitivity syndrome may be intellectually satisfying, differences of opinion remain as to whether this newly recognized entity is of clinical significance, i.e., useful for the treatment of patients suffering from chronic cough. The Third American Cough Conference, held in New York in June 2011, provided an ideal forum for the debate of this issue between two internationally recognized authorities in the field of cough.

Metabolomic Profiling of In Vivo Plasma Responses to DioxinAssociated Dietary Contaminant Exposure in Rats: Implications for Identification of Sources of Animal and Human Exposure

Dioxin contamination of the food chain typically occurs when cocktails of combustion residues or polychlorinated biphenyl (PCB) containing oils become incorporated into animal feed. These highly toxic compounds are bioaccumulative with small amounts posing a major health risk. The ability to identify animal exposure to these compounds prior to their entry into the food chain may be an invaluable tool to safeguard public health. Dioxin-like compounds act by a common mode of action and this suggests that markers or patterns of response may facilitate identification of exposed animals. However, secondary co-contaminating compounds present in typical dioxin sources may affect responses to compounds. This study has investigated for the first time the potential of a metabolomics platform to distinguish between animals exposed to different sources of dioxin contamination through their diet. Sprague-Dawley rats were given feed containing dioxin-like toxins from hospital incinerator soot, a common PCB oil standard and pure 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (normalized at 0.1 µg/kg TEQ) and acquired plasma was subsequently biochemically profiled using ultra high performance liquid chromatography (UPLC) quadropole time-of-flight-mass spectrometry (QTof-MS). An OPLS-DA model was generated from acquired metabolite fingerprints and validated which allowed classification of plasma from individual animals into the four dietary exposure study groups with a level of accuracy of 97-100%. A set of 24 ions of importance to the prediction model, and which had levels significantly altered between feeding groups, were positively identified as deriving from eight identifiable metabolites including lysophosphatidylcholine (16:0) and tyrosine. This study demonstrates the enormous potential of metabolomic-based profiling to provide a powerful and reliable tool for the detection of dioxin exposure in food-producing animals.

Pellino3 targets RIP1 and regulates the pro-apoptotic effects of TNF-∝

Tumour necrosis factor-a (TNF) can activate NF-?B to induce pro-inflammatory genes but can also stimulate the caspase cascade to promote apoptosis. Here we show that deficiency of the ubiquitin E3 ligase, Pellino3, sensitizes cells to TNF-induced apoptosis without inhibiting the NF-?B pathway. Suppressed expression of Pellino3 leads to enhanced formation of the death-induced signalling complex, complex II, in response to TNF. We show that Pellino3 targets RIP1, in a TNF-dependent manner, to inhibit TNF-induced complex II formation and caspase 8-mediated cleavage of RIP1 in response to TNF/cycloheximide co-stimulation. Pellino3-deficient mice also show increased sensitivity to TNF-induced apoptosis and greatly increased lethality in response to TNF administration. These findings define Pellino3 as a novel regulator of TNF signalling and an important determining factor in dictating whether TNF induces cell survival or death.

Use of SLAM and PVRL4 and Identification of Pro-HB-EGF as Cell Entry Receptors for Wild Type Phocine Distemper Virus

Signalling lymphocyte activation molecule (SLAM) has been identified as an immune cell receptor for the morbilliviruses, measles (MV), canine distemper (CDV), rinderpest and peste des petits ruminants (PPRV) viruses, while CD46 is a receptor for vaccine strains of MV. More recently poliovirus like receptor 4 (PVRL4), also known as nectin 4, has been identified as a receptor for MV, CDV and PPRV on the basolateral surface of polarised epithelial cells. PVRL4 is also up-regulated by MV in human brain endothelial cells. Utilisation of PVRL4 as a receptor by phocine distemper virus (PDV) remains to be demonstrated as well as confirmation of use of SLAM. We have observed that unlike wild type (wt) MV or wtCDV, wtPDV strains replicate in African green monkey kidney Vero cells without prior adaptation, suggesting the use of a further receptor. We therefore examined candidate molecules, glycosaminoglycans (GAG) and the tetraspan proteins, integrin β and the membrane bound form of heparin binding epithelial growth factor (proHB-EGF),for receptor usage by wtPDV in Vero cells. We show that wtPDV replicates in Chinese hamster ovary (CHO) cells expressing SLAM and PVRL4. Similar wtPDV titres are produced in Vero and VeroSLAM cells but more limited fusion occurs in the latter. Infection of Vero cells was not inhibited by anti-CD46 antibody. Removal/disruption of GAG decreased fusion but not the titre of virus. Treatment with anti-integrin β antibody increased rather than decreased infection of Vero cells by wtPDV. However, infection was inhibited by antibody to HB-EGF and the virus replicated in CHO-proHB-EGF cells, indicating use of this molecule as a receptor. Common use of SLAM and PVRL4 by morbilliviruses increases the possibility of cross-species infection. Lack of a requirement for wtPDV adaptation to Vero cells raises the possibility of usage of proHB-EGF as a receptor in vivo but requires further investigation.

A Randomized Controlled Trial Evaluation of an After-School Pro-Social Behavior Program in an Area of Socioeconomic Disadvantage

A randomized controlled trial was used to evaluate the effects of a pro-social behavior after-school program called Mate-Tricks for nine and ten year old children and their parents living in an area of significant socioeconomic disadvantage. The children were randomly assigned to an intervention (n=220) or a control group (n=198). Children were compared on measures of pro-social behavior, anti-social behavior and related outcome measures. The trial found adverse effects on four outcomes among the intervention group compared to the control group: anti-social behavior increased on two different measures (d=+0.20) and (d=+0.18); child reported liberal parenting increased (d=+0.16); and child reported authoritarian parenting also increased (d=+0.20). In addition, parental participation was significantly associated with several program outcomes. It was concluded, that group based after-school behavior programs may have the potential to cause iatrogenic effects and must be designed, piloted, evaluated and implemented with a high degree of care.

Pro-fragrant ionic liquids with stable hemiacetal motifs: water-triggered release of fragrances

Stable liquid and solid salts in the form of elusive hemiacetals, appended with fragrant alcohols, have been synthesised as pro-fragrances, and the controlled release of these fragrances, triggered by water, is demonstrated

Pro-active protection against racialist discrimination in employment law - lessons from South Africa?

This study investigates the potential of the prohibition of indirect race discrimination to be used for law reform, and to uncover discriminatory practices. It reflects on the history and contents of the concept, and focuses in particular on its application in the Republic of South Africa

Rationale and Means to Target Pro-Inflammatory Interleukin-8 (CXCL8) Signaling in Cancer

It is well established that chronic inflammation underpins the development of a number of human cancers, with pro-inflammatory signaling within the tumor microenvironment contributing to tumor progression and metastasis. CXCL8 is an ELR+ pro-inflammatory CXC-chemokine which mediates its effects via signaling through two G protein-coupled receptors, CXCR1 and CXCR2. Elevated CXCL8-CXCR1/2 signaling within the tumor microenvironment of numerous cancers is known to enhance tumor progression via activation of signaling pathways promoting proliferation, angiogenesis, migration, invasion and cell survival. This review provides an overview of established roles of CXCL8-CXCR1/2 signaling in cancer and subsequently, discusses the possible strategies of targeting CXCL8-CXCR1/2 signaling in cancer, covering indirect strategies (e.g., anti-inflammatories, NFκB inhibitors) and direct CXCL8 or CXCR1/2 inhibition (e.g., neutralizing antibodies, small molecule receptor antagonists, pepducin inhibitors and siRNA strategies). Reports of pre-clinical cancer studies and clinical trials using CXCL8-CXCR1/2-targeting strategies for the treatment of inflammatory diseases will be discussed. The future translational opportunities for use of such agents in oncology will be discussed, with emphasis on exploitation in stratified populations.