Background: Peanut allergy is a severe and increasingly frequent disease with high medical, psychosocial, and economic burden for affected patients and wider society. A causal, safe, and effective therapy is not yet available. Objective: We sought to develop an immunogenic, protective, and nonreactogenic vaccine candidate against peanut allergy based on virus-like particles (VLPs) coupled to single peanut allergens. Methods: To generate vaccine candidates, extracts of roasted peanut (Ara R) or the single allergens Ara h 1 or Ara h 2 were coupled to immunologically optimized Cucumber Mosaic Virus-derived VLPs (CuMVtt). BALB/c mice were sensitized intraperitoneally with peanut extract absorbed to alum. Immunotherapy consisted of a single subcutaneous injection of CuMVtt coupled to Ara R, Ara h 1, or Ara h 2. Results: The vaccines CuMVtt-Ara R, CuMVtt-Ara h 1, and CuMVtt-Ara h 2 protected peanut-sensitized mice against anaphylaxis after intravenous challenge with the whole peanut extract. Vaccines did not cause allergic reactions in sensitized mice. CuMVtt-Ara h 1 was able to induce specific IgG antibodies, diminished local reactions after skin prick tests, and reduced the infiltration of the gastrointestinal tract by eosinophils and mast cells after oral challenge with peanut. The ability of CuMVtt-Ara h 1 to protect against challenge with the whole extract was mediated by IgG, as shown via passive IgG transfer. FcgRIIb was required for protection, indicating that immune complexes with single allergens were able to block the allergic response against the whole extract, consisting of a complex allergen mixture. Conclusions: Our data suggest that vaccination using single peanut allergens displayed on CuMVtt may represent a novel therapy against peanut allergy with a favorable safety profile. (J

INTRODUCTIONFunctional, or non-ulcer, dyspepsia is a common gastrointestinal disorder characterized by upper abdominal pain or discomfort in the absence of identi®able organic aetiologies. 1 A review of oesophagogastroduodenoscopy results found that ulcers, re¯ux oesophagitis and cancer account for diagnoses in less than half of patients with dyspepsia-like symptoms. 2 Functional dyspepsia is therefore considered to be the underlying cause of the majority (50±60%) of dyspepsia-like symptoms that occur in the general population. 2±4 Functional dyspepsia is usually a life-long, recurring condition that impacts quality of life and contributes signi®cantly to healthcare expenses. Functional dyspepsia accounts for a signi®cant number of gastrointestinal consultations from primary care providers, and is a common diagnosis in gastroenterology practices. 4, 5 A signi®cant percentage of overall costs associated with functional dyspepsia appear to be due to an increased use Results: Twelve-week average rates of adequate relief of pain or discomfort were 46% (95% CI: 37±54%) 2 , 55%

The MA.17 trial demonstrated a significant improvement in disease-free survival with the use of letrozole as extended adjuvant therapy post tamoxifen. Results from this study suggests that letrozole does not significantly alter serum cholesterol, HDL cholesterol, LDL cholesterol, triglycerides or Lp(a) in non-hyperlidiemic postmenopausal women with primary breast cancer treated up to 36 months following at least 5 years of adjuvant tamoxifen therapy. These findings further support the tolerability of extended adjuvant letrozole in postmenopausal women following standard tamoxifen therapy.

Allergen-specific Immunotherapy (AIT) is the only available treatment aimed to tackle the underlying causes of allergy. The active components of subcutaneous vaccines traditionally consist of natural or modified allergen extracts which can be combined with adjuvant platforms. In recent years new targets have been further developed in an attempt to raise the safety and efficacy profile of AIT. Areas covered: In this review, we discuss the desirable attributes of adjuvants and delivery systems from empiricism to rational design, for current and future clinical applications in AIT. Expert commentary: The introduction of novel adjuvants, in combination with active targets, has been demonstrated to reduce symptoms of AIT, increase clinical efficacy of allergy treatment and reduce the number of doses. The evolution of vaccine development for AIT is entering a phase of scientific progress that challenges dogmas. Over the past century the traditional concept of immunotherapy, entailing long-course administration of native extract preparations and first generation adjuvants, has seen evolution in the past decade from proof-of-concept to clinical development pipelines encompassing the advent of second generation adjuvants and delivery systems forming essential components of modern AIT development.

Allergen immunotherapy (AIT) is the only modality that can modify immune responses to allergen exposure, but therapeutic coverage is low. One strategy to improve AIT safety and efficacy is the use of new or improved adjuvants. This study investigates immune responses produced by microcrystalline tyrosine (MCT)–based vaccines as compared with conventional aluminum hydroxide (alum). Wild-type, immune-signaling–deficient, and TCR-transgenic mice were treated with different Ags (e.g., OVA and cat dander Fel d 1), plus MCT or alum as depot adjuvants. Specific Ab responses in serum were measured by ELISA, whereas cytokine secretion was measured both in culture supernatants by ELISA or by flow cytometry of spleen cells. Upon initiation of AIT in allergic mice, body temperature and further clinical signs were used as indicators for anaphylaxis. Overall, MCT and alum induced comparable B and T cell responses, which were independent of TLR signaling. Alum induced stronger IgE and IL-4 secretion than MCT. MCT and alum induced caspase-dependent IL-1β secretion in human monocytes in vitro, but inflammasome activation had no functional effect on inflammatory and Ab responses measured in vivo. In sensitized mice, AIT with MCT-adjuvanted allergens caused fewer anaphylactic reactions compared with alum-adjuvanted allergens. As depot adjuvants, MCT and alum are comparably effective in strength and mechanism of Ag-specific IgG induction and induction of T cell responses. The biocompatible and biodegradable MCT seems therefore a suitable alternative adjuvant to alum-based vaccines and AIT.

BackgroundThe aim of the study was to investigate the abductor hallucis muscle characteristics, defined as dorso-plantar (DP) thickness, medio-lateral (ML) width, and cross-sectional area (CSA) in relation to the severity of hallux valgus using musculoskeletal ultrasound. One hundred and two feet, mean (SD) age of 60.3 (20.54) years old, displaying varying severities of hallux valgus were stratified into four groups representing the four grades of the Manchester Scale (grade 0: no deformity, grade 1: mild deformity, grade 2: moderate deformity and grade 3: severe deformity).MethodsThe abductor hallucis muscle was imaged in each foot using a portable ultrasound system. The mean (SD) DP thickness, ML width, and CSA measurements were compared across the four Manchester Scale grades using a one-way ANOVA.ResultsSignificant differences in DP thickness were found between feet with no hallux valgus (grade 0) and feet with hallux valgus grade 2 (p = 0.001) and 3 (p < 0.001). Significant differences were also found in ML width between feet with no hallux valgus (grade 0) and feet with grade 2 hallux valgus (p = 0.010). Significant differences in CSA were found between feet with no hallux valgus (grade 0) and feet with grade 2 (p < 0.001) and grade 3 (p < 0.001) hallux valgus. No significant differences in these three muscle characteristics were found between grades 1, 2 and 3 (p > 0.0125).ConclusionsWe speculate that morphological changes to the abductor hallucis muscle occur early in the development of the deformity.

The study yields novel findings regarding the prevalence and incidence of cataract in the dog and forms the basis for considerable further work on the epidemiology and pathophysiology of age-related cataract in the dog.

NikA is a periplasmic binding protein involved in nickel uptake in Escherichia coli. NikA was identified as a heme-binding protein in the periplasm of anaerobically grown cells overexpressing CydDC, an ABC transporter that exports reductant to the periplasm. CydDC-overexpressing cells accumulate a heme biosynthesis-derived pigment, P-574. For further biochemical and spectroscopic analysis, unliganded NikA was overexpressed and purified. NikA was found to comigrate with both hemin and protoporphyrin IX during gel filtration. Furthermore, tryptophan fluorescence quenching titrations demonstrated that both hemin and protoporphyrin IX bind to NikA with similar affinity. The binding affinity of NikA for these pigments (Kd approximately 0.5 microM) was unaltered in the presence and absence of saturating concentrations of nickel, suggesting that these tetrapyrroles bind to NikA in a manner independent of nickel. To test the hypothesis that NikA is required for periplasmic heme protein assembly, the effects of a nikA mutation (nikA::Tn5, Km(R) insertion) on accumulation of P-574 by CydDC-overexpressing cells was assessed. This mutation significantly lowered P-574 levels, implying that NikA may be involved in P-574 production. Thus, in the reducing environment of the periplasm, NikA may serve as a heme chaperone as well as a periplasmic nickel-binding protein. The docking of heme onto NikA was modeled using the published crystal structure; many of the predicted complexes exhibit a heme-binding cleft remote from the nickel-binding site, which is consistent with the independent binding of nickel and heme. This work has implications for the incorporation of heme into b- and c-type cytochromes.