Structural optimisation of a conformational epitope improves antigenicity when expressed as a recombinant fusion protein

A conformationally restricted B cell epitope has been identified as a potential safe vaccine candidate from the major group A streptococcal virulence factor, the M protein. To maintain α-helical secondary structure, the minimal epitope is flanked with heterologous sequences to produce the chimeric vaccine candidate called J14. As a strategy toward developing an affordable multivalent GAS vaccine, we have expressed J14 recombinantly with a second GAS protective antigen H12 (rJ14H12). When administered to mice sub-cutaneously, the fusion protein stimulated a strong serum IgG response to the H12 component, but J14 was poorly immunogenic. To increase the immunogenicity of J14 when expressed with the model fusion partner, amino acid modifications were made to the initial recombinant J14 construct to produce rJJo. These changes stabilised the α-helical conformation of the recombinant antigen as assessed by circular dichroism. Mice immunised with rJJoH12, the fusion protein incorporating JJo, effectively stimulated a humoral response to both of the included antigens. These data support the feasibility of developing a multivalent vaccine incorporating the conformationally restricted protective antigen J14.     

Novel orthobunyavirus in Cattle, Europe, 2011

In 2011, an unidentified disease in cattle was reported in Germany and the Netherlands. Clinical signs included fever, decreased milk production, and diarrhea. Metagenomic analysis identified a novel orthobunyavirus, which subsequently was isolated from blood of affected animals. Surveillance was initiated to test malformed newborn animals in the affected region.     

Controlled release of lipase from Candida rugosa loaded into hydrogels of N-isopropylacrylamide and itaconic acid

The series of poly(N-isopropylacrylamide-co-itaconic acid) hydrogels, with lipase from Candida rugosa as a model protein, were synthesized by free radical copolymerization. The composition of hydrogels was varied by monomers ratio, crosslinking agent concentration and amounts of lipase, which was loaded by in situ polymerization. All samples were characterized regarding morphology. The investigation of hydrogel swelling properties revealed their pH and temperature sensitive character. Protein loading efficiency, release profiles and the specific activity yield of the released lipase were also investigated as a function of hydrogel composition, protein content and pH, at the physiological temperature of 37°C. Copolymers of N-isopropylacrylamide and itaconic acid presented high lipase loading efficiency. Another very important feature of these copolymers was that the protein release kinetic strongly depended on the pH value of the medium. The diffusion exponents values around 1 denoted that these hydrogel compositions could be adjusted to follow near zero-order kinetics. Namely, hydrogel formulations released low amounts of lipase at pH 2.20, but much higher released protein quantities were observed at pH 6.80 enabling these copolymers to be attractive candidates as site specific protein oral drug delivery systems.     

Relationship of chemical structure and anti-inflammatory activity of dihydrocorynantheol and its analogues

BackgroundDihydrocorynantheol (DHC) is an alkaloid compound isolated from Esenbeckia leiocarpa Engl. that has demonstrated anti-inflammatory properties in experimental models. The aim of this study was to investigate whether the modification of the chemical structure of DHC could alter its anti-inflammatory effect in a mouse model of pleurisy induced by carrageenan.MethodsDHC was isolated from Esenbeckia leiocarpa Engl. Capillary electrophoresis, physical characteristics, spectral data produced by infrared analysis and nuclearmagnetic resonance (¹H and ¹³C), andmass spectrometry analysiswere used to identify and elucidate DHC structure. The DHC compound was subjected to chemical structural modifications by nucleophilic substitution reactions, yielding five analogous compounds: acetyl (1), p-methylbenzoyl (2), benzoyl (3), p-methoxybenzoyl (4) and p-chlorobenzoyl (5). Swiss mice were used throughout the experiments. Pro-inflammatory parameters leukocyte migration, exudate concentrations and myeloperoxidase (MPO) activity were quantified in the fluid leakage from the mouse pleural cavities at 4 h after pleurisy induction.ResultsDHC and its analogues acetyl, p-methylbenzoyl, benzoyl, p-methoxybenzoyl and p-chlorobenzoyl inhibited total and differential leukocyte migration andMPOactivity (p < 0.05). OnlyDHCsignificantly decreased the exudate concentrations (p < 0.01).ConclusionsDHC was more effective than its analogues as an anti-inflammatory agent in the mouse model of pleurisy induced by carrageenan.We did not determine what physicochemical modifications altered the anti-inflammatory effect of DHC, but this effect may be due to the modifications on the hydroxyl group at carbon 17 of the DHC.     

Treatment of mixed bipolar states

Mixed bipolar states are associated with more severe symptoms and outcome. Our aim is to review the literature examining their treatment. We conducted a literature search of randomized clinical studies and post-hoc analyses on mixed bipolar states' treatment. Remarkably, there is only one double-blind, placebo-controlled trial, recruiting a mixed episode cohort, and one post-hoc analysis of this trial, while most data come from post-hoc analyses of trials including both manic and mixed patients. Improvement of manic symptoms in mixed episodes is similar to that seen in pure manic episodes and independent of baseline depressive features. The magnitude of response to manic symptoms' treatment probably exceeds that of depressive symptoms, which appear to resolve later. Valproate and carbamazepine are effective in acute mixed episodes, but the efficacy of lithium appears questionable. Atypical antipsychotic monotherapy improves both manic and depressive symptoms. Mood-stabilizer-atypical antipsychotic combination increases this effect. Atypical antipsychotic-antidepressant combination against acute mixed depression does not increase the risk for mania, although its superior efficacy vs. atypical antipsychotic monotherapy cannot be supported by current data. As regards prophylaxis, atypical antipsychotic monotherapy is associated with a lower incidence of and a longer time to relapse of any kind. The augmentation of lithium or divalproex with atypical antipsychotics increases prophylactic efficacy. Lithium or divalproex monotherapy have not been associated with significant prophylactic benefits following mixed mania. New, randomized prospective trials involving homogeneous cohorts of mixed bipolar patients are needed in order to delineate the appropriate pharmacological treatment of mixed states.     

GP and patient predictors of PSA screening in Australian general practice

OBJECTIVE: We determined GP and patient variables associated first with men's prior uptake of prostate-specific antigen (PSA) screening and, subsequently, its initiation during an 'index consultation' in Australian general practice. METHODS: From the practices of 60 GPs, we recruited a sample of 423 male patients aged 40-70 years. In a waiting room questionnaire completed before their 'index consultation' (retrospective component), men reported their previous PSA screening status. We obtained demographic and clinical data, including the presence of lower urinary tract symptoms (LUTS). Men also were mailed a questionnaire 2 days after their 'index consultation' to ascertain whether the GP had discussed PSA screening (prospective component) for prostate cancer and other behaviours. GPs themselves completed questionnaires eliciting demographic and practice characteristics as well as their propensity to screen and understanding of the evidence about PSA testing. GP and patient study variables were modelled simultaneously in analyses. RESULTS: Of those 348 men consulting with their regular GP, 80 (23.0%) reported previously having had a PSA screening test. Men were significantly and independently more likely ever to have had PSA screening if their regular GP reported a propensity to initiate screening [adjusted odds ratio (AOR) = 2.27, 95% confidence interval (CI) 1.23-4.20; P = 0.009]. GP age also was independently associated with men's PSA screening status [chi-squared (3) P < 0.0001] as was men's age and severity of LUTS (AOR = 2.38, 95% CI 1.58-3.57, P < 0.0001 and AOR = 1.79, 95% CI 1.00-3.19, P = 0.004, respectively). Current smokers were less likely ever to have had a PSA screening test (AOR = 0.34, 95% CI 0.16-0.69; P = 0.003). Discussion of PSA screening in their 'index consultation' was recalled independently more often by older men (AOR = 1.46, 95% CI 1.00-2.13; P = 0.04), those with moderate/severe LUTS (AOR = 1.94, 1.07-3.49; P = 0.04), those whose GP had performed or discussed a cholesterol test (AOR = 2.26, 95% CI 1.03-4.92; P = 0.04) and those whose GP had postgraduate training in family medicine (AOR = 3.13, 95% CI 1.23-8.00; P = 0.02). CONCLUSION: In the absence as yet of compelling evidence that PSA screening will prolong life or enhance its quality, our findings identify GP and patient factors that could be targeted to modify PSA screening.     

Does Distance Matter? Access to Family Planning Clinics and Adolescent Sexual Behaviors

The study examines the relationship between adolescent geographic access (distance, travel time, density) to Family Planning Clinics and adolescent sexual behaviors, including sexual initiation, number of partners and condom use. This cross-sectional study, conducted in 2005 in 10 California counties, utilized data from NICHD-funded study on adolescent sexual behavior (n = 921), geospatial coordinates of publicly-funded FPCs, and neighborhood characteristics. A series of regression models were used to assess the relationship between FPC distance, and density (number of FPCs within 1- and 3- mile radii of each adolescent’s home), and adolescent sexual behaviors. Significant main effects between access measures of FPC and sexual behavior did not emerge. However, among older youth a significant inverse relationship emerged between number of FPCs within a 1-mile radius and initiating sexual intercourse. While not significant at α = .10, the results also indicate a negative relationship between density of FPCs and sexual partners (b = −.22, p < .15) among older youth. Access to FPCs was not associated with condom use. Conclusions: Results suggest that increased options for family planning services may lead to less risky sexual behaviors among older youth. This finding has significant implications with regards to making family planning resources more readily available to older adolescents.     

MOZ-TIF2-induced acute myeloid leukemia requires the MOZ nucleosome binding motif and TIF2-mediated recruitment of CBP

The MOZ-TIF2 fusion is associated with acute myeloid leukemia (AML) with inv(8)(p11q13). MOZ is a MYST family histone acetyltransferase (HAT), whereas TIF2 is a nuclear receptor coactivator that associates with CREB binding protein (CBP). Here we demonstrate that MOZ-TIF2 has transforming properties in vitro and causes AML in a murine bone marrow transplant assay. The C2HC nucleosome recognition motif of MOZ is essential for transformation, whereas MOZ HAT activity is dispensable. However, MOZ-TIF2 interaction with CBP through the TIF2 CBP interaction domain (CID) is essential for transformation. These results indicate that nucleosomal targeting by MOZ and recruitment of CBP by TIF2 are critical requirements for MOZ-TIF2 transformation and indicate that MOZ gain of function contributes to leukemogenesis.     

Relationship between anxiety disorders and opiate dependence— A systematic review of the literature : Implications for diagnosis and treatment

Our objective was to evaluate the prevalence and temporal sequence of co-occurrence of anxiety disorders with opiate dependence in order to better define the relationship between these two disorders and to improve diagnosis and treatment. The search used Medline and Toxibase up to January 1, 2009, and was based on a systematic review method. Eighteen studies were found. Prevalence of anxiety disorders assessed by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria was high in opiate-dependent treated persons (lifetime prevalence ranged from 26% to 35%). Among anxiety disorders, phobic disorders have been shown to often precede the onset of opiate dependence. The identification of substance-induced versus independent anxiety disorder has important treatment implication. The monitoring of anxiety symptoms after several weeks of abstinence may allow physicians to determine the relationship between dependence and anxiety and make a reliable diagnosis of any initial anxious disorder. Specific management of anxiety disorder may then be used.