The role of the palatine tonsils in the pathogenesis and treatment of psoriasis

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/96289/1/bjd11215.pd

Novel expression of Haemonchus contortus vaccine candidate aminopeptidase H11 using the free-living nematode Caenorhabditis elegans

With the problem of parasitic nematode drug resistance increasing, vaccine development offers an alternative sustainable control approach. For some parasitic nematodes, native extracts enriched for specific proteins are highly protective. However, recombinant forms of these proteins have failed to replicate this protection. This is thought to be due to differences in glycosylation and/or conformation between native and recombinant proteins. We have exploited the free-living nematode Caenorhabditis elegans to examine its suitability as an alternative system for recombinant expression of parasitic nematode vaccine candidates. We focussed on Haemonchus contortus aminopeptidase H11 glycoprotein, which is enriched in a gut membrane fraction capable of inducing significant protection against this important ovine gastrointestinal nematode. We show that H. contortus H11 expressed in C. elegans is enzymatically active and MALDI mass spectrometry identifies similar di- and tri-fucosylated structures to those on native H11, with fucose at the 3- and/or 6-positions of the proximal GlcNAc. Some glycan structural differences were observed, such as lack of LDNF. Serum antibody to native H11 binds to C. elegans recombinant H11 and most of the antibody to rH11 or native H11 is directed to glycan moieties. Despite these similarities, no reduction in worm burden or faecal egg count was observed following immunisation of sheep with C. elegans-expressed recombinant H11 protein. The findings suggest that the di- and tri-fucosylated N-glycans expressed on rH11 do not contribute to the protective effect of H11 and that additional components present in native H11-enriched extract are likely required for enhancing the antibody response necessary for protection

Natural abundance 14N and 15N solid-state NMR of pharmaceuticals and their polymorphs

14N ultra-wideline (UW), 1H{15N} indirectly-detected HETCOR (idHETCOR) and 15N dynamic nuclear polarization (DNP) solid-state NMR (SSNMR) experiments, in combination with plane-wave density functional theory (DFT) calculations of 14N EFG tensors, were utilized to characterize a series of nitrogen-containing active pharmaceutical ingredients (APIs), including HCl salts of scopolamine, alprenolol, isoprenaline, acebutolol, dibucaine, nicardipine, and ranitidine. A case study applying these methods for the differentiation of polymorphs of bupivacaine HCl is also presented. All experiments were conducted upon samples with naturally-abundant nitrogen isotopes. For most of the APIs, it was possible to acquire frequency-stepped UW 14N SSNMR spectra of stationary samples, which display powder patterns corresponding to pseudo-tetrahedral (i.e., RR′R′′NH+ and RR′NH2+) or other (i.e., RNH2 and RNO2) nitrogen environments. Directly-excited 14N NMR spectra were acquired using the WURST-CPMG pulse sequence, which incorporates WURST (wideband, uniform rate, and smooth truncation) pulses and a CPMG (Carr-Purcell Meiboom-Gill) refocusing protocol. In certain cases, spectra were acquired using 1H → 14N broadband cross-polarization, via the BRAIN-CP (broadband adiabatic inversion – cross polarization) pulse sequence. These spectra provide 14N electric field gradient (EFG) tensor parameters and orientations that are particularly sensitive to variations in local structure and intermolecular hydrogen-bonding interactions. The 1H{15N} idHETCOR spectra, acquired under conditions of fast magic-angle spinning (MAS), used CP transfers to provide 1H–15N chemical shift correlations for all nitrogen environments, except for two sites in acebutolol and nicardipine. One of these two sites (RR′NH2+ in acebutolol) was successfully detected using the DNP-enhanced 15N{1H} CP/MAS measurement, and one (RNO2 in nicardipine) remained elusive due to the absence of nearby protons. This exploratory study suggests that this combination of techniques has great potential for the characterization of solid APIs and numerous other organic, biological, and inorganic systems

Respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease

The effects of respiratory viral infection on the time course of chronic obstructive pulmonary disease (COPD) exacerbation were examined by monitoring changes in systemic inflammatory markers in stable COPD and at exacerbation. Eighty-three patients with COPD (mean [SD] age, 66.6 [7.1] yr, FEV1, 1.06 [0.61] L) recorded daily peak expiratory flow rate and any increases in respiratory symptoms. Nasal samples and blood were taken for respiratory virus detection by culture, polymerase chain reaction, and serology, and plasma fibrinogen and serum interleukin-6 (IL-6) were determined at stable baseline and exacerbation. Sixty-four percent of exacerbations were associated with a cold occurring up to 18 d before exacerbation. Seventy-seven viruses (39 [58.2%] rhinoviruses) were detected in 66 (39.2%) of 168 COPD exacerbations in 53 (64%) patients. Viral exacerbations were associated with frequent exacerbators, colds with increased dyspnea, a higher total symptom count at presentation, a longer median symptom recovery period of 13 d, and a tendency toward higher plasma fibrinogen and serum IL-6 levels. Non-respiratory syncytial virus (RSV) respiratory viruses were detected in 11 (16%), and RSV in 16 (23.5%), of 68 stable COPD patients, with RSV detection associated with higher inflammatory marker levels. Respiratory virus infections are associated with more severe and frequent exacerbations, and may cause chronic infection in COPD. Prevention and early treatment of viral infections may lead to a decreased exacerbation frequency and morbidity associated with COPD

Determination of superconducting anisotropy from magnetization data on random powders as applied to LuNi2_2B2_2C, YNi2_2B2_2C and MgB2_2

The recently discovered intermetallic superconductor MgB2 appears to have a highly anisotopic upper critical field with Hc2(max)/Hc2(min} = \gamma > 5. In order to determine the temperature dependence of both Hc2(max) and Hc2(min) we propose a method of extracting the superconducting anisotropy from the magnetization M(H,T) of randomly oriented powder samples. The method is based on two features in dM/dT the onset of diamagnetism at Tc(max), that is commonly associated with Hc2, and a kink in dM/dT at a lower temperature Tc(min). Results for LuNi2B2C and YNi2B2C powders are in agreement with anisotropic Hc2 obtained from magneto-transport measurements on single crystals. Using this method on four different types of MgB2 powder samples we are able to determine Hc2(max)(T) and Hc2(min)(T) with \gamma \approx 6

Validity and Reliability of a Brief Dietary Assessment Questionnaire in a Cardiac Rehabilitation Program

Purpose: Dietary assessment is vital to inform individualized nutrition care and to evaluate the success of interventions aimed at improving diet for participants in cardiac rehabilitation (CR) programs. The purpose of this study was to assess the validity and reliability of an instrument developed to reflect current evidence-informed dietary recommendations advocated to reduce cardiovascular risk. Methods: This study was conducted at a single CR program at the University of North Carolina, Chapel Hill. Two dietary assessments were administered: Picture Your Plate (PYP) and a reference instrument, the Harvard/Willett Food Frequency Questionnaire (HWFFQ). The PYP is a modification of a previously validated instrument, the Dietary Risk Assessment-New Leaf (DRA-New Leaf). Concurrent validity was assessed by comparing the PYP total score with 3 diet quality indexes (Alternative Health Eating Index [AHEI], Dietary Approaches to Stop Hypertension [DASH], and Alternative Mediterranean Diet [aMED]) calculated from the HWFFQ and by assessment of agreement in tertile cross-classification. An intraclass correlation (ICC) was calculated to assess test-retest reliability. Results: Among the 108 participants, crude and adjusted Spearmen correlation coefficients between the PYP and 3 indexes of dietary quality were AHEI-2010 (0.71-0.72), DASH (0.70-0.71), and aMED (0.52-0.58) (P <.0001, all comparisons). Agreement of tertiles comparing PYP and AHEI-2010 was 67% and the score in opposite tertiles was 6%. The weighted kappa value (κw) = 0.71. The test-retest ICC was 0.91 (95% CI, 0.85-0.93; n = 91). Conclusions: Results support the PYP as a valid and reliable dietary assessment tool for use in CR programs. Continued research in additional CR program populations is recommended

Bosonic Excitations in Random Media

We consider classical normal modes and non-interacting bosonic excitations in disordered systems. We emphasise generic aspects of such problems and parallels with disordered, non-interacting systems of fermions, and discuss in particular the relevance for bosonic excitations of symmetry classes known in the fermionic context. We also stress important differences between bosonic and fermionic problems. One of these follows from the fact that ground state stability of a system requires all bosonic excitation energy levels to be positive, while stability in systems of non-interacting fermions is ensured by the exclusion principle, whatever the single-particle energies. As a consequence, simple models of uncorrelated disorder are less useful for bosonic systems than for fermionic ones, and it is generally important to study the excitation spectrum in conjunction with the problem of constructing a disorder-dependent ground state: we show how a mapping to an operator with chiral symmetry provides a useful tool for doing this. A second difference involves the distinction for bosonic systems between excitations which are Goldstone modes and those which are not. In the case of Goldstone modes we review established results illustrating the fact that disorder decouples from excitations in the low frequency limit, above a critical dimension $d_c$, which in different circumstances takes the values $d_c=2$ and $d_c=0$. For bosonic excitations which are not Goldstone modes, we argue that an excitation density varying with frequency as $\rho(\omega) \propto \omega^4$ is a universal feature in systems with ground states that depend on the disorder realisation. We illustrate our conclusions with extensive analytical and some numerical calculations for a variety of models in one dimension

Transverse Beam Spin Asymmetries in Forward-Angle Elastic Electron-Proton Scattering

We have measured the beam-normal single-spin asymmetry in elastic scattering of transversely-polarized 3 GeV electrons from unpolarized protons at Q^2 = 0.15, 0.25 (GeV/c)^2. The results are inconsistent with calculations solely using the elastic nucleon intermediate state, and generally agree with calculations with significant inelastic hadronic intermediate state contributions. A_n provides a direct probe of the imaginary component of the 2-gamma exchange amplitude, the complete description of which is important in the interpretation of data from precision electron-scattering experiments.Comment: 5 pages, 3 figures, submitted to Physical Review Letters; shortened to meet PRL length limit, clarified some text after referee's comment

Australian recommendations on perioperative use of disease-modifying anti-rheumatic drugs in people with inflammatory arthritis undergoing elective surgery.

OnlinePublDisease-modifying antirheumatic drugs (DMARDs) are effective treatments for inflammatory arthritis but carry an increased risk of infection. For patients undergoing surgery there is a need to consider the trade-off between a theoretical increased risk of infection with continuation of DMARDs perioperatively versus an increased risk of disease flare if they are temporarily withheld. We used GRADE methodology to develop recommendations for perioperative use of DMARDs for people with inflammatory arthritis undergoing elective surgery. The recommendations form part of the NHMRC-endorsed Australian Living Guideline for the Pharmacological Management of Inflammatory Arthritis. Conditional recommendations were made against routinely discontinuing conventional synthetic (cs) and biologic (b) DMARDs in the perioperative period but to consider temporary discontinuation of bDMARDs in individuals with a high risk of infection or where the impact of infection would be severe. A conditional recommendation was made in favour of temporary discontinuation of targeted synthetic (ts) DMARDs in the perioperative period.Rachelle Buchbinder, Vanessa Glennon, Renea V. Johnston, Sue E. Brennan, Chris Fong, Suzie Edward May, Sean O, Neill, Peter Smitham, Lyndal Trevena, Glen Whittaker, Anita Wluka, and Samuel L. Whittl