Inhibition of interleukin-6 synthesis in an animal model of septic shock by anti-C5a monoclonal antibodies

The complement activation fragment C5a was recently shown to induce interleukin (IL)-6 synthesis by peripheral blood mononuclear cells. To understand better the role of C5a in cytokine regulation in vivo, we investigated the effects of complement depletion by cobra venom factor (CVF) or of anti-C5a monoclonal antibodies (mAb) on IL-6 generation in an animal model of septic shock. Complement-depleted pigs which were subsequently challenged with Escherichia coli generated significantly (p < 0.05) less IL-6 during the 6-h observation period than complement-sufficient controls. To address specifically the role of C5a in IL-6 regulation, we produced a C5a(57–74) peptide-specific mAb (T13/9) which neutralizes the bioactivity of porcine C5a. The mAb T13/9 does not crossreact with the precursor protein C5. The pretreatment of pigs with anti-C5a mAb T13/9 prior to the induction of sepsis resulted in a decrease of over 75 % in serum IL-6 bioactivity compared to control animals (p < 0.0001). These results indicate a role for C5a in the modulation of IL-6 synthesis in Gram-negative bacteremia.     

Analysis of a terminal Xp22.3 deletion in a patient with six monogenic disorders: implications for the mapping of X linked ocular albinism.

The molecular characterisation of chromosomal aberrations in Xp22.3 has established the map position of several genes with mutations resulting in diverse phenotypes such as short stature (SS), chondrodysplasia punctata (CDPX), mental retardation (MRX), ichthyosis (XLI), and Kallmann syndrome (KAL). We describe the clinical symptoms of a patient with a complex syndrome compatible with all these conditions plus ocular albinism (OA1). He has a terminal Xp deletion of at least 10 Mb of DNA. Both the mother and sister of the patient are carriers of the deletion and show a number of traits seen in Turner's syndrome. The diagnosis of ocular albinism was confirmed in the patient and his mother, who shows iris translucency, patches and streaks of hypopigmentation in the fundus, and macromelanosomes in epidermal melanocytes. By comparative deletion mapping we can define a deletion interval, which locates the OA1 gene proximal to DXS143 and distal to DXS85, with the breakpoints providing valuable starting points for cloning strategies.     

Swelling,Elasticity and Spatial Inhomogeneity of Poly(N,N‐dimethylacrylamide) Hydrogels Formed at Various Polymer Concentrations

Summary: The equilibrium swelling degree, modulus of elasticity and the spatial inhomogeneity of poly(N,N‐dimethylacrylamide) (PDMAAm) hydrogels were investigated over the entire range of the initial monomer concentration. The degree of dilution of the networks after their preparation was denoted by ν, the volume fraction of crosslinked polymer after the gel preparation. The linear swelling ratio of the gels increased linearly with increasing ν. Depending on the value of ν, three different gel regimes were observed: (1) For ν < 0.3, increasing ν decreases the extent of cyclization during crosslinking so that the effective crosslink density of gels increases with rising ν. (2) For 0.3 < ν < 0.7, increasing ν reduces the accessibility of the pendant vinyl groups during crosslinking due to steric hindrance at high polymer concentrations. As a result, the effective crosslink density of gels decreases with increasing ν. (3) For ν > 0.7, the modulus of elasticity increases sharply with increasing ν due to the increasing extent of chain entanglements in this high concentration regime. Static light scattering measurements on the gels show that the degree of spatial gel inhomogeneity in PDMAAm gels attains a maximum value at ν = 0.06. The appearance of a maximum as well as the ν‐dependence of scattered light intensities from gels was successfully reproduced by the theory proposed by Panyukov and Rabin.

Effective crosslink density ν_e of the hydrogels shown as a function of ν.     

An Approach for Widening the Bioequivalence Acceptance Limits in the Case of Highly Variable Drugs

Purpose. Highly variable drugs pose a problem in bioequivalence assessment because they often fail to meet current regulatory acceptance criteria for average bioequivalence (80–125%). This paper examines alternative approaches to establishing bioequivalence. Methods. Suggested solutions have included alternate study designs, e.g., replicate and multiple dose studies, reducing the level of the confidence interval, and widening the acceptance limits. We focus on the latter approach. Results. A rationale is presented for defining wider acceptance limits for highly variable drugs. Two previously described methods are evaluated, and a new method having more desirable properties is proposed. Conclusions. We challenge the one size fits all current definition of bioequivalence acceptance limits for highly variable drugs, proposing alternative limits or goal posts which vary in accordance with the intrasubject variability of the reference product.