Detection of refractive photokeratectomy traces during eye banking: impossible with organ culture but possible with an active storage machine: case report

Cell and Tissue Banking - The detection of corneas operated on for refractive surgery [LASIK or photorefractive keratectomy (PRK)] will become a major concern for eye banks in the coming years...     

B-cell depletion in SLE: clinical and trial experience with rituximab and ocrelizumaband implications for study design

B cells are believed to be central to the disease process in systemic lupuserythematosus (SLE), making them a target for new therapeutic intervention. In recentyears there have been many publications regarding the experience in SLE of B-celldepletion utilising rituximab, an anti-CD20 mAb that temporarily depletes B cells,reporting promising results in uncontrolled open studies and in routine clinical use.However, the two large randomised controlled trials in extra-renal lupus (EXPLORERstudy) and lupus nephritis (LUNAR study) failed to achieve their primary endpoints.Based on the clinical experience with rituximab this failure was somewhat unexpectedand raised a number of questions and concerns, not only into the true level ofbenefit of B-cell depletion in a broad population but also how to test the true levelof effectiveness of an investigational agent as we seek to improve the design oftherapeutic trials in SLE. A better understanding of what went wrong in these trialsis essential to elucidate the underlying reasons for the disparate observations notedin open studies and controlled trials. In this review, we focus on various factorsthat may affect the ability to accurately and confidently establish the level oftreatment effect of the investigational agent, in this case rituximab, in the twostudies and explore hurdles faced in the randomised controlled trials investigatingthe efficacy of ocrelizumab, the humanised anti-CD20 mAb, in SLE. Further, based onthe lessons learned from the clinical trials, we make suggestions that could beimplemented in future clinical trial design to overcome the hurdles faced.     

Neisseria meningitidis colonization of the brain endothelium and cerebrospinal fluid invasion

The brain and meningeal spaces are protected from bacterial invasion by the blood–brain barrier, formed by specialized endothelial cells and tight intercellular junctional complexes. However, once in the bloodstream, Neisseria meningitidis crosses this barrier in about 60% of the cases. This highlights the particular efficacy with which N. meningitidis targets the brain vascular cell wall. The first step of central nervous system invasion is the direct interaction between bacteria and endothelial cells. This step is mediated by the type IV pili, which induce a remodelling of the endothelial monolayer, leading to the opening of the intercellular space. In this review, strategies used by the bacteria to survive in the bloodstream, to colonize the brain vasculature and to cross the blood–brain barrier will be discussed.     

The relative effects of local management and landscape context on weed seed predation and carabid functional groups

Farmland biodiversity and its associated ecosystem services are affected by agricultural activities at multiple spatial scales. Among these services, the regulation of weeds by invertebrate seed predators has received much attention recently but little is known about the relative effect of local management and landscape context of fields on this process. We monitored seed predation on four common weed species and carabid communities in 28 winter-cereals fields during five consecutive weeks in spring 2010. These fields were situated in contrasted landscape contexts and varied in terms of intensity of pesticide treatments and soil tillage regimes. Weed seed predation was strongly and positively related to the Shannon diversity of (strictly) granivorous carabids and to the activity–density of omnivorous carabids but negatively to the richness of omnivorous carabids. Weed seed predation and granivore diversity were positively related to landscape diversity and the proportion cover of temporary grassland within a 1000 m radius around focal fields and were negatively affected by the intensity of local pesticide treatments. No-till systems sheltered higher diversity of granivorous carabids but did not show higher seed predation rates. We showed that landscape composition factors had a higher relative influence than local practices factors on weed seed predation service. Consequently, weed management strategies should not only consider the management of single fields but also the surrounding landscape to preserve carabid biodiversity and enhance weed seed predation service.     

The Cholinergic Anti-Inflammatory Pathway Delays TLR-Induced Skin Allograft Rejection in Mice: Cholinergic Pathway Modulates Alloreactivity

Activation of innate immunity through Toll-like receptors (TLR) can abrogate transplantation tolerance by revealing hidden T cell alloreactivity. Separately, the cholinergic anti-inflammatory pathway has the capacity to dampen macrophage activation and cytokine release during endotoxemia and ischemia reperfusion injury. However, the relevance of the α7 nicotinic acetylcholine receptor (α7nAChR)-dependent anti-inflammatory pathway in the process of allograft rejection or maintenance of tolerance remains unknown. The aim of our study is to investigate whether the cholinergic pathway could impact T cell alloreactivity and transplant outcome in mice. For this purpose, we performed minor-mismatched skin allografts using donor/recipient combinations genetically deficient for the α7nAChR. Minor-mismatched skin grafts were not rejected unless the mice were housed in an environment with endogenous pathogen exposure or the graft was treated with direct application of imiquimod (a TLR7 ligand). The α7nAChR-deficient recipient mice showed accelerated rejection compared to wild type recipient mice under these conditions of TLR activation. The accelerated rejection was associated with enhanced IL-17 and IFN-γ production by alloreactive T cells. An α7nAChR-deficiency in the donor tissue facilitated allograft rejection but not in recipient mice. In addition, adoptive T cell transfer experiments in skin-grafted lymphopenic animals revealed a direct regulatory role for the α7nAChR on T cells. Taken together, our data demonstrate that the cholinergic pathway regulates alloreactivity and transplantation tolerance at multiple levels. One implication suggested by our work is that, in an organ transplant setting, deliberate α7nAChR stimulation of brain dead donors might be a valuable approach for preventing donor tissue inflammation prior to transplant.     

Evidence of Coat Color Variation Sheds New Light on Ancient Canids

We have used a paleogenetics approach to investigate the genetic landscape of coat color variation in ancient Eurasian dog and wolf populations. We amplified DNA fragments of two genes controlling coat color, Mc1r (Melanocortin 1 Receptor) and CBD103 (canine-β-defensin), in respectively 15 and 19 ancient canids (dogs and wolf morphotypes) from 14 different archeological sites, throughout Asia and Europe spanning from ca. 12 000 B.P. (end of Upper Palaeolithic) to ca. 4000 B.P. (Bronze Age). We provide evidence of a new variant (R301C) of the Melanocortin 1 receptor (Mc1r) and highlight the presence of the beta-defensin melanistic mutation (CDB103-K locus) on ancient DNA from dog-and wolf-morphotype specimens. We show that the dominant K^B allele (CBD103), which causes melanism, and R301C (Mc1r), the variant that may cause light hair color, are present as early as the beginning of the Holocene, over 10 000 years ago. These results underline the genetic diversity of prehistoric dogs. This diversity may have partly stemmed not only from the wolf gene pool captured by domestication but also from mutations very likely linked to the relaxation of natural selection pressure occurring in-line with this process.