Fatal varicella associated with selective natural killer cell deficiency

A 2-year-old girl with recurrent severe varicella infections had a fatal outcome. Studies of cellular and humoral immunity were normal. No natural killer (NK) cells were detected, and NK activity was markedly decreased. The interleukin (IL)15/IL15R signaling pathway was intact. This case emphasizes the role of NK cells in controlling herpes viral infection.     

Generating an ex vivo vascular model

Realistic ex vivo anthropometric vascular environments are required for endovascular device optimization and for preclinical evaluation of interventional procedures. The objective of this research is to build an anthropomorphic model of the human carotid artery. The combination of magnetic resonance angiography image processing and computer-aided design and manufacturing techniques allowed fabrication of multicomponent morphologically precise casts of the carotid artery. The lost core technique was used to produce a hollow vessel prototype incorporating polyvinyl alcohol cryogel (PVA-C) as a tissue-mimicking vessel wall material. PVA-C was mechanically characterized by uniaxial tensile testing after different numbers of freeze/thaw cycles. The novel model construction approach outlined in this study accounts for the morphologic complexities of the human vasculature, and proved successful for the production of realistic compliant ex vivo arterial model.     

Antibody polyspecificity and neutralization of HIV-1: a hypothesis

HIV-1 has evolved many ways to evade protective host immune responses, thus creating a number of problems for HIV vaccine developers. In particular, durable, broadly specific neutralizing antibodies to HIV-1 have proved difficult to induce with current HIV-1 vaccine candidates. The recent observation that some broadly neutralizing anti-HIV-1 envelope monoclonal antibodies have polyspecific reactivities to host antigens have raised the hypothesis that one reason antibodies against some of the conserved HIV-1 envelope trimer neutralizing epitopes are not routinely made may be down-regulation of some specificities of anti-HIV-1 antibody producing B cells by host B cell tolerance mechanisms.     

Genetic dissection of immunity in leprosy

Leprosy is a chronic infectious disease caused by Mycobacterium leprae that affects an estimated 700,000 new individuals each year. A strong contribution of host genetics to susceptibility to leprosy has long been suggested to account for the considerable variability observed between individuals exposed to M. leprae. As there is no relevant animal model for human leprosy, forward genetics is the main strategy used to identify the genes and, consequently, the immunological pathways involved in protective immunity to M. leprae. With respect to genome-wide screens, a major breakthrough has been reported this year; variants in the regulatory region shared by PARK2 and PACRG have been identified as being common risk factors for leprosy.     

What are the effects of maternal and pre-adult environments on ageing in humans, and are there lessons from animal models?

An open issue in research on ageing is the extent to which responses to the environment during development can influence variability in life span in animals, and the health profile of the elderly in human populations. Both affluence and adversity in human societies have profound impacts on survivorship curves, and some of this effect may be traceable to effects in utero or in infancy. The Barker Hypothesis that links caloric restriction in very early life to disruptions of glucose-insulin metabolism in later life has attracted much attention, as well as some controversy, in medical circles. It is only rarely considered by evolutionary biologists working on phenotypic plasticity, or by biogerontologists studying model organisms such as C. elegans or Drosophila. One crucial mechanism by which animals can respond in an adaptive manner to adverse conditions, for example in nutrition or infection, during development is phenotypic plasticity. Here we begin with a discussion of adaptive plasticity in animals before asking what such phenomena may reveal of relevance to rates of ageing in animals, and in humans. We survey the evidence for effects on adult ageing of environmental conditions during development across mammalian and invertebrate model organisms, and ask whether evolutionary conserved mechanisms might be involved. We conclude that the Barker Hypothesis is poorly supported and argue that more work in human populations should be integrated with multi-disciplinary studies of ageing-related phenomena in experimental populations of different model species that are subjected to nutritional challenges or infections during pre-adult development.     

Functional mu opioid receptors are expressed in cholinergic interneurons of the rat dorsal striatum: territorial specificity and diurnal variation

Striatal cholinergic interneurons play a crucial role in the control of movement as well as in motivational and learning aspects of behaviour. Neuropeptides regulate striatal cholinergic transmission and particularly activation of mu opioid receptor (MOR) inhibits acetylcholine (ACh) release in the dorsal striatum. In the present study we investigated whether this cholinergic transmission could be modulated by an enkephalin/MOR direct process. We show that mRNA and protein of MORs are expressed by cholinergic interneurons in the limbic/prefrontal territory but not by those in the sensorimotor territory of the dorsal striatum. These MORs are functional because potassium-evoked release of ACh from striatal synaptosomes was dose-dependently reduced by a selective MOR agonist, this effect being suppressed by a MOR antagonist. The MOR regulation of cholinergic interneurons presented a diurnal variation. (i) The percentage of cholinergic interneurons containing MORs that was 32% at the beginning of the light period (morning) increased to 80% in the afternoon. (ii) The MOR-mediated inhibition of synaptosomal ACh release was higher in the afternoon than in the morning. (iii) While preproenkephalin mRNA levels remained stable, enkephalin tissue content was the lowest (-32%) in the afternoon when the spontaneous (+35%) and the N-methyl-d-aspartate-evoked (+140%) releases of enkephalin (from microsuperfused slices) were the highest. Therefore, by acting on MORs present on cholinergic interneurons, endogenously released enkephalin reduces ACh release. This direct enkephalin/MOR regulation of cholinergic transmission that operates only in the limbic/prefrontal territory of the dorsal striatum might contribute to information processing in fronto-cortico-basal ganglia circuits.     

Apoptotic cell death progression after photothrombotic focal cerebral ischaemia: effects of the lipophilic iron chelator 2,2'-dipyridyl

Two different forms of cell death have been distinguished morphologically following cerebral ischaemia: necrotic and apoptotic cell death. The aim of this study was to investigate the contribution of apoptosis to ischaemic damage by carefully depicting the temporal and spatial neuronal death following focal ischaemia. For this purpose, rats were subjected to chemical photothrombosis, and histological and biochemical analyses were performed over a period of 24 h after the onset of ischaemia. In addition, the effects of the lipophilic antioxidant iron chelator 2,2'-dipyridyl (DP) were evaluated 24 h after photothrombosis when the lesion volume was maximal. Our results showed two separate waves of neuronal death. In the first wave, shrunken dark neurons were massively present as early as 2 h after photothrombosis in the infarct core. From this initial neuronal abnormal population, progressive and time-dependent changes of both necrotic and apoptotic cell death were observed, leading to ghost neurons and apoptotic bodies after 24 h. The extension of the lesion coincided with a second wave of cell death. Massive and rapid neuronal loss occurred at the infarct border, which appeared as a sharply demarcated pale region. Procaspase and poly(ADP-ribose) polymerase-1 (PARP-1) cleavages were also detected in the infarct core and surrounding damaged tissue. DP treatment markedly blocked the enlargement of the lesion, the infarct border being rescued from infarction. Furthermore, a large decrease of apoptotic bodies was associated with a significant drop of caspase and PARP-1 cleavages, suggesting that the protective effect of DP closely correlates with limitation of apoptosis expansion.     

Dynamic reorganization of the astrocyte actin cytoskeleton elicited by cAMP and PACAP: a role for phosphatidylInositol 3-kinase inhibition

Cyclic AMP (cAMP)-raising agents induce astrocytes grown in vitro to adopt a stellate morphology resembling their in vivo appearance, through the depolymerization of actomyosin stress fibres. The signalling pathways responsible for cAMP-induced astrocyte stellation have thus far remained largely elusive. We showed in this study that the neurotrophic peptide PACAP (pituitary adenylate cyclase-activating polypeptide) mimicked the effect of forskolin, a direct activator of adenylate cyclase, on the actin cytoskeleton of primary rat astrocytes. The depolymerization of stress fibres induced by PACAP or forskolin was prevented by the expression of a constitutively active mutant of RhoA, but not by a protein kinase A (PKA) blocker, indicating that cAMP-raising agents act upstream of RhoA, in a PKA-independent manner. In addition, PACAP and forskolin inhibited basal Akt phosphorylation, and basal and epidermal growth factor (EGF)-stimulated phosphatidylinositol 3-kinase (PI 3-K) activities. Incubation with a PI 3-K blocker resulted in the depolymerization of stress fibres. This effect was blocked by the expression of a constitutively active mutant of RhoA, indicating that PI 3-K inhibition acted upstream of RhoA. Together, these data demonstrate for the first time that depolymerization of stress fibres, and the resulting astrocyte stellation, induced by stimulation of cAMP production involves the inhibition of the PI 3-K-RhoA pathway.