BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain

Neuropathic pain that occurs after peripheral nerve injury depends on the hyperexcitability of neurons in the dorsal horn of the spinal cord. Spinal microglia stimulated by ATP contribute to tactile allodynia, a highly debilitating symptom of pain induced by nerve injury. Signalling between microglia and neurons is therefore an essential link in neuropathic pain transmission, but how this signalling occurs is unknown. Here we show that ATP-stimulated microglia cause a depolarizing shift in the anion reversal potential (E(anion)) in spinal lamina I neurons. This shift inverts the polarity of currents activated by GABA (gamma-amino butyric acid), as has been shown to occur after peripheral nerve injury. Applying brain-derived neurotrophic factor (BDNF) mimics the alteration in E(anion). Blocking signalling between BDNF and the receptor TrkB reverses the allodynia and the E(anion) shift that follows both nerve injury and administration of ATP-stimulated microglia. ATP stimulation evokes the release of BDNF from microglia. Preventing BDNF release from microglia by pretreating them with interfering RNA directed against BDNF before ATP stimulation also inhibits the effects of these cells on the withdrawal threshold and E(anion). Our results show that ATP-stimulated microglia signal to lamina I neurons, causing a collapse of their transmembrane anion gradient, and that BDNF is a crucial signalling molecule between microglia and neurons. Blocking this microglia-neuron signalling pathway may represent a therapeutic strategy for treating neuropathic pain.     

Holism and Understanding Sustainability

In work undertaken in both Malta and Lebanon we have been reflecting on the current means by which the international community apply concepts intended to achieve what is called “sustainable development.” In an attempt to make means and ends conform to each other we have developed a holistic approach to what is essentially a timeless need for understanding, systemic planning, and compassionate stewardship. This essay indicates that we may be closer to holistic means with which to realize these goals than we know. It describes how some planning and analysis methods have their origins in ancient traditions. However, the milieu in which sustainability occurs is often unsympathetic to and sometimes incompatible with the ideals of holism. The essay assesses the current understanding of sustainability and points to the need for a wider and more inclusive base to contemporary sustainability as practiced in the community.     

The peptidylarginine deiminases expressed in human epidermis differ in their substrate specificities and subcellular locations

Deimination, a post-translational modification catalyzed by peptidylarginine deiminases (PADs), appears as a crucial Ca²⁺-dependent event in the last steps of epidermal differentiation. In normal human epidermis, where the deiminated proteins are filaggrin and keratins, PAD1, 2 and 3 are expressed but their relative role is unknown. The three PADs, produced as active recombinant forms, showed distinct synthetic-substrate specificities, various efficiencies to deiminate filaggrin and particular calcium and pH sensitivities. Immunoelectron microscopy demonstrated that PAD1 and PAD3 are co-located with filaggrin within the filamentous matrix of the deeper corneocytes where the protein is deiminated. This result strongly suggests that both isoforms are involved in the deimination of filaggrin, an essential step leading to free amino acid production necessary for epidermal barrier function. Moreover, PAD1 was shown to persist up to the upper corneocytes where it deiminates keratin K1, a modification supposed to be related to ultrastructural changes of the matrix.Received 10 May 2005; received after revision 21 June 2005; accepted 29 June 2005     

Human recombination hot spots hidden in regions of strong marker association

The fine-scale distribution of meiotic recombination events in the human genome can be inferred from patterns of haplotype diversity in human populations but directly studied only by high-resolution sperm typing. Both approaches indicate that crossovers are heavily clustered into narrow recombination hot spots. But our direct understanding of hot-spot properties and distributions is largely limited to sperm typing in the major histocompatibility complex (MHC). We now describe the analysis of an unremarkable 206-kb region on human chromosome 1, which identified localized regions of linkage disequilibrium breakdown that mark the locations of sperm crossover hot spots. The distribution, intensity and morphology of these hot spots are markedly similar to those in the MHC. But we also accidentally detected additional hot spots in regions of strong association. Coalescent analysis of genotype data detected most of the hot spots but showed significant differences between sperm crossover frequencies and historical recombination rates. This raises the possibility that some hot spots, particularly those in regions of strong association, may have evolved very recently and not left their full imprint on haplotype diversity. These results suggest that hot spots could be very abundant and possibly fluid features of the human genome.     

Shivering in intact and spinal rabbits during spinal cord cooling

Zusammenfassung Bei spinalen wie auch bei intakten, leicht narkotisierten Kaninchen konnte durch Kühlung des Rückenmarkes Muskelzittern ausgelöst werden. Im Vergleich zu den intakten Tieren war der Effekt der Rückenmark-Kühlung bei spinalen Tieren schwächer, und die Temperatur zu Beginn und bei Beendïgung der elektromyographisch erfassten Aktivität war niedriger, bzw. streute in einem weiteren Temperaturbereich. Die während des Kältezitterns intakter Tiere häufig zu beobachtenden phasischen Aktivitätsschwankungen im Elektromyogramm waren bei spinalen Tieren nur selten nachweisbar.