Rapid application and removal of second messengers to cyclic nucleotide-gated channels from olfactory epithelium.

The last step in the second-messenger cascade mediating vertebrate olfactory transduction is the direct opening of a nonspecific cation channel by cAMP. The kinetic properties of this interaction are critical in determining the time course of the sensory response. To analyze these properties, excised inside-out membrane patches containing either the native channel from salamander olfactory-receptor neurons or a recombinant rat olfactory cyclic nucleotide-gated channel were exposed to short pulses of known concentrations of cAMP or cGMP to mimic a rapid and transient production of second messenger. Channel activity outlasted cyclic nucleotide pulses for several hundred milliseconds. This effect was due to an intrinsic property of the olfactory channel protein because it did not occur with cGMP-activated channels from retinal photoreceptors. Gating kinetics of the olfactory channel were both voltage and agonist dependent. These results demonstrate that the overall slow channel-gating kinetics could account for the difference in time course between the odor-induced changes in cAMP concentration and the subsequent sensory generator current.     

Inhibition of TRPV1 for the treatment of sensitive skin

Please cite this paper as: Inhibition of TRPV1 for the treatment of sensitive skin. Experimental Dermatology 2010; 19 : 980–986. Abstract: During the past years, the topic sensitive skin became one of the most important fields in dermatology. The tremendous interest is based on several studies showing that about 50% of the population declares to have sensitive skin. The human thermoreceptor hTRPV1 was previously identified to contribute to this skin condition while facilitating neurogenic inflammation leading to hyperalgesia. Furthermore, skin sensitivity towards capsaicin, a natural activator of TRPV1, was shown to correlate with sensitive skin. In a screening campaign based on recombinant HEK293‐cells stably transfected with hTRPV1, the selective antagonist trans‐4‐tert‐butylcyclohexanol was identified. This antagonist is able to inhibit capsaicin‐induced hTRPV1 activation with an IC₅₀ value of 34 ± 5 μm tested in HEK293‐cells as well as in electrophysiological recordings performed in oocytes expressing hTRPV1. Strikingly, in a clinical study with 30 women using topical treatment with o/w emulsions containing 31.6 ppm capsaicin, we were able to show that 0.4% of this inhibitor significantly reduces capsaicin‐induced burning (P < 0.0001) in vivo. Thus trans‐4‐tert‐butylcyclohexanol has the potential as a novel bioactive for the treatment of sensitive skin.     

Incorporation of wavelet-based denoising in iterative deconvolution for partial volume correction in whole-body PET imaging

Purpose  Partial volume effects (PVEs) are consequences of the limited resolution of emission tomography. The aim of the present study was to compare two new voxel-wise PVE correction algorithms based on deconvolution and wavelet-based denoising. Materials and methods  Deconvolution was performed using the Lucy-Richardson and the Van-Cittert algorithms. Both of these methods were tested using simulated and real FDG PET images. Wavelet-based denoising was incorporated into the process in order to eliminate the noise observed in classical deconvolution methods. Results  Both deconvolution approaches led to significant intensity recovery, but the Van-Cittert algorithm provided images of inferior qualitative appearance. Furthermore, this method added massive levels of noise, even with the associated use of wavelet-denoising. On the other hand, the Lucy-Richardson algorithm combined with the same denoising process gave the best compromise between intensity recovery, noise attenuation and qualitative aspect of the images. Conclusion  The appropriate combination of deconvolution and wavelet-based denoising is an efficient method for reducing PVEs in emission tomography.     

Developmental regulation of subunit composition of extrasynaptic NMDA receptors in neocortical neurones

NMDA receptors undergo drastic changes in their subunit composition during development of the mammalian neocortex. An increase in the expression of the NR2A subunit correlates with developmental changes in the properties of synaptic NMDA receptors. In this study, we investigated whether these developmental alterations are restricted to synaptic NMDA receptors or whether similar developmental changes also occur at extrasynaptic NMDA receptors. To analyse the properties of extrasynaptic receptors, glutamate-evoked ion currents mediated by extrasynaptic NMDA receptors were isolated by irreversibly blocking synaptic NMDA receptors with MK-801. Whole-cell ion currents mediated by extrasynaptic receptors showed developmental changes in their sensitivity against the NR2B subunit-specific antagonist ifenprodil similar to that of synaptic receptors. In summary, our results strongly suggest that NR2A subunit-containing NMDA receptors increasingly contribute also to extrasynaptic NMDA receptors during in vitro differentiation.     

The place of transsaccal dacryocystorhinostomy in modern lacrimal surgery

Despite the advances in transnasal and external dacryocystorhinostomy, transsaccal dacryocystorhinostomy is an excellent addition to the armamentarium in chronic fistulizing dacryocystitis with a dilated tear sac in elderly patients. A large incision with excision of the fistula opens the lacrimal sac, from where a wide dacryocystorhinostomy can be opened into the nose. The skin and tear sac incision can be closed in one layer.     

A novel function for chemokines: downregulation of neutrophil migration

Migration is a key function of stem cells during ontogenesis, of fibroblasts in wound healing and of immune cells in host defence. The signals that initiate migration are as important as signals that terminate migration, once the destination has been reached. We now show that formyl-methionyl-leucyl-phenylalanine (fMLP)-induced migration of neutrophils was inhibited by increasing concentrations of interleukin-8 (IL-8). IL-8 dose dependently increased the frequency and the duration of stop-periods, whereas the percentage of cells of a population that was locomotory active remained constant. The stop-signal delivered by IL-8 was intracellularly transduced by a dichotomic pathway: (i) the activation of the adenylyl cyclase leads to an increase of cytosolic cyclic adenosine monophosphate, which results in an activation of the sarcoplasmatic/endoplasmatic reticulum calcium ATPase pump and a calcium sequestration; (ii) the activation of the phospholipase Cbeta (PLCbeta) generates inositol-1,4,5-phosphate (IP3) and diacylglycerol (DAG), which results in IP3-mediated release of intracellularly stored calcium in the endoplasmatic reticulum and DAG-mediated activation of protein kinase C. Thus, we show for the first time that a chemokine, IL-8, in concert with fMLP, downregulates the neutrophil migration through the regulation of the intracellular calcium concentration via the adenylyl cyclase and the PLCbeta2.     

Nonsympathetic increased inotropic state early after aortic insufficiency

The very early left ventricular response to chronic volume overload induced by aortic insufficiency (AI) was examined in conscious dogs previously instrumented with a left ventricular micromanometer and ultrasonic crystals measuring internal diameter, segmental length, and parietal wall thickness. Acute volume loading with dextran (AVL) was compared with that 24 and 48 h after AI induced by a perforation of the aortic valve. beta-Blockade was also produced before and after AI. For a similar increase in preload in AVL and after AI, the percent change in systolic shortening of diameters and segments (% delta L) increased from 30.4 to 34.1% after AI (P less than 0.01). For matched calculated wall stress during AVL and AI, % delta L and peak velocity of shortening were significantly increased after AI, and the same results were reproduced after beta-blockade. We conclude that, at the early phase of chronic volume overload before hypertrophy appears, left ventricular hyperfunction is mainly due to a nonsympathetic increased contractility and that, in the conscious dog, the inotropic state appears to be modified by a sustained increased preload.