Tamás Szabó

How best to fight that nasty itch – from new insights into the neuroimmunological, neuroendocrine, and neurophysiological bases of pruritus to novel therapeutic approaches

While the enormous clinical and psychosocial importance of pruritus in many areas of medicine and the detrimental effects of chronic ‘itch’ on the quality of life of an affected individual are widely appreciated, the complexity of this sensation is still often grossly underestimated. The current Controversies feature highlights this complexity by portraying pruritus as a truly interdisciplinary problem at the crossroads of neurophysiology, neuroimmunology, neuropharmacology, protease research, internal medicine, and dermatology, which is combated most successfully if one keeps the multilayered nature of ‘itch’ in mind and adopts a holistic treatment approach – beyond the customary, frequently frustrane monotherapy with histamine receptor antagonists. In view of the often unsatisfactory, unidimensional, and altogether rather crude standard instruments for pruritus management that we still tend to use in clinical practice today, an interdisciplinary team of pruritus experts here critically examines recent progress in pruritus research that future itch management must take into consideration. Focusing on new insights into the neuroimmunological, neuroendocrine, and neurophysiological bases of pruritus, and discussing available neuropharmacological tools, specific research avenues are highlighted, whose pursuit promises to lead to novel, and hopefully more effective, forms of pruritus management.

The analgesic drug, tramadol, acts as an agonist of the transient receptor potential vanilloid-1

BACKGROUND:Tramadol is an effective analgesic substance widely used in medical practice. Its therapeutic action have been mainly attributed to the activation of &mgr;-opioid receptors as well as to the inhibition of neurotransmitter reuptake mechanisms and various voltage- and ligand-gated ion channels of the nociceptive system. As transient receptor potential vanilloid-1 (TRPV1, “the capsaicin receptor”) has been shown to function as a central integrator molecule of pain sensation, our aim in the current study was to define the involvement of TRPV1 in the complex mechanism of action of tramadol. METHODS:To achieve these goals, we used single-cell Ca-imaging as well as fluorescent image plate reader assays on Chinese hamster ovary (CHO) cells heterologously over-expressing TRPV1. RESULTS:We found that (1) tramadol, similar to the well-known TRPV1 agonist, capsaicin, significantly increased [Ca2+]i of TRPV1-CHO cells in a concentration-dependent fashion; (2) its effect was reversibly prevented by the TRPV1 antagonist capsazepine; (3) repeated application of tramadol resulted in marked tachyphylaxis; and (4) tramadol did not modify [Ca2+]i in control (empty vector expressing) CHO cells. CONCLUSIONS:Collectively, these findings strongly support the intriguing and novel concept that tramadol acts as an agonist of TRPV1. Considering that activation of TRPV1 on sensory neurons is followed by a local release of vasoactive neuropeptides and a marked desensitization of the afferent fibers (hence termination of pain sensation), our findings may equally explain both the desired analgesic as well as the often-seen, yet “unexpected,” local side effects (e.g., initiation of burning pain and erythema) of tramadol.

Acute psychological benefits of aerobic exercise: a field study into the effects of exercise characteristics.

Abstract Eighty volunteers were tested in their natural exercise environment consisting of a fitness centre they regularly attended. Half of the sample exercised on a stationary bicycle, the other half on a treadmill. All participants filled in the Exercise-Induced Feeling Inventory before and after their 20 min of exercise that was performed at self-selected workload. The results revealed that exercise intensity and the other parallel measures like heart rate, perceived exercise intensity and estimates of burned calories were higher in participants who ran in contrast to those who cycled. There were no differences in self-reports of enjoyment of the exercise sessions and in the psychological improvements from pre- to post-exercise between the groups. It is concluded that significant psychological improvements occur even after a 20-min bout of exercise and these changes are independent of the workload or exercise intensity.

Blood pressure and heart rate reactivity to mental strain in adolescent judo athletes

This exploratory investigation examined the association between maximal aerobic power (VO2max) and blood pressure (BP) and heart rate (HR) reactivity to mental challenge. Adolescent male judo athletes (n = 20) performed a 2-min mental arithmetic. Heart rate was recorded before, during, and after the arithmetic, and BP was recorded before and after the mental challenge. Blood pressure in the immediate stress-recovery period was not related to VO2max, but subjects having a higher maximal aerobic power showed faster HR recovery from mental stress than those having a lower VO2max. Subjects who showed earlier peak HR responses, during the stress episode, demonstrated lower average HR reactivity than subjects who attained the maximal HR response later in the stress period. The relationship between the interval to reach peak HR and the magnitude of reactivity deserves further attention. However, at present these findings should be viewed as tentative because of the uniqueness and size of the sample.

Glycosylation via mixed disulfide formation using glycosylthio-phthalimides and -succinimides as glycosylsulfenyl-transfer reagents

The silver salts of tetra-O-acetyl α- or -β-D-glycopyranosyl thiols 1a-4a react smoothly with N-bromophthalimide and N-bromosuccinimide to furnish glycosylthio-phthalimide (1b-4b) and -succinimide (1c-3c) derivatives. Reactions of these reagents with aliphatic, aromatic, and glycosyl thiols as well as with cysteine and glutathione result in the formation of glycosylated mixed disulfides under mild conditions and in good yields. The S-glycosyl-N-acylsulfenamides described here represent novel, convenient glycosylsulfenyl-transfer reagents in effecting glycosylation of various thiols, including sugars, amino acids and peptides, through disulfide formation and can, therefore, be useful in controlled glycosylation of proteins as well.

Intraoperative recombinant activated factor VII for emergent epidural hematoma evacuation.

We report a case of a chronically anticoagulated 59-yr-old woman who underwent an L4 to L5 epidural block to relieve her low back pain and subsequently developed a T7 to L5 epidural hematoma with cauda equina and conus compression. Fresh frozen plasma and vitamin K were given before surgery, whereas recombinant activated factor VII was administered during surgery to reverse the coagulopathy and to enable the emergent laminectomy and hematoma evacuation. Recombinant activated factor VII administration proved to be a useful adjunct in the emergent surgical management of a thoracolumbar epidural hematoma.

Inhibition of TRPC6 by protein kinase C isoforms in cultured human podocytes

Transient receptor potential canonical‐6 (TRPC6) ion channels, expressed at high levels in podocytes of the filtration barrier, are recently implicated in the pathogenesis of various forms of proteinuric kidney diseases. Indeed, inherited or acquired up‐regulation of TRPC6 activities are suggested to play a role in podocytopathies. Yet, we possess limited information about the regulation of TRPC6 in human podocytes. Therefore, in this study, we aimed at defining how the protein kinase C (PKC) system, one of the key intracellular signalling pathways, regulates TRPC6 function and expression. On human differentiated podocytes, we identified the molecular expressions of both TRPC6 and several PKC isoforms. We also showed that TRPC6 channels are functional since the TRPC6 activator 1‐oleoyl‐2‐acetyl‐sn‐glycerol (OAG) induced Ca2+‐influx to the cells. By assessing the regulatory roles of the PKCs, we found that inhibitors of the endogenous activities of classical and novel PKC isoforms markedly augmented TRPC6 activities. In contrast, activation of the PKC system by phorbol 12‐myristate 13‐acetate (PMA) exerted inhibitory actions on TRPC6 and suppressed its expression. Importantly, PMA treatment markedly down‐regulated the expression levels of PKCα, PKCβ, and PKCη reflecting their activation. Taken together, these results indicate that the PKC system exhibits a ‘tonic’ inhibition on TRPC6 activity in human podocytes suggesting that pathological conditions altering the expression and/or activation patterns of podocyte‐expressed PKCs may influence TRPC6 activity and hence podocyte functions. Therefore, it is proposed that targeted manipulation of certain PKC isoforms might be beneficial in certain proteinuric kidney diseases with altered TRPC6 functions.

Regulation of TRPC6 ion channels in podocytes - Implications for focal segmental glomerulosclerosis and acquired forms of proteinuric diseases.

The glomerular filtration barrier is a highly specialized tri-layer structure with unique functional properties. Podocyte dysfunction and cytoskeletal disorganization leads to disruption of the slit diaphragma, and proteinuria. Inflammatory diseases involving the kidney as well as inherited podocytopathies or diabetic nephropathy cause injury of the podocyte network. Focal segmental glomerulosclerosis (FSGS) is a pathologic entity that is a common cause of nephrotic syndrome with severe proteinuria in both adults and children. Several causative genes have been identified in the pathogenesis of FSGS. Mutations of the transient receptor potential canonical-6 (TRPC6), a non-selective cation channel that is directly activated by diacylglycerol (DAG), cause a particularly aggressive form of FSGS. Angiotensin II, acting through its AT1 receptor, plays a critical role in generation of proteinuria and progression of kidney injury in a number of kidney diseases, including FSGS. Mounting evidence suggest the central role of TRPC6 and perhaps other TRPC channels in the pathogenesis of FSGS as well as of acquired forms of proteinuria such as diabetic nephropathy or hypertension. Identification of signaling pathways downstream of TRPC6 may provide novel targets for the treatment of proteinuria and prevent progression of podocyte injury.

Management of Aortic Valve Bypass Surgery

The 3 leading causes of aortic stenosis (AS) in adults are calcific degeneration of a normal trileaflet aortic valve (AV), calcific degeneration of a congenital bicuspid AV, and rheumatic AS. Therapeutic options in patients with severe AS include aortic valve replacement (AVR), transcatheter aortic valve implantation (TAVI), or aortic valve bypass (AVB). An AVB involves the placement of a valved conduit between the apex of the left ventricle and the descending thoracic aorta. AVB serves as a useful alternative to treat severe AS in patients deemed high risk for conventional AVR (ie, porcelain aorta, previous cardiac surgery) or TAVI (ie, severe aorto-iliac disease, limited experience, lack of hybrid operating room). Advantages of on-pump AVB include the avoidance of aortic cannulation, cross-clamping, and cardioplegic cardiac arrest. The procedure can also be performed without cardiopulmonary bypass. In this article, the authors review the circulatory physiology, perioperative anesthetic management, the role of intraoperative transesophageal echocardiography, and surgical considerations of AVB surgery through 3 cases.

Bivalent O-glycoside mimetics with S/disulfide/Se substitutions and aromatic core: Synthesis, molecular modeling and inhibitory activity on biomedically relevant lectins in assays of increasing physiological relevance

The emerging significance of recognition of cellular glycans by lectins for diverse aspects of pathophysiology is a strong incentive for considering development of bioactive and non-hydrolyzable glycoside derivatives, for example by introducing S/Se atoms and the disulfide group instead of oxygen into the glycosidic linkage. We report the synthesis of 12 bivalent thio-, disulfido- and selenoglycosides attached to benzene/naphthalene cores. They present galactose, for blocking a plant toxin, or lactose, the canonical ligand of adhesion/growth-regulatory galectins. Modeling reveals unrestrained flexibility and inter-headgroup distances too small to bridge two sites in the same lectin. Inhibitory activity was first detected by solid-phase assays using a surface-presented glycoprotein, with relative activity enhancements per sugar unit relative to free cognate sugar up to nearly 10fold. Inhibitory activity was also seen on lectin binding to surfaces of human carcinoma cells. In order to proceed to characterize this capacity in the tissue context monitoring of lectin binding in the presence of inhibitors was extended to sections of three types of murine organs as models. This procedure proved to be well-suited to determine relative activity levels of the glycocompounds to block binding of the toxin and different human galectins to natural glycoconjugates at different sites in sections. The results on most effective inhibition by two naphthalene-based disulfides and a selenide raise the perspective for broad applicability of the histochemical assay in testing glycoclusters that target biomedically relevant lectins.