Thioredoxin, a redox enzyme released in infection and inflammation, is a unique chemoattractant for neutrophils, monocytes, and T cells.

Thioredoxin (Trx) is a ubiquitous intracellular protein disulfide oxidoreductase with a CXXC active site that can be released by various cell types upon activation. We show here that Trx is chemotactic for monocytes, polymorphonuclear leukocytes, and T lymphocytes, both in vitro in the standard micro Boyden chamber migration assay and in vivo in the mouse air pouch model. The potency of the chemotactic action of Trx for all leukocyte populations is in the nanomolar range, comparable with that of known chemokines. However, Trx does not increase intracellular Ca2+ and its activity is not inhibited by pertussis toxin. Thus, the chemotactic action of Trx differs from that of known chemokines in that it is G protein independent. Mutation of the active site cysteines resulted in loss of chemotactic activity, suggesting that the latter is mediated by the enzyme activity of Trx. Trx also accounted for part of the chemotactic activity released by human T lymphotropic virus (HTLV)-1-infected cells, which was inhibited by incubation with anti-Trx antibody. Since Trx production is induced by oxidants, it represents a link between oxidative stress and inflammation that is of particular interest because circulating Trx levels are elevated in inflammatory diseases and HIV infection.

Effects of short-term risedronate on bone resorption and patient satisfaction in postmenopausal osteoporosis patients.

This multicenter, open-label study evaluated the effects of short-term risedronate on bone resorption and patient satisfaction in postmenopausal women with osteoporosis in Brazil. Entry requirements included: osteoporosis of the spine/femoral neck diagnosed by a bone mineral density (BMD) T-scoreor=1 dose of study drug (intent-to-treat [ITT] population), and 390 completed treatment (81%). After 12 wk, CTX decreased in 94% of patients (from 0.419+/-0.234 to 0.158+/-0.171 microg/L, p<0.0001). Mean CTX reduction was 60.6%. Patient satisfaction was good/excellent in 91.7% of patients. A total of 156 adverse events (AEs) were reported by 113 (23.5%) patients in the ITT population. Digestive symptoms emerged or worsened in 7.1% and 3.5%, respectively. Five patients (1.0%) experienced serious AEs, not considered to be related to risedronate. In conclusion, risedronate significantly reduced serum CTX after 12-wk treatment. Almost all patients reported good/excellent satisfaction.

IL-1 beta primes IL-8-activated human neutrophils for elastase release, phospholipase D activity, and calcium flux.

Interleukin-8 (IL-8), the prototype of the alpha (e.i., C-X-C branch) chemokine family, induced elastase release in a concentration-dependent manner (50-1000 ng/mL) in cytochalasin B-treated human polymorphonuclear leukocytes (PMNs). This response was potentiated about twofold if PMNs were preexposed to interleukin-1 beta (IL-1 beta) at concentrations that were by themselves inactive. The effect of IL-1 beta was clearly observed after 5 min and was maximal after a 30-min preincubation of the cells. The effect was present over the whole active concentration range of IL-8 and was completely blocked by the presence of IL-1 receptor antagonist. Priming of elastase release by IL-1 beta was not associated with a change in receptor number or affinity for IL-8. On the contrary, it was correlated with priming of phospholipase D activity and calcium flux activated by IL-8. Preincubation of the cells with ethanol and/or La3+ inhibited IL-8-induced degranulations, suggesting that activation of phospholipase D and increase of [Ca2+]i were important for this response. In contrast, ethanol and La3+ did not decrease the priming effect of IL-1 beta. IL-8 and IL-1 beta have been shown to be released by the same cell types and may be concomitantly present at sites of inflammation, giving rise to an amplification of the inflammatory response.

Peripheral blood mononuclear cell production of interleukin-8 and IL-8-dependent neutrophil function in hypercholesterolemic patients.

Interleukin-8 is a cytokine produced by mononuclear cells that is involved in polymorphonuclear neutrophil leukocyte (PMN) recruitment and activation. Several studies have previously demonstrated a leukocyte activation during hypercholesterolemia and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been found to play a role in the prevention of atherothrombotic disease. The purpose of this study was to determine interleukin-8 (IL-8) mRNA expression and ex vivo production from peripheral blood mononuclear cells (PBMCs) and IL-8-dependent PMN activation of hypercholesterolemic (HC) patients with respect to normocholesterolemic (NC) subjects. Using Northern blot analysis, we found a four- and threefold increase in the amount of IL-8 transcript in PBMC from HC patients, in unstimulated and LPS stimulated cultures, respectively. A specific immunoassay showed a correspondingly significant increase of IL-8 immunoactivity in the conditioned medium of PBMC from HC subjects as compared with controls (unstimulated PBMC: 15 +/- 4 vs. 4.2 +/- 3 ng/ml; P < 0.0001; LPS stimulated PBMC: 65.3 +/- 8 vs. 36.6 +/- 9 ng/ml; P < 0.0001). PMN of HC patients stimulated with IL-8 showed a reduced elastase release with respect to NC subjects before physiological granule release after f-Met-Leu-Phe (fMLP) treatment. These results indicate an upregulation of the IL-8 system in dyslipidemic patients and provide evidence for ongoing in vivo IL-8-dependent PMN activation during hypercholesterolemia.

Interleukin-1 beta primes interleukin-8-stimulated chemotaxis and elastase release in human neutrophils via its type I receptor.

Interleukin-1 (IL-1) is a pleiotropic proinflammatory cytokine which binds to human neutrophils (PMN) and can directly or indirectly activate their functions. In this study we show that a brief exposure to IL-1 beta induces a potentiation of both PMN elastase release and chemotactic response to interleukin-8 (IL-8), the prototype of C-X-C chemokines. Priming by IL-1 beta was maximal at 100 ng/ml, was completely blocked in the presence of IL-1 receptor antagonist (IL-1ra) and, in the chemotaxis assay, was best observed at suboptimal (3-6 ng/ml) or inactive (0.75 ng/ml) concentrations of IL-8. Priming of PMN by IL-1 beta was completely blocked by M1, a specific antibody against the type I IL-1 receptor (IL-1RI). On the other hand M22, an antibody directed against the IL-1 decoy type II IL-1 receptor did not affect IL-1 beta action and slightly increased the priming effect. Thus, exclusively via its type I receptor, IL-1 beta can act on PMN at multiple levels, by promoting their accumulation in tissues through the induction of chemotactic factors (e.g. IL-8) and the upregulation of adhesion molecules, and by priming their response to chemotactic agonists.

Genetic and environmental influences on facial profile.

Observed variation in facial morphology results from the influences of both genetic and environmental factors. To investigate the role of genetic influences on variation in facial profile, lateral photographs of 23 male and 19 female monozygous (MZ), and 15 male and 22 female dizygous (DZ) twin pairs were selected from the records of the South Australian Twin Study. Soft tissue landmarks and facial profiles were identified, traced and digitized. Linear and angular measures defined by the landmarks were calculated and a series of Fourier functions derived to describe the facial profiles. These Fourier amplitudes were interpreted in terms of the specific regions which they represented. Correlations within MZ pairs were consistently higher than within DZ pairs for both the facial dimensions and the Fourier amplitudes, providing evidence of significant genetic contribution to facial convexity, facial height and facial depth. Variability in nose and lip morphology appeared to be under stronger environmental influence.

Hyperhidrosis treatment with bornaprine in the acute phase of spinal cord-injured patients.

STUDY DESIGN: Original article. OBJECTIVE: To test the use of bornaprine in the hyperhidrosis treatment in the acute phase of spinal cord-injured patients. SETTING: Patients with acute spinal cord lesions in the Spinal Unit of Pietra Ligure, Savona, Italy. METHOD: In 4 years, 12 patients have been treated, for a maximum period of 75 days, with dosages ranging from 2 to 4 mg day(-1). RESULTS: All of them reported long-lasting subjective benefits, without side effects, even after the interruption of the therapy. CONCLUSION: The bornaprine treatment, at 2 or 4 mg day(-1) dosage, has been effective and safe to contrast hyperhidrosis, in the acute phase of spinal cord-injured patients. This positive experience would require additional trials and a larger number of cases to gain a more solid support.