Serum interleukin-8 in inflammatory bowel disease

To investigate the relationship between serum concentrations of interleukin-8 (IL-8) and disease activity in inflammatory bowel disease, serum IL-8 concentrations were measured by enzyme-linked immunosorbent assay (ELISA) in 93 patients. Interleukin-8 levels were compared with plasma interleukin-6 (IL-6) levels in 80 of these patients. Interleukin-8 levels were also measured in ten patients with active Crohn's disease, before and after treatment with a defined formula polymeric diet. Of these patients, 70 out of 93 IL-8 concentrations were below the detection limit of the assay. Levels were higher in patients with active ulcerative colitis (median < 20 pg/mL, 75th centile value = 190) compared with inactive disease (median and 75th centile value < 20; P 0.05). Interleukin-8 concentrations correlated with a combined score for disease severity and extent (P= 0.01). Thirty-eight per cent (8/20) of patients with active Crohn's disease also had high levels of IL-8 but there was no significant difference between active and inactive disease. There was no correlation between serum IL-8 and plasma IL-6; on the contrary, very few patients had raised blood levels of both cytokines. In the diet treated group, serum IL-8 fell significantly after treatment (median = 37 pg/mL, range < 20–4615 before treatment, median < 20, range < 20–104 after treatment; P= 0.03). The results suggest that although IL-8 may be involved in the inflammatory process in inflammatory bowel disease, it is a poor marker of disease activity.     

Heart Rate Turbulence after Ventricular Pacing Trains During Programmed Ventricular Stimulation

Background: This study tested the hypothesis that heart rate turbulence (HRT) following ventricular pacing trains depends on train cycle length, presence of retrograde ventriculoatrial (VA) conduction, and left ventricular (LV) function.
Methods: We analyzed digital recordings of programmed ventricular stimulation (PVS) performed in 82 patients (57 men) referred for electrophysiologic studies of ventricular arrhythmias, whose mean age was 64 ± 12 years and LV ejection fraction (EF) was 47 ± 15%. Profiles of sinus RR intervals after all available 8-beat ventricular pacing trains (600-and 400-ms) were averaged. Heart rate turbulence slope (HRTS) was analyzed as the maximum positive slope of a regression line through a sequence of 2–5 (HRTS2 - HRTS5) consecutive RR intervals within the first 5 RR intervals after the pacing train.
Results: Dynamics of RR intervals had biphasic and monophasic patterns, in patients with and without VA conduction, respectively. Sinus nodal response was less prominent after 600-ms than 400-ms pacing trains. After 400-ms pacing trains, HRTS was significantly shallower in patients with LVEF ≤40% than in those with LVEF >40%. HRTS4 was the best discriminator between the two groups (6.8 ± 8.6 ms/RR vs 19.6 ± 26.0 ms/RR, P = 0.017).
Conclusion: In patients with VA conduction, HRT after ventricular pacing trains reflects a combination of vagal withdrawal due to transient hypotension and suppression of sinus node automaticity. Attenuation of vagal modulation was detected in patients with LV dysfunction during standard PVS.     

CXC and CC chemokines induced in human renal epithelial cells by inflammatory cytokines

Human renal epithelial cells might play an important role during the allograft rejection by producing chemokines in response to proinflammatory cytokines such as tumor necrosis factor (TNF)‐α and interleukin (IL)‐1β produced by endothelial and epithelial cells early after transplantation. The production of chemokines allows inflammatory cells to be drawn into the kidney graft and therefore plays a critical role in the pathophysiologic processes that lead to the rejection of renal transplant. In this process, two chemokine superfamilies, the CC and the CXC chemokines, are the most important. The CC chemokines target mainly monocytes and T lymphocytes, while most of the CXC chemokines attract neutrophils. We showed in our study that in vitro, in unstimulated cells, basal mRNA expression of CXC chemokines (Groα, Groβ, Groγ, ENA‐78 and GCP‐2, IL‐8) that attract neutrophils was detectable and expression of these genes and chemokine release were increased in TNF‐α‐ and IL‐1β‐induced renal epithelial cells. Most of the CC chemokines [monocyte chemotactic protein‐1 (MCP‐1), macrophage Inflammatory protein 1 beta (MIP‐1β), regulated upon activation, normal T cell expressed and secreted (RANTES) and macrophage inflammatory protein (MIP‐3α)] showed detectable mRNA expression only after stimulation with proinflammatory cytokines and not in control cells. TNF‐α seems to induce preferably the expression of RANTES, MCP‐1, interferon‐inducible protein (IP‐10) and Interferon‐Inducible T‐cell Alpha Chemoattractant (I‐TAC), while IL‐1β induces mainly IL‐8 and epithelial neutrophil‐activating peptide 78 (ENA‐78).     

Metabolic Alterations Induced by Topical Dimethylacetylenedicarboxylate

Metabolic Alterations Induced by Topical Dimethylacetylenedicarboxylate.KLAIN, G. J., BONNER, S. J., AND BELL, W. G. (1988). Fundam.Appl Toxicol 10, 730–735. The disposition of topical dimethylacetylenedicarboxylate(DMAD) in tissue and its effect on glucose metabolism were studiedin vivo, using skin grafted athymic nude mice, and in vitro,using excised pig skin. [¹⁴C]DMAD that penetrated skin graftswas distributed throughout the body. At 24 hr, the liver contained15.62% of the applied dose. The kidneys, lungs, brain, and theheart contained 12.73, 5.61,0.36, and 3.24% of the dose, respectively.One hour postapplication, DMAD markedly decreased [U-¹⁴C]glucoseoxidation and the syntheses of fatty acids and glycogen in thelivers and skin grafts. Similar effects were observed in excisedpig skin. In addition, the activities of hepatic glucose-6-phosphatedehydrogenase, isocitric and NADP-mahc dehydrogenase, and acetyl-CoAcarboxylase were significantly reduced in DMAD-treated mice.In contrast, no effect was observed on the activity of glucokinase.The data indicate that DMAD rapidly penetrates the skin andcauses aberrations in the activities of the glycogenic. lipogenic,and tricarboxylic acid metabolic pathways.     

Bi-weekly epirubicin, etoposide and low-dose dexamethasone for hormone-refractory prostate cancer

BACKGROUND: Recent studies have demonstrated the efficacy and favorable toxicity profile of chemotherapy regimens given at lower doses and frequent intervals. The aim of our study was to evaluate the efficacy and toxicity of a bi-weekly chemohormonal regimen consisting of epirubicin, etoposide, and low-dose dexamethasone (EED) in patients with hormone-refractory prostate cancer (HRPC). METHODS: We treated a total of 32 patients who had failed hormonal therapy and antiandrogen withdrawal. Chemotherapy was given every 2 weeks and consisted of epirubicin (30 mg/m2 intravenously, day 1) and etoposide (50 mg/m2 orally, days 1-7). Dexamethasone (1.5 mg orally, every other day) was given continuously until disease progression. Twenty patients (63%) had received prior treatment with estramustine phosphate. Each patient's pain response was evaluated according to analgesic use. Toxicity was graded using the Common Toxicity Criteria (version 2.0). RESULTS: Prostate-specific antigen (PSA) levels showed a decline of 50% or greater in 16 of 32 patients (50%, 95% confidence interval [CI], 32-68%) with a median time to biochemical progression of 5 months (range, 4-9 months). The median survival for all patients was 10.5 months (range, 3-35 months). Four of 10 patients (40%) with measurable soft tissue lesions achieved partial response according to standard criteria. Eleven of 23 symptomatic patients (48%, 95% CI, 27-69%) experienced an improvement in pain with a median duration of 6 months. The regimen was tolerated well by the patients, with only four patients (12%) having grade 3 leukopenia. CONCLUSION: Chemohormonal EED regimen proved to be active and well-tolerated in patients with HRPC.     

Mucosal immunity and strategies for novel microbial vaccines

Infectious diseases continue to be the leading cause of morbidity and mortality worldwide. Increased awareness of the fact that mucosal membranes are the most frequent portals of entry of pathogenic microorganisms has prompted studies aimed at the development of vaccination protocols and antigen delivery systems that would lead to an increased protection of mucosae. Although systemic and strictly local immunizations are of limited effectiveness in the induction of mucosal protection, ingestion or inhalation of antigens results in a generalized immune response manifested by the appearance of specific antibodies of the secretory immunoglobulin (Ig) isotype in external secretions due to the dissemination of IgA precursor cells from IgA-inductive lymphoid tissues. Furthermore, additional inductive sites strategically positioned at the opening of the respiratory and digestive tracts may also be suitable targets for induction of immune responses at desired effector sites. To prevent degradation and the increase of ingested antigens absorption, novel strategies including enclosure of antigens into biodegradable microspheres, liposomes or their expression in viral and bacterial vectors and plants are currently being considered. Forthcoming technological advances in antigen preparation and routes of delivery will undoubtedly have a profound impact on immunization practices in the future.