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).     

The Effect of Simian Immunodeficiency Virus Infectionin Vitroandin Vivoon the Cytokine Production of Isolated Microglia and Peripheral Macrophages from Rhesus Monkey

Microglia are the major target for human immunodeficiency virus (HIV) infection within the central nervous system. Because only a few cells are productively infected, it has been suggested that an aberrant cytokine production by this cell population may be an indirect mechanism leading to the development of neurological disorders in HIV-infected patients. Therefore we decided to study the secretion pattern of several interleukins (IL) by microglial cells and peripheral blood macrophages isolated from uninfected and simian immunodeficiency virus (SIV)-infected Rhesus monkeys. We found that uninfected, unstimulated primate microglia produce more IL-6 and less TNFα than peripheral blood macrophages, but generate comparable levels of IL-1β and IL-8. After infection with SIVin vitro,synthesis of all cytokines tested is increased compared to uninfected cultures and to peripheral blood macrophages. Microglia isolated from infected animals produce more IL-8 and TNFα than the uninfected cultures and display a strongly increased capacity to secrete TNFα upon stimulation with lipopolysaccharide. In addition, production of IL-6 byin vivo-infected microglia increases with time in culture to very high levels despite the fact that only a few cells contained replicating virus. These findings clearly show that the cytokine production of microglia is impaired after SIV infection bothin vitroandin vivoand that a low level of viral replication is sufficient for these alterations to occur. In conclusion, the results of this study further support a possible role of cytokines in the pathogenesis of neuro-AIDS.     

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.     

Development of an Intravenous Membrane Oxygenator: Enhanced Intravenous Gas Exchange Through Convective Mixing of Blood around Hollow Fiber Membranes

Abstract: In vitro testing of a new prototype intravenous membrane oxygenator (IMO) is reported. The new IMO design consists of matted hollow fiber membranes arranged around a centrally positioned tripartite balloon. Short gas flow paths and consistent, reproducible fiber geometry after insertion of the device result in an augmented oxygen flux of up to 800% with balloon activation compared with the static mode (balloon off). Operation of the new IMO device with the balloon on versus the balloon off results in a 400% increase in carbon dioxide flux. Gas flow rates of up to 9. 5 L/min through the 14–cm–long hollow fibers have been achieved with vacuum pressures of 250 mm Hg. Gas exchange efficiency for intravenous membrane oxygenators can be increased by emphasizing the following design features: short gas flow paths, consistent and reproducible fiber geometry, and most importantly, an active means of enhancing convective mixing of blood around the hollow fiber membranes     

Presence of NAP-1/IL-8 in Synovial Fluids Indicates a Possible Pathogenic Role in Rheumatoid Arthritis

The synovial fluid in affected joints of rheumatoid arthritis (RA) patients contains many cells, in numbers strongly correlated with the severity of disease. As the disease worsens and the cell count increases, the polymorphonuclear leucocyte becomes the predominant cell type. Although the inflammatory cytokines interleukin 1 (IL-1) and tumour necrosis factor (TNF) have no direct neutrophil-attractant activity, they are both potent inducers of interleukin 8 (IL-8) in a variety of cell types. Chemotactic attraction of neutrophils is a major activity of IL-8. Examination of a number of synovial fluids showed that significant levels of IL-8 are present in a high proportion of RA cases (10 out of 17), at concentrations directly related to the number of cells in the joint, and to circulating C-reactive protein (CRP) levels. The cytokine is present only at background levels in other diseases accompanied by arthritic manifestations, including systemic lupus erythematosus (SLE) and induced arthritis. The progressive joint destruction seen in all cases where high IL-8 levels were measured, coupled with the neutrophil-rich cell count and the strong correlation between concentration of IL-8 and both serum CRP and cellular influx into the joint, is strongly suggestive of a pathogenic role for IL-8 in RA.