Reye's and Reye's-like syndromes.

The review reports various questions about Reye's syndrome and Reye's-like syndromes. Although there is a significant decrease in the classic Reye's syndrome cases, because of the reduced employment of salicylates in children (salicylate seems to be the most important inducing factor of the syndrome in paediatric subjects affected by viral infection), the problem is still of interest considering the presence of different Reye's-like forms. All these pathological situations are associated with various aetiologic or predisposing causes that are examined in the text. Particular attention is placed on metabolic disorders, especially of fatty acid metabolism, and also of one amino acid. In fact, a latent form can also be the basis of possible biochemical disturbances induced by various exogenous factors such as viral infections, particularly of the respiratory tract (more rarely of bacterial aetiology), or produced by microbial toxins, or by chemical substances, including some therapeutic drugs. A full discussion of biochemical mechanisms of salicylate-induced Reye's syndrome is reported. Finally a possible diagnostic differentiation from classic Reye's syndrome and Reye's-like syndromes plus therapeutic prospects are briefly examined.

Regulation of interleukin-18 by THP-1 monocytoid cells stimulated with HIV-1 and Nef viral protein.

Interleukin (IL)-18 is a proinflammatory cytokine that plays an important role in both innate and adaptive immune responses against several infectious pathogens. Relatively little is known about its production in HIV-1 infection, and there are controversial data on the influence of IL-18 on HIV-1 replication in vitro. In this study, we investigated the effect of HIV-1 infection, and challenge with recombinant HIV-1 proteins, on IL-18 production by THP-1 cells. This is a monocytoid cell line spontaneously producing IL-18, and consequently is particularly suitable for the study of HIV-1 effects on this type of cytokine regulation. The results reported here demonstrate a significant reduction in IL-18 secretion during HIV-infection. In fact, low levels of IL-18 were released until 120 h from viral challenge (15 +/- 11 pg/mL at 24 h and 17 +/- 13 at 96 h and < 12.5 at 120 h), whereas IL-18 production by uninfected control cells was 193 +/- 104 pg/mL and 214 +/- 114 pg/mL at 24 h and 120 h respectively. At 168 h of incubation, IL-18 production by infected and uninfected cells was found to be 164 +/- 88 pg/mL and 325 +/- 101 pg/mL respectively (p = 0.001). Of the following viral proteins: gp 120, p24 and Nef, only the last one induced decreased IL-18 secretion in the supernatants of THP-1 cells. This effect is more evident with the concentrations of 5 -1.25 microg/mL of Nef protein (p < 0.0001). In conclusion, our data show that HIV-1 and its regulatory protein, Nef, are able to down-regulate the release of IL-18, in vitro. These results confirm that a variety of modulating effects on the immune response, induced by HIV-infection, may facilitate progression of HIV-1 infection.

Role of nitric oxide in HIV-1 infection: friend or foe?

Nitric oxide (NO) is an important biologically active molecule that plays a key part in host defence against bacteria, protozoa, and tumour cells. NO has antiviral effects against several DNA viruses, such as murine poxvirus, herpes simplex virus, and Epstein-Barr virus, and some RNA viruses, such as coxsackievirus. In several studies, in vitro and in vivo, overproduction of NO has been noted in the presence of HIV-1 infection. Furthermore, increased NO production may contribute directly to the pathogenesis of HIV-1-associated dementia. The mechanisms of virus infection mediated by NO may be related to: direct antiviral effects of NO; impairment of antiviral defence mediated by T-helper-1 immune response by suppressing T-helper-1 functions; NO-induced cytotoxic effects by oxidative injury with cellular and organ dysfunctions; and NO-induced oxidative stress leading to rapid viral evolution with productions of drug-resistant and immunologically tolerant mutants. By contrast, there is some evidence of NO activity--directly, indirectly, or both--decreasing or blocking HIV-1 replication, through inhibition of viral enzymes, such as reverse transcriptase, protease, or cellular nuclear transcription factor (NF-kappa B) and long-terminal repeat-driven transcription. Therefore, although NO surely plays an important part in HIV-1 infection, that role is sometimes helpful and other times damaging to the host. Future challenges are to learn more about the beneficial and harmful effects of NO in HIV-1 infection, and how to selectively inhibit excessive NO production or to use NO-releasing drugs to decrease viral replication. This review discusses the role of NO in the pathogenesis of HIV-1 infection, inasmuch as its role against HIV-1 is unequivocal in inhibiting or increasing viral replication.

Circulating levels of FAS/APO-1 in patients with the systemic inflammatory response syndrome.

Resolution of inflammation/infection involves removal of neutrophils and other inflammatory cells by the induction of apoptosis. Fas/Apo-1 is a widely occurring apoptotic signal receptor molecule expressed by almost any type of cell, which is also released in a soluble circulating form. In this study we investigated the role of circulating Fas/Apo-1 in patients with systemic inflammatory response syndrome (SIRS). We evaluated 57 critically ill patients, 34 with infectious SIRS (sepsis and septic shock), and 23 patients with noninfectious SIRS. Circulating Fas/Apo-1 was determined by a commercially available immunoassay. Our results clearly show that levels of Fas/Apo-1 were significantly elevated in patients with infectious and noninfectious SIRS (10.4 +/- 8.1 pg/mL, controls: 5.0 +/- 0.7 pg/mL; p < 0.0001). In addition, Fas/Apo-1 levels were not able in predicting in predicting poor outcome of patients with SIRS. In conclusion, these results show that increased levels of Fas/Apo-1 from patients with SIRS is a mechanism which contribute to inflammatory response through accumulation of neutrophils at sites of inflammation/infection.

Antiretroviral drug resistance testing in patients with HIV-1 infection: a meta-analysis study.

BACKGROUND: HIV-1 resistance tests, both phenotype and genotype, have been entering clinical practice during the last years, but limited prospective studies have been reported in antiretroviral-treated patients with virological failure. PURPOSE: A meta-analysis of randomized controlled trials (RCTs) published or presented at the most important international conferences until February 2001 was performed to estimate the impact of resistance-guided antiretroviral therapy on virological outcome. METHOD: A search for RCTs was performed by using a MEDLINE database, Internet sources, and international conference presentations and was updated September 2001. All RCTs available, including four RCTs on genotype resistance testing, one RCT on phenotype resistance testing, and one RCT on genotypic and phenotypic testing, were analyzed. The rate of patients with undetectable viremia at 3 months was reported in all RCTs and the rate at 6 months was reported in 4 of 6 RCTs. RESULTS: The rate of patients with undetectable viral load after 3 months was 42.6% in patients who were treated based on genotype results and was 33.2% in patients who were treated based on standard of care (SOC; odds ratio [OR] 1.7; 95% CI: 1.3-2.2). At 6 months, undetectable viremia was observed in 38.8% and 28.7% of the patients, respectively (OR: 1.6; 95% CI: 1.2-2.2). In 142 patients, expert advice was provided to optimize clinical use of genotypic data. The higher rate of viral suppression was achieved in this subgroup of patients (50.7% vs. SOC 35.8%; OR 2.4; 95% CI 1.5-3.7). In contrast, undetectable viremia was achieved in 37.5% patients who were treated based on phenotype results versus 33.8% patients who were treated based on SOC (OR 1.1; 95% CI 0.8-1.6). CONCLUSION: These results support the use of a genotypic test in patients experiencing virological failure during antiretroviral treatment. Expert interpretation of the test may increase the probability of virological response.

Nitric oxide production in HIV-1 infected patients receiving intermittent cycles of interleukin-2 and antiretrovirals.

BACKGROUND: Interleukin-2 (IL-2) has been investigated as an adjunct to antiretroviral therapy (ART) because of its well-demonstrated capacity of stably increasing the number of peripheral CD4+ T cell lymphocytes. However, IL-2-related adverse events (AEs), including fever, tachycardia, hypotension, and respiratory failure, are typically dose- and schedule-dependent and can potentially limit the application of IL-2 therapy in an outpatient setting. Nitric oxide (NO) is a potent vasodilator potentially responsible for some of the AEs caused by IL-2. PURPOSE: In this study, we determined NO production in a cohort of HIV-1 infected individuals receiving ART either alone or together with IL-2. METHOD: NO production, detected as plasma nitrate/nitrite levels by the Griess reaction, was evaluated in 3 groups of 10 individuals each. In the first group, subcutaneous (sc) administration of 12-15 million international units per day (MIU/d) of IL-2 was administered for 5 days every 8 weeks for 6 cycles together with ART; in the second group, IL-2 (6 MIU/d) was given sc for 5 days every 4 weeks for 12 cycles together with ART; whereas the third group received ART alone. RESULTS: At baseline, the plasma nitrate/nitrite levels in the 2 groups of patients who received high and low doses of the cytokine along with ART were 28.5 +/- 18.1 micromol/L and 34.2 +/- 29.0 micromol/L, respectively. These levels were comparable to those of patients treated with only ART (18.6 +/- 22.4 micromol/L) and to those of 20 healthy controls (19.9 +/- 5.9 micromol/L). No significant increase of plasma nitrate/nitrite levels was observed by administration of either ART or ART+IL-2. In addition, NO production was not associated significantly with different levels of tumor necrosis factor-alpha, IL-6, or soluble IL-2 receptor alpha chain in 9 individuals with WHO grade 2 and 3 AEs. CONCLUSION: Our results indicate that NO is unlikely to be responsible for most side effects of IL-2 therapy in HIV-1 infected individuals. Because both IL-2 and virus multiplication have been reported to independently stimulate NO production, concomitant ART may curtail NO production through inhibition of HIV-1 replication.

Good safety profile and efficacy of leucocyte interferon-alpha in combination with oral ribavirin in treatment-naive patients with chronic hepatitis C: a multicentre, randomised, controlled study.

BACKGROUND: The differential tolerability profile of various interferon (IFN)-alpha preparations used in combination with ribavirin for the treatment of chronic hepatitis C needs to be elucidated. Approximately 8% of patients receiving recombinant IFNalpha-2b plus ribavirin discontinue treatment because of adverse events. Human leucocyte IFNalpha is deemed to have a better safety profile than recombinant IFNalpha. We therefore compared the safety profile and efficacy of ribavirin combined with leucocyte IFNalpha or with recombinant IFNalpha-2b in treatment-naive patients with chronic hepatitis C. STUDY DESIGN: We randomised 423 patients to either leucocyte IFNalpha 3MU three times weekly plus ribavirin (210 patients) or the same dose of recombinant IFNalpha-2b plus ribavirin (213 patients). Patients were treated for 24 weeks and followed-up for a further 48 weeks. The primary endpoint was the safety profile of the two therapies; the secondary endpoint was the rate of sustained response. RESULTS: In patients receiving leucocyte IFNalpha, the total number of adverse events was lower than in the group receiving recombinant IFNalpha (259 vs 441 patients), and the percentage of patients discontinuing treatment because of adverse events or laboratory abnormalities was significantly reduced (4% vs 11%; p = 0.013). Sustained response was observed in 47% of patients receiving leucocyte IFNalpha plus ribavirin and in 44% of patients receiving IFNalpha-2b plus ribavirin. CONCLUSIONS: Both therapeutic regimens were effective in inducing a sustained response in naive patients. However, the safety profile of leucocyte IFNalpha plus ribavirin was more favourable than that observed with the administration of recombinant IFNalpha-2b plus ribavirin, suggesting that leucocyte IFNalpha may be an alternative option in patients with reduced tolerability to other IFNs.

Circulating levels of granulocyte macrophage colony-stimulating factor in patients with the systemic inflammatory response syndrome.

OBJECTIVES: Granulocyte-macrophage colony stimulating factor (GM-CSF) is a key regulator cytokine that modulates the proliferation and maturation of polymorphonuclear and mononuclear progenitors. This study was designed to investigate and clarify the role of GM-CSF in 52 critically ill patients with systemic inflammatory response syndrome (SIRS). METHODS: Serum levels of GM-CSF were detected by an immunoenzyme assay. RESULTS: Our results clearly show that the serum concentrations of GM-CSF were significantly elevated in patients with infectious and noninfectious SIRS (33.2+/-45.7pg/ml, controls: 17.2+/-9.8pg/ml; p=0.0303). In addition, GM-CSF levels significantly decreased in patients with SIRS, particularly in patients with infectious SIRS, 5 and 7 days later. There was a clear tendency toward higher levels of GM-CSF in patients with poor, as compared with those having a good outcome of the disease. CONCLUSION: These results show that GM-CSF may play an important role in patients with infectious and noninfectious SIRS, and that GM-CSF levels progressively and significantly decrease in patients with infectious SIRS.

Interleukin 18 and cardiovascular disease in HIV-1 infection: a partner in crime?

Cardiovascular disease has been frequent in HIV-infected patients both before and after the advent of antiretroviral therapy (HAART). The pathogenic basis for the increase of cardiovascular disease, in particular myocardial lesions, may involve HIV-1 itself or other mechanisms including endothelial dysfunction, activation of proinflammatory cytokines, and changes in platelets, which lead to atherosclerotic lesions of blood vessels. In the last decade, among the proinflammatory cytokines, interleukin 18 seems to play a central role in the inflammatory cascade, leading to development of atherosclerotic disease and the occurrence of ischemic heart disease in uninfected HIV-1 people. Increased levels of interleukin 18 were observed in HIV-1 infected patients. This review attempts to evaluate the role of interleukin 18 in cardiovascular disease, especially in myocardial infarction, in HIV-1 infection, as well as the relationship between interleukin 18 and atherosclerotic plaque formation. Two other characteristic aspects in HIV-1 infection, metabolic syndrome and lipodystrophy, will be evaluated in light of activity of interleukin 18. Moreover, the role of platelets and interleukin 18 as an important linkage between chronic inflammation, endothelial dysfunction, and atherogenesis will be highlighted. Finally, experimental an animal model of rhesus macaques infected with simian immunodeficiency virus clearly demonstrates the involvement of interleukin 18 in myocardial lesions, and that circulating levels of interleukin 18 are important predictors of coronary heart disease. In conclusion, interleukin 18 may be considered a partner in crime with other factors, including endothelial dysfunction, increased expression and production of adhesion molecules and proinflammatory cytokines in determining cardiovascular disease.