Comparison of statins for secondary prevention in patients with ischemic stroke or transient ischemic attack: a systematic review and network meta-analysis.

BACKGROUND: Statins may prevent recurrent ischemic events after ischemic stroke. Determining which statin to use remains controversial. We aimed to summarize the evidence for the use of statins in secondary prevention for patients with ischemic stroke by comparing benefits and harms of various statins. METHODS: We searched for randomized controlled trials (RCTs) assessing statins in patients with ischemic stroke or transient ischemic attack (TIA) in MEDLINE, EMBASE, and CENTRAL up to July 2017. Two authors extracted data and appraised risks of bias. We performed pairwise meta-analyses and trial sequential analyses (TSA) to compare statins versus placebo/no statin, and network meta-analyses using frequentist random-effects models to compare statins through indirect evidence. We used GRADE to rate the overall certainty of evidence. Primary outcomes were all-cause mortality and all strokes. Secondary outcomes were different types of strokes, cardiovascular events, and adverse events. RESULTS: We identified nine trials (10,741 patients). No head-to-head RCTs were found. The median follow-up period was 2.5 years. Statins did not seem to modify all stroke and all-cause mortality outcomes; they were associated with a decreased risk of ischemic stroke (odds ratio, OR, 0.81 [95% CI, 0.70 to 0.93]; absolute risk difference, ARD, - 1.6% [95% CI, - 2.6 to - 0.6%]), ischemic stroke or TIA (OR, 0.75 [95% CI, 0.64 to 0.87]; ARD, - 4.2% [95% CI, - 6.2 to - 2.1%]), and cardiovascular event (OR, 0.75 [95% CI, 0.69 to 0.83]; ARD, - 5.4% [95% CI, - 6.8 to - 3.6%]), and did not seem to modify rhabdomyolysis, myalgia, or rise in creatine kinase. In the comparison of different statins, moderate- to high-quality evidence indicated that differences between pharmaceutical products seemed modest, with high doses (e.g., atorvastatin 80 mg/day and simvastatin 40 mg/day) associated with the greatest benefits. TSA excluded random error as a cause of the findings for ischemic stroke and cardiovascular event outcomes. Evidence for increased risk of hemorrhagic stroke was sensitive to the exclusion of the SPARCL trial. CONCLUSIONS: Evidence strongly suggests that statins are associated with a reduction in the absolute risk of ischemic strokes and cardiovascular events. Differences in effects among statins were modest, signaling potential therapeutic equivalence. TRIAL REGISTRATION: PROSPERO CRD42018079112.

E-learning for health professionals.

BACKGROUND: The use of e-learning, defined as any educational intervention mediated electronically via the Internet, has steadily increased among health professionals worldwide. Several studies have attempted to measure the effects of e-learning in medical practice, which has often been associated with large positive effects when compared to no intervention and with small positive effects when compared with traditional learning (without access to e-learning). However, results are not conclusive. OBJECTIVES: To assess the effects of e-learning programmes versus traditional learning in licensed health professionals for improving patient outcomes or health professionals' behaviours, skills and knowledge. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, five other databases and three trial registers up to July 2016, without any restrictions based on language or status of publication. We examined the reference lists of the included studies and other relevant reviews. If necessary, we contacted the study authors to collect additional information on studies. SELECTION CRITERIA: Randomised trials assessing the effectiveness of e-learning versus traditional learning for health professionals. We excluded non-randomised trials and trials involving undergraduate health professionals. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies, extracted data and assessed risk of bias. We graded the certainty of evidence for each outcome using the GRADE approach and standardised the outcome effects using relative risks (risk ratio (RR) or odds ratio (OR)) or standardised mean difference (SMD) when possible. MAIN RESULTS: We included 16 randomised trials involving 5679 licensed health professionals (4759 mixed health professionals, 587 nurses, 300 doctors and 33 childcare health consultants).When compared with traditional learning at 12-month follow-up, low-certainty evidence suggests that e-learning may make little or no difference for the following patient outcomes: the proportion of patients with low-density lipoprotein (LDL) cholesterol of less than 100 mg/dL (adjusted difference 4.0%, 95% confidence interval (CI) -0.3 to 7.9, N = 6399 patients, 1 study) and the proportion with glycated haemoglobin level of less than 8% (adjusted difference 4.6%, 95% CI -1.5 to 9.8, 3114 patients, 1 study). At 3- to 12-month follow-up, low-certainty evidence indicates that e-learning may make little or no difference on the following behaviours in health professionals: screening for dyslipidaemia (OR 0.90, 95% CI 0.77 to 1.06, 6027 patients, 2 studies) and treatment for dyslipidaemia (OR 1.15, 95% CI 0.89 to 1.48, 5491 patients, 2 studies). It is uncertain whether e-learning improves or reduces health professionals' skills (2912 health professionals; 6 studies; very low-certainty evidence), and it may make little or no difference in health professionals' knowledge (3236 participants; 11 studies; low-certainty evidence).Due to the paucity of studies and data, we were unable to explore differences in effects across different subgroups. Owing to poor reporting, we were unable to collect sufficient information to complete a meaningful 'Risk of bias' assessment for most of the quality criteria. We evaluated the risk of bias as unclear for most studies, but we classified the largest trial as being at low risk of bias. Missing data represented a potential source of bias in several studies. AUTHORS' CONCLUSIONS: When compared to traditional learning, e-learning may make little or no difference in patient outcomes or health professionals' behaviours, skills or knowledge. Even if e-learning could be more successful than traditional learning in particular medical education settings, general claims of it as inherently more effective than traditional learning may be misleading.

Effectiveness of computerized decision support systems linked to electronic health records: a systematic review and meta-analysis.

We systematically reviewed randomized controlled trials (RCTs) assessing the effectiveness of computerized decision support systems (CDSSs) featuring rule- or algorithm-based software integrated with electronic health records (EHRs) and evidence-based knowledge. We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Abstracts of Reviews of Effects. Information on system design, capabilities, acquisition, implementation context, and effects on mortality, morbidity, and economic outcomes were extracted. Twenty-eight RCTs were included. CDSS use did not affect mortality (16 trials, 37395 patients; 2282 deaths; risk ratio [RR] = 0.96; 95% confidence interval [CI] = 0.85, 1.08; I(2) = 41%). A statistically significant effect was evident in the prevention of morbidity, any disease (9 RCTs; 13868 patients; RR = 0.82; 95% CI = 0.68, 0.99; I(2) = 64%), but selective outcome reporting or publication bias cannot be excluded. We observed differences for costs and health service utilization, although these were often small in magnitude. Across clinical settings, new generation CDSSs integrated with EHRs do not affect mortality and might moderately improve morbidity outcomes.

Systemic safety of bevacizumab versus ranibizumab for neovascular age-related macular degeneration.

BACKGROUND: Neovascular age-related macular degeneration (AMD) is the leading cause of legal blindness in elderly populations of industrialised countries. Bevacizumab (Avastin®) and ranibizumab (Lucentis®) are targeted biological drugs (a monoclonal antibody) that inhibit vascular endothelial growth factor, an angiogenic cytokine that promotes vascular leakage and growth, thereby preventing its pathological angiogenesis. Ranibizumab is approved for intravitreal use to treat neovascular AMD, while bevacizumab is approved for intravenous use as a cancer therapy. However, due to the biological similarity of the two drugs, bevacizumab is widely used off-label to treat neovascular AMD. OBJECTIVES: To assess the systemic safety of intravitreal bevacizumab (brand name Avastin®; Genentech/Roche) compared with intravitreal ranibizumab (brand name Lucentis®; Novartis/Genentech) in people with neovascular AMD. Primary outcomes were death and All serious systemic adverse events (All SSAEs), the latter as a composite outcome in accordance with the International Conference on Harmonisation Good Clinical Practice. Secondary outcomes examined specific SSAEs: fatal and non-fatal myocardial infarctions, strokes, arteriothrombotic events, serious infections, and events grouped in some Medical Dictionary for Regulatory Activities System Organ Classes (MedDRA SOC). We assessed the safety at the longest available follow-up to a maximum of two years. SEARCH METHODS: We searched CENTRAL, MEDLINE, EMBASE and other online databases up to 27 March 2014. We also searched abstracts and clinical study presentations at meetings, trial registries, and contacted authors of included studies when we had questions. SELECTION CRITERIA: Randomised controlled trials (RCTs) directly comparing intravitreal bevacizumab (1.25 mg) and ranibizumab (0.5 mg) in people with neovascular AMD, regardless of publication status, drug dose, treatment regimen, or follow-up length, and whether the SSAEs of interest were reported in the trial report. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies and assessed the risk of bias for each study. Three authors independently extracted data.We conducted random-effects meta-analyses for the primary and secondary outcomes. We planned a pre-specified analysis to explore deaths and All SSAEs at the one-year follow-up. MAIN RESULTS: We included data from nine studies (3665 participants), including six published (2745 participants) and three unpublished (920 participants) RCTs, none supported by industry. Three studies excluded participants at high cardiovascular risk, increasing clinical heterogeneity among studies. The studies were well designed, and we did not downgrade the quality of the evidence for any of the outcomes due to risk of bias. Although the estimated effects of bevacizumab and ranibizumab on our outcomes were similar, we downgraded the quality of the evidence due to imprecision.At the maximum follow-up (one or two years), the estimated risk ratio (RR) of death with bevacizumab compared with ranibizumab was 1.10 (95% confidence interval (CI) 0.78 to 1.57, P value = 0.59; eight studies, 3338 participants; moderate quality evidence). Based on the event rates in the studies, this gives a risk of death with ranibizumab of 3.4% and with bevacizumab of 3.7% (95% CI 2.7% to 5.3%).For All SSAEs, the estimated RR was 1.08 (95% CI 0.90 to 1.31, P value = 0.41; nine studies, 3665 participants; low quality evidence). Based on the event rates in the studies, this gives a risk of SSAEs of 22.2% with ranibizumab and with bevacizumab of 24% (95% CI 20% to 29.1%).For the secondary outcomes, we could not detect any difference between bevacizumab and ranibizumab, with the exception of gastrointestinal disorders MedDRA SOC where there was a higher risk with bevacizumab (RR 1.82; 95% CI 1.04 to 3.19, P value = 0.04; six studies, 3190 participants).Pre-specified analyses of deaths and All SSAEs at one-year follow-up did not substantially alter the findings of our review.Fixed-effect analysis for deaths did not substantially alter the findings of our review, but fixed-effect analysis of All SSAEs showed an increased risk for bevacizumab (RR 1.12; 95% CI 1.00 to 1.26, P value = 0.04; nine studies, 3665 participants): the meta-analysis was dominated by a single study (weight = 46.9%).The available evidence was sensitive to the exclusion of CATT or unpublished results. For All SSAEs, the exclusion of CATT moved the overall estimate towards no difference (RR 1.01; 95% CI 0.82 to 1.25, P value = 0.92), while the exclusion of LUCAS yielded a larger RR, with more SSAEs in the bevacizumab group, largely driven by CATT (RR 1.19; 95% CI 1.06 to 1.34, P value = 0.004). The exclusion of all unpublished studies produced a RR of 1.12 for death (95% CI 0.78 to 1.62, P value = 0.53) and a RR of 1.21 for SSAEs (95% CI 1.06 to 1.37, P value = 0.004), indicating a higher risk of SSAEs in those assigned to bevacizumab than ranibizumab. AUTHORS' CONCLUSIONS: This systematic review of non-industry sponsored RCTs could not determine a difference between intravitreal bevacizumab and ranibizumab for deaths, All SSAEs, or specific subsets of SSAEs in the first two years of treatment, with the exception of gastrointestinal disorders. The current evidence is imprecise and might vary across levels of patient risks, but overall suggests that if a difference exists, it is likely to be small. Health policies for the utilisation of ranibizumab instead of bevacizumab as a routine intervention for neovascular AMD for reasons of systemic safety are not sustained by evidence. The main results and quality of evidence should be verified once all trials are fully published.

Development of specific receptors for N-formylated chemotactic peptides in a human monocyte cell line stimulated with lymphokines.

A human monocyte-like cell line, U937, when grown in continuous culture, does not secrete lysosomal enzymes or migrate towards chemotactic factors. When the cells are stimulated by lymphokines, however, they develop the ability both to migrate directionally and to secrete enzymes in response to several types of chemoattractants. The development, by stimulated cells, of chemotactic and secretory responses to one class of chemoattractants, the N- formylated peptides, is accompanied by the appearance on the cells of specific binding sites for these substances. Using tritiated N-formyl- methionyl-leueyl-phenylalanine (fMet-Leu-[(3)H]Phe) as a ligand, it was determined that unstimulated U937 cells possess no detectable binding sites. However, after stimulation with lymphocyte culture supernates for 24, 48, and 72 h, they developed 4,505 (+/-) 1,138, 22,150(+/-) 4,030, and 37,200 (+/-) 8,000 sites/cell, respectively. The dissociation constants for the interaction of fMet-Leu-[SH]Phe with the binding sites were approximately the same regardless of stimulation time and ranged between 15 and 30 nM. The binding of fMet-Leu-[(3)H]Phe by stimulated U937 cells was rapid and readily reversed by the addition of a large excess of unlabeled peptide. The affinity of a series of N-formylated peptides for binding to U937 cells exactly reflected the potency of the peptides in inducing lysosomal enzyme secretion and chemotaxis. The availability of a continuous human monocytic cell line that can be induced to express receptors for N-formylated peptides will provide a useful tool not only for the characterization of such receptors but also for the delineation of regulatory mechanisms involved in cellular differentiation and the chemotactic response.

Cell-mediated lympholysis of N-(3-nitro-4-hydroxy-5-iodophenylacetyl)-beta-anaylglycylglycyl-modified autologous lymphocytes. Effector cell specificity to modified cell surface components controlled by the H-2K and H-2D serological regions of the murine major histocompatibility complex.

Splenic lymphocytes from four C57BL/10 congenic mouse strains were sensitized in vitro to N(-3-nitro-4-hydroxy-5-iodophenylacetyl)-beta-alanylglycylglycyl-(N) modified autologous lymphocytes. The effector cells generated after 5 days of culture were assayed on a series of either N-modified phytohemagglutinin-stimulated spleen cells or N-modified tumor cells. The results indicated in all cases that both N modification of the targets and H-2 homology between the modified stimulating and target cells are required for lysis to occur. In each case the effector cells were found to lyse N-modified target cells only when there was homology at either or both ends of the major histocompatibility complex (MHC) between the stimulator and target cells. B10.BR lysed targets sharing alleles at K (or K plus I-A) and/or at D. B10.A effector cell specificity was mapped to K (or K plus I-A) and/or the D half of the MHC (D or D plus I-C and/or S). The two regions of specificity determined for B10.D2 effector cells were D (or D plus S plus I-C) and a region not including D of the MHC. C57BL/10 effector cells lysed N-modified targets only if there was target cell H-2 homology at K, I-A, and I-B or at the D serological region. As in the trinitrophenyl (TNP) system (6) B10.BR and B10.A effector cells lysed targets sharing K end H-2 serological regions greater than target cells sharing D-end serological regions. The C57BL/10 effector cells were shown to react to the K end greater than the D end, which differed from the equal reactivity seen in the TNP system for this strain. The data are consistent with the hypothesis that the antigen recognized by the effector cell includes an altered H-2 serological cell surface product. That the reaction is not "hapten specific" and the H-2 homology is required only for effector:target cell interaction was excluded by the use of two F1 combinations in which lysis of only N-modified target cells sharing the H-2 haplotype with the stimulating parental strain was obtained. Finally, it was demonstrated that N and TNP modification create distinct new antigenic determinants, since an effector cell sensitized to one modifying agent will lyse only H-2 matched target modified with that same modifying agent.

Elastase of U-937 monocytelike cells. Comparisons with elastases derived from human monocytes and neutrophils and murine macrophagelike cells.

As an approach to facilitating the understanding of proteinases associated with monocytes we have studied U-937 monocytelike cells. Elastase activity was identified in U-937 cell extracts and compared to monocyte elastase activity, neutrophil elastase, and the elastase activity from a continuous line of murine macrophagelike cells (P388D1). Serine proteinase activity which solubilized (14)C-labeled elastin accounted for >90% of the neutral proteinase activity of both U-937 cells and monocyte extracts. U-937 cell and monocyte elastase activities were similar catalytically, resembling neutrophil elastase. U-937 cells and monocytes showed other similarities: (a) both had activities reacting with [(3)H]diisopropylfluorophosphate that migrated in sodium dodecyl sulfate (SDS) polyacrylamide gels at approximately 30,000 and 60,000 daltons and (b) both contained material that cross-reacted with antiserum raised to neutrophil elastase. Preliminary characterization of U-937 cell elastase activity by affinity chromatography and ion-exchange chromatography suggested the presence of at least two distinct elastases. Minimal elastase activity was found in U-937 cell-conditioned medium, indicating that the activity is not spontaneously released by the cells. In contrast to the elastase activity associated with U-937 cells and monocytes, the elastase activity associated with P388D1 cells was a metalloproteinase and was found principally in the culture medium. These results indicate (a) U-937 cells will be useful for further investigation of proteinases associated with normal monocytes; (b) monocytes and U-937 cells contain material with catalytic and immunologic similarities to neutrophil elastase; (c) monocyte elastase activity differs from elastase activity secreted by murine macrophages and murine macrophagelike cells of the P388D1 line.

What hinders the uptake of computerized decision support systems in hospitals? A qualitative study and framework for implementation.

BACKGROUND: Advanced Computerized Decision Support Systems (CDSSs) assist clinicians in their decision-making process, generating recommendations based on up-to-date scientific evidence. Although this technology has the potential to improve the quality of patient care, its mere provision does not guarantee uptake: even where CDSSs are available, clinicians often fail to adopt their recommendations. This study examines the barriers and facilitators to the uptake of an evidence-based CDSS as perceived by diverse health professionals in hospitals at different stages of CDSS adoption. METHODS: Qualitative study conducted as part of a series of randomized controlled trials of CDSSs. The sample includes two hospitals using a CDSS and two hospitals that aim to adopt a CDSS in the future. We interviewed physicians, nurses, information technology staff, and members of the boards of directors (n = 30). We used a constant comparative approach to develop a framework for guiding implementation. RESULTS: We identified six clusters of experiences of, and attitudes towards CDSSs, which we label as "positions." The six positions represent a gradient of acquisition of control over CDSSs (from low to high) and are characterized by different types of barriers to CDSS uptake. The most severe barriers (prevalent in the first positions) include clinicians' perception that the CDSSs may reduce their professional autonomy or may be used against them in the event of medical-legal controversies. Moving towards the last positions, these barriers are substituted by technical and usability problems related to the technology interface. When all barriers are overcome, CDSSs are perceived as a working tool at the service of its users, integrating clinicians' reasoning and fostering organizational learning. CONCLUSIONS: Barriers and facilitators to the use of CDSSs are dynamic and may exist prior to their introduction in clinical contexts; providing a static list of obstacles and facilitators, irrespective of the specific implementation phase and context, may not be sufficient or useful to facilitate uptake. Factors such as clinicians' attitudes towards scientific evidences and guidelines, the quality of inter-disciplinary relationships, and an organizational ethos of transparency and accountability need to be considered when exploring the readiness of a hospital to adopt CDSSs.

Phase I study of pharmacological and immunological effects of human lymphoblastoid interferon given to patients with cancer.

An extensive Phase I evaluation of human lymphoblastoid interferon has been completed which, in addition to describing its clinical and pharmacological effects, emphasized a broad-scale evaluation of the immune response as a function of interferon dosage. Dose-limiting toxicity was generally due to constitutional symptoms which are remarkably similar to those produced by influenza, although transient peripheral and central neurotoxicity (including deterioration in cognitive and behavioral functions) is observed at higher doses. It is difficult to establish "clean" dose-response effects except for fever and bone marrow suppression, neither of which is a major dose limitation. Enhancement of the immune system was limited to natural killer cells which had a complex dose-response relationship, whereby low interferon concentrations were less stimulatory (than were high doses) following a single dose but gave more sustained stimulation over a 5-week course of 3 times per week i.m. administration. The effects on various measures of monocyte function and of nonspecific immunity (hypersensitivity, immunoglobulins, complement) were negative. We suspect that in practice it may be difficult to exploit the narrow dosage window of immunostimulation, but it is important to note that the nontoxic lower doses were more stimulatory than were the very high doses which are being used in numerous clinical trials.

Differences in arachidonic acid metabolism by human myelomonocytic cell lines.

The production of arachidonic acid metabolites by the HL60, ML3, and U937 human phagocyte cell lines was determined after incubation with interferon-gamma (IFN-gamma, 500 U/ml) or vehicle for 4 days. Cells were prelabeled with tritiated arachidonic acid, [3H]AA, for 4 h, and media supernatants were analyzed by high-performance liquid chromatography. None of the cell lines produced [3H]AA metabolites in large amounts during an unstimulated, basal release period (30 or 60 min). In response to 10 microM calcium ionophore A23187 incubation (30 min), undifferentiated and IFN-gamma-differentiated HL60 cells formed both cyclooxygenase products (thromboxane and prostaglandins) and lipoxygenase products (leukotrienes and hydroxyeicosatetraenoic acids). In contrast to the HL60 cells, IFN-gamma-differentiated U937 cells formed primarily cyclooxygenase products and undifferentiated and IFN-gamma-differentiated ML3 cells did not form any [3H]AA metabolites in response to A23187. These results indicate the need to be careful in selecting a cell line for use in a phagocyte assay system when cyclooxygenase and/or lipoxygenase products could influence the assay results.

Heterogeneity of human natural killer (NK) cells: enrichment of NK by negative-selection with the lectin from Erythrina cristagalli.

A novel technique for the isolation and enrichment of human natural killer (NK) cells from peripheral blood mononuclear cells (MNC) is described. Negative selection of MNC with the lectin from Erythrina cristagalli (ECA), whether by panning or agglutination in solution, resulted in a population of lymphocytes (5-20% of original MNC) highly enriched in cells exhibiting NK function. This enrichment was evident by a significant increase (range of 3-50-fold) in cells with large granular lymphocyte (LGL) morphology, K562 tumor-binding cells, cytotoxic activity, and cells expressing NK phenotypic markers (Leu 11+, OKM1+). Analysis of the cytolytic specificity of the cells demonstrated that the lytic spectrum was typical of endogenous NK. The effector cells were responsive to augmentation of cytotoxic potential by lymphokines (IL-2, IFN alpha, and IFN gamma) and capable of antibody-dependent cell-mediated cytotoxicity (ADCC). ECA-negative [ECA(-)] cells were equivalent to NK isolated by Percoll gradient fractionation. NK heterogeneity was demonstrated by the observation of a small percentage (1-5% of MNC) of NK in the ECA(+) population. This technique was found to be advantageous for the study of NK heterogeneity and NK biology.

Modulation of human NK cells by interferon and prostaglandin E2.

Our studies have shown that stimulation of human natural killer (NK) cells by poly I:C does not depend on or require monocytes. In contrast, the presence of monocytes in a mixed population of mononuclear cells stimulated by poly I:C suppresses NK activity. The suppression can be partially overcome if indomethacin (10(-6) M) is added to the culture during stimulation. Culture supernatants from poly I:C stimulated monocytes do not have detectable levels of anti-viral activity but contained appreciable amounts of PGE2. Our results offer an explanation as to how NK cells may protect themselves from suppression by PGE2. We have demonstrated that IFN-activated NK cells become resistant to PGE2-mediated suppression; moreover the suppression does not require cells other than the large granular lymphocytes, the major effector cell type for NK. Taken together, the data suggest that stimulation of NK cells is dependent on and regulated by the relative levels of interferon produced by lymphocytes and PGE2 produced by monocytes.

Photodynamic therapy--an alternative pathway in the treatment of recurrent breast cancer.

PURPOSE: Validity of photodynamic therapy for treatment of recurrent breast cancer. METHODS AND MATERIALS: Patients were intravenously administered with a metal-free haematoporphyrine derivative for tumor sensibilization. For irradiation both monochromatic and white light was used. Monochromatic light at a wavelength of 632 nm was supplied by an Argon-Dye laser, whereas a halogen lamp provided white light. Narrowband red light came into use in case of one patient. Therapy included recurrent diseases of breast carcinoma, especially disseminary skin metastases, local recurrences, and lymphangiosis. Classical pretreatment was ineffective for the therapeuted patient group. RESULTS: The healing potency of photodynamic therapy for our patient group is enumerated in detail. No differences in the therapeutic effect were seen using either Argon Dye laser or noncoherent light sources. CONCLUSION: Photodynamic therapy appears to be a valuable treatment to classical therapeutic intervention providing a selective destruction of tumor cells without further affecting life quality.

Associations between criteria air pollutants and asthma.

The evidence that asthma is increasing in prevalence is becoming increasingly compelling. This trend has been demonstrated not only in the United States, but also in the United Kingdom, New Zealand, Australia, and several other Western countries. In the United States, the increase is largest in the group under 18 years of age. There is mounting evidence that certain environmental air pollutants are involved in exacerbating asthma. This is based primarily on epidemiologic studies and more recent clinical studies. The U.S. Clean Air Act of 1970 provides special consideration to the class of outdoor air pollutants referred to as criteria pollutants, including O3, sulfur dioxide (SO2), particulate matter (PM), NOx, CO, and Pb. Standards for these pollutants are set by the U.S. Environmental Protection Agency with particular concern for populations at risk. Current evidence suggests that asthmatics are more sensitive to the effects of O3, SO2, PM, and NO2, and are therefore at risk. High SO2 and particulate concentrations have been associated with short-term increases in morbidity and mortality in the general population during dramatic air pollution episodes in the past. Controlled exposure studies have clearly shown that asthmatics are sensitive to low levels of SO2. Exercising asthmatics exposed to SO2 develop bronchoconstriction within minutes, even at levels of 0.25 ppm. Responses are modified by air temperature, humidity, and exercise level. Recent epidemiologic studies have suggested that exposure to PM is strongly associated with morbidity and mortality in the general population and that hospital admissions for bronchitis and asthma were associated with PM10 levels. In controlled clinical studies, asthmatics appear to be no more reactive to aerosols than healthy subjects. Consequently, it is difficult to attribute the increased mortality observed in epidemiologic studies to specific effects demonstrated in controlled human studies. Epidemiologic studies of hospital admissions for asthma have implicated O3 as contributing to the exacerbation of asthma; however, most study designs could not separate the O3 effects from the concomitant effects of acid aerosols and SO2. Controlled human clinical studies have suggested that asthmatics have similar changes in spirometry and airway reactivity in response to O3 exposure compared to healthy adults. However, a possible role of O3 in worsening atopic asthma has recently been suggested in studies combining allergen challenge following exposure to O3. Attempts at identification of factors that predispose asthmatics to responsiveness to NO2 has produced inconsistent results and requires further investigation. In summary, asthmatics have been shown to be a sensitive subpopulation relative to several of the criteria pollutants. Further research linking epidemiologic, clinical, and toxicologic approaches is required to better understand and characterize the risk of exposing asthmatics to these pollutants.

Effects of ozone exposure on lipid metabolism in human alveolar macrophages.

Alveolar macrophages (AM) store arachidonic acid (AA), which is esterified in cellular phospholipids until liberated by phospholipase A2 or C after exposure to inflammatory stimuli. After release, there can be subsequent metabolism of AA into various potent, biologically active mediators including prostaglandins and platelet-activating factor (PAF). To examine the possibility that these mediators may account for some of the pathophysiologic alterations seen in the lung after ozone (O3) exposure, human AM were collected by bronchoalveolar lavage of normal subjects, plated into tissue culture dishes, and the adherent cells were incubated with [3H]AA or [3H]lysoPAF. Human AM exposed to 1.0 ppm O3 for 2 hr released 65 +/- 12% more tritium, derived from [3H]AA, than paired, air-exposed controls into media supernatants. In other studies using a similar O3 exposure protocol, there was also a significant increase in human AM prostaglandin E2 production (2.0 +/- 0.5-fold increase above air-exposure values, p less than 0.01, n = 17). In additional studies, using a similar O3 exposure protocol (1.0 ppm for 1 hr), there was also a significant increase in human AM PAF content (1.7 +/- 0.2-fold increase above air-exposure values, p less than 0.02, n = 5). These potent lipid mediators, originally derived from human AM, may play an important role in the mechanisms of O3 lung toxicity.

Modulation of eicosanoid production by human alveolar macrophages exposed to silica in vitro.

Repeated inhalation of silica dust can lead to inflammation and fibrosis in human lung and in experimental animal models. The alveolar macrophage is believed to play a pivotal role in this process. Numerous macrophage-derived growth factors, cytokines, and arachidonic acid metabolites have been shown to contribute to inflammation and fibrosis. The objective of this study was to determine the eicosanoid production by human alveolar macrophages in response to silica exposure in vitro and to assess the contribution of alveolar macrophages to silica-induced fibrosis and inflammation. Macrophages were obtained from healthy volunteers and were incubated for 3 or 24 hr in the presence of silica (100, 60, and 0 micrograms/mL). Supernatants were removed for eicosanoid analysis. Eicosanoids were analyzed by both high performance liquid chromatography and radioimmunoassay. The data suggest that silica causes an increased release of leukotriene B4, leukotrienes C4/D4/E4, and 5-hydroxyeicosatetraenoic acid (5-HETE) after 3 hr and decreases in prostaglandin E2 and thromboxane B2 production after 24 hr of exposure to 100 micrograms/mL silica. In addition, 12-HETE and 15-HETE production remained unchanged at either time point. These opposing effects seen with the metabolites of lipoxygenase and cyclooxygenase pathways could contribute to silica-induced fibrosis. The pattern of eicosanoid production after exposure to silica was different from that obtained when macrophages were stimulated with lipopolysaccharide for 3 or 24 hr, indicating that the response to the particles was not just due to general cellular activation.

Chemical nature and immunotoxicological properties of arachidonic acid degradation products formed by exposure to ozone.

Ozone (O3) exposure in vivo has been reported to degrade arachidonic acid (AA) in the lungs of rodents. The O3-degraded AA products may play a role in the responses to this toxicant. To study the chemical nature and biological activity of O3-exposed AA, we exposed AA in a cell-free, aqueous environment to air, 0.1 ppm O3, or 1.0 ppm O3 for 30-120 min. AA exposed to air was not degraded. All O3 exposures degraded > 98% of the AA to more polar products, which were predominantly aldehydic substances (as determined by reactivity with 2,4-dinitrophenylhydrazine and subsequent separation by HPLC) and hydrogen peroxide. The type and amount of aldehydic substances formed depended on the O3 concentration and exposure duration. A human bronchial epithelial cell line (BEAS-2B, S6 subclone) exposed in vitro to either 0.1 ppm or 1.0 ppm O3 for 1 hr produced AA-derived aldehydic substances, some of which eluted with similar retention times as the aldehydic substances derived from O3 degradation of AA in the cell-free system. In vitro, O3-degraded AA induced an increase in human peripheral blood polymorphonuclear leukocyte (PMN) polarization, decreased human peripheral blood T-lymphocyte proliferation in response to mitogens, and decreased human peripheral blood natural killer cell lysis of K562 target cells. The aldehydic substances, but not hydrogen peroxide, appeared to be the principal active agents responsible for the observed effects. O3-degraded AA may play a role in the PMN influx into lungs and in decreased T-lymphocyte mitogenesis and natural killer cell activity observed in humans and rodents exposed to O3.