Defining the Problem and Searching for Solutions: Health Care Providers and Consumers

A panel consisting of health care providers and consumers discussed defining the problem and searching for solutions. Richard Buxbaum of the Greater Cleveland Hospital Association addressed uncompensated care, otherwise known as charity care, as a problem for hospitals. Mandating employer based health insurance was offered as a solution. Frank Kimbler of the Federation for Community Planning gave an overview of the consumer side of the uninsured problem. He mentioned a joint pilot project to insure the working poor. Henry Manning of Metrohealth explained how price competition between hospitals creates a problem for urban teaching hospitals which bear the costs of caring for the poor and training doctors. He also shared figures for unreimbursed care costs accrued by Metrohealth in various categories. Dr. van Heeckeren presented the physician\u27s view on the insurance issue. The panel then answered questions

HE3286, an oral synthetic steroid, treats lung inflammation in mice without immune suppression

<p>Abstract</p> <p>Background</p> <p>17α-Ethynyl-5-androsten-3β, 7β, 17β-triol (HE3286) is a synthetic derivative of an endogenous steroid androstenetriol (β-AET), a metabolite of the abundant adrenal steroid deyhdroepiandrosterone (DHEA), with broad anti-inflammatory activities. We tested the ability of this novel synthetic steroid with improved pharmacological properties to limit non-productive lung inflammation in rodents and attempted to gauge its immunological impact.</p> <p>Methods and Results</p> <p>In mice, oral treatment with HE3286 (40 mg/kg) significantly (<it>p </it>< 0.05) decreased neutrophil counts and exudate volumes (~50%) in carrageenan-induced pleurisy, and myeloperoxidase in lipopolysaccharide-induced lung injury. HE3286 (40 mg/kg) was not found to be profoundly immune suppressive in any of the classical animal models of immune function, including those used to evaluate antigen specific immune responses <it>in vivo </it>(ovalbumin immunization). When mice treated for two weeks with HE3286 were challenged with <it>K. pneumoniae</it>, nearly identical survival kinetics were observed in vehicle-treated, HE3286-treated and untreated groups.</p> <p>Conclusions</p> <p>HE3286 represents a novel, first-in-class anti-inflammatory agent that may translate certain benefits of β-AET observed in rodents into treatments for chronic inflammatory pulmonary disease.</p

Dietary n-3 fatty acids have suppressive effects on mucin upregulation in mice infected with Pseudomonas aeruginosa

International audienceMucin hypersecretion and mucus plugging in the airways are characteristic features of chronic respiratory diseases like cystic fibrosis (CF) and contribute to morbidity and mortality. In CF, Pseudomonas aeruginosa superinfections in the lung exacerbate inflammation and alter mucus properties. There is increasing evidence that n-3 polyunsaturated fatty acids (PUFAs) exhibit anti-inflammatory properties in many inflammatory diseases while n-6 PUFA arachidonic acid (AA) favors inflammatory mediators such as eicosanoids prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) that may enhance inflammatory reactions. This suggests that n-3 PUFAs may have a protective effect against mucus over-production in airway diseases. Therefore, we hypothesized that n-3 PUFAs may downregulate mucins expression. We designed an absolute real-time PCR assay to assess the effect of a 5-week diet enriched either with n-3 or n-6 PUFAs on the expression of large mucins in the lungs of mice infected by P. aeruginosa. Dietary fatty acids did not influence mucin gene expression in healthy mice. Lung infection induced an increase of the secreted gel-forming mucin Muc5b and a decrease of the membrane bound mucin Muc4. These deregulations are modulated by dietary fatty acids with a suppressive effect of n-3 PUFAs on mucin (increase of Muc5b from 19-fold up to 3.6 x 10(5)-fold for the n-3 PUFAs treated group and the control groups, respectively, 4 days post-infection and decrease of Muc4 from 15-fold up to 3.2 x 10(4)-fold for the control and the n-3 PUFAs treated groups, respectively, 4 days post-infection). Our data suggest that n-3 PUFAs enriched diet represents an inexpensive strategy to prevent or treat mucin overproduction in pulmonary bacterial colonization

Azithromycin reduces spontaneous and induced inflammation in ΔF508 cystic fibrosis mice

BACKGROUND: Inflammation plays a critical role in lung disease development and progression in cystic fibrosis. Azithromycin is used for the treatment of cystic fibrosis lung disease, although its mechanisms of action are poorly understood. We tested the hypothesis that azithromycin modulates lung inflammation in cystic fibrosis mice. METHODS: We monitored cellular and molecular inflammatory markers in lungs of cystic fibrosis mutant mice homozygous for the ΔF508 mutation and their littermate controls, either in baseline conditions or after induction of acute inflammation by intratracheal instillation of lipopolysaccharide from Pseudomonas aeruginosa, which would be independent of interactions of bacteria with epithelial cells. The effect of azithromycin pretreatment (10 mg/kg/day) given by oral administration for 4 weeks was evaluated. RESULTS: In naive cystic fibrosis mice, a spontaneous lung inflammation was observed, characterized by macrophage and neutrophil infiltration, and increased intra-luminal content of the pro-inflammatory cytokine macrophage inflammatory protein-2. After induced inflammation, cystic fibrosis mice combined exaggerated cellular infiltration and lower anti-inflammatory interleukin-10 production. In cystic fibrosis mice, azithromycin attenuated cellular infiltration in both baseline and induced inflammatory condition, and inhibited cytokine (tumor necrosis factor-α and macrophage inflammatory protein-2) release in lipopolysaccharide-induced inflammation. CONCLUSION: Our findings further support the concept that inflammatory responses are upregulated in cystic fibrosis. Azithromycin reduces some lung inflammation outcome measures in cystic fibrosis mice. We postulate that some of the benefits of azithromycin treatment in cystic fibrosis patients are due to modulation of lung inflammation

Increased plasma membrane cholesterol in cystic fibrosis cells correlates with CFTR genotype and depends on de novo cholesterol synthesis

<p>Abstract</p> <p>Background</p> <p>Previous observations demonstrate that <it>Cftr</it>-null cells and tissues exhibit alterations in cholesterol processing including perinuclear cholesterol accumulation, increased <it>de novo </it>synthesis, and an increase in plasma membrane cholesterol accessibility compared to wild type controls. The hypothesis of this study is that membrane cholesterol accessibility correlates with CFTR genotype and is in part influenced by <it>de novo </it>cholesterol synthesis.</p> <p>Methods</p> <p>Electrochemical detection of cholesterol at the plasma membrane is achieved with capillary microelectrodes with a modified platinum coil that accepts covalent attachment of cholesterol oxidase. Modified electrodes absent cholesterol oxidase serves as a baseline control. Cholesterol synthesis is determined by deuterium incorporation into lipids over time. Incorporation into cholesterol specifically is determined by mass spectrometry analysis. All mice used in the study are on a C57Bl/6 background and are between 6 and 8 weeks of age.</p> <p>Results</p> <p>Membrane cholesterol measurements are elevated in both R117H and ΔF508 mouse nasal epithelium compared to age-matched sibling wt controls demonstrating a genotype correlation to membrane cholesterol detection. Expression of wt CFTR in CF epithelial cells reverts membrane cholesterol to WT levels further demonstrating the impact of CFTR on these processes. In wt epithelial cell, the addition of the CFTR inhibitors, Gly H101 or CFTR_inh-172, for 24 h surprisingly results in an initial drop in membrane cholesterol measurement followed by a rebound at 72 h suggesting a feedback mechanism may be driving the increase in membrane cholesterol. <it>De novo </it>cholesterol synthesis contributes to membrane cholesterol accessibility.</p> <p>Conclusions</p> <p>The data in this study suggest that CFTR influences cholesterol trafficking to the plasma membrane, which when depleted, leads to an increase in <it>de novo </it>cholesterol synthesis to restore membrane content.</p

The selective elimination of messenger RNA underlies the mitosis–meiosis switch in fission yeast

The cellular programs for meiosis and mitosis must be strictly distinguished but the mechanisms controlling the entry to meiosis remain largely elusive in higher organisms. In contrast, recent analyses in yeast have shed new light on the mechanisms underlying the mitosis–meiosis switch. In this review, the current understanding of these mechanisms in the fission yeast Schizosaccharomyces pombe is discussed. Meiosis-inducing signals in this microbe emanating from environmental conditions including the nutrient status converge on the activity of an RRM-type RNA-binding protein, Mei2. This protein plays pivotal roles in both the induction and progression of meiosis and has now been found to govern the meiotic program in a quite unexpected manner. Fission yeast contains an RNA degradation system that selectively eliminates meiosis-specific mRNAs during the mitotic cell cycle. Mmi1, a novel RNA-binding protein of the YTH-family, is essential for this process. Mei2 tethers Mmi1 and thereby stabilizes the transcripts necessary for the progression of meiosis

Addition of Bevacizumab to Chemotherapy in Advanced Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis

INTRODUCTION: Recently, studies have demonstrated that the addition of bevacizumab to chemotherapy could be associated with better outcomes in patients with advanced non-small cell lung cancer (NSCLC). However, the benefit seems to be dependent on the drugs used in the chemotherapy regimens. This systematic review evaluated the strength of data on efficacy of the addition of bevacizumab to chemotherapy in advanced NSCLC. METHODS: PubMed, EMBASE, and Cochrane databases were searched. Eligible studies were randomized clinical trials (RCTs) that evaluated chemotherapy with or without bevacizumab in patients with advanced NSCLC. The outcomes included overall survival (OS), progression-free survival (PFS), response rate (RR), toxicities and treatment related mortality. Hazard ratios (HR) and odds ratios (OR) were used for the meta-analysis and were expressed with 95% confidence intervals (CI). RESULTS: We included results reported from five RCTs, with a total of 2,252 patients included in the primary analysis, all of them using platinum-based chemotherapy regimens. Compared to chemotherapy alone, the addition of bevacizumab to chemotherapy resulted in a significant longer OS (HR 0.89; 95% CI 0.79 to 0.99; p = 0.04), longer PFS (HR 0.73; 95% CI 0.66 to 0.82; p<0.00001) and higher response rates (OR 2.34; 95% CI 1.89 to 2.89; p<0.00001). We found no heterogeneity between trials, in all comparisons. There was a slight increase in toxicities in bevacizumab group, as well as an increased rate of treatment-related mortality. CONCLUSIONS: The addition of bevacizumab to chemotherapy in patients with advanced NSCLC prolongs OS, PFS and RR. Considering the toxicities added, and the small absolute benefits found, bevacizumab plus platinum-based chemotherapy can be considered an option in selected patients with advanced NSCLC. However, risks and benefits should be discussed with patients before decision making

Sequence dependent antitumour efficacy of the vascular disrupting agent ZD6126 in combination with paclitaxel

The clinical success of small-molecule vascular disrupting agents (VDAs) depends on their combination with conventional therapies. Scheduling and sequencing remain key issues in the design of VDA–chemotherapy combination treatments. This study examined the antitumour activity of ZD6126, a microtubule destabilising VDA, in combination with paclitaxel (PTX), a microtubule-stabilising cytotoxic drug, and the influence of schedule and sequence on the efficacy of the combination. Nude mice bearing MDA-MB-435 xenografts received weekly cycles of ZD6126 (200 mg kg−1 i.p.) administered at different times before or after PTX (10, 20, and 40 mg kg−1 i.v.). ZD6126 given 2 or 24 h after PTX showed no significant benefit, a result that was attributed to a protective effect of PTX against ZD6126-induced vascular damage and tumour necrosis, a hallmark of VDA activity. Paclitaxel counteracting activity was reduced by distancing drug administrations, and ZD6126 given 72 h after PTX potentiated the VDA's antitumour activity. Schedules with ZD6126 given before PTX improved therapeutic activity, which was paralleled by a VDA-induced increase in cell proliferation in the viable tumour tissue. Paclitaxel given 72 h after ZD6126 yielded the best response (50% tumours regressing). A single treatment with ZD6126 followed by weekly administration of PTX was sufficient to achieve a similar response (57% remissions). These findings show that schedule, sequence and timing are crucial in determining the antitumour efficacy of PTX in combination with ZD6126. Induction of tumour necrosis and increased proliferation in the remaining viable tumour tissue could be exploited as readouts to optimise schedules and maximise therapeutic efficacy