SABRE: a bio-inspired fault-tolerant electronic architecture.

As electronic devices become increasingly complex, ensuring their reliable, fault-free operation is becoming correspondingly more challenging. It can be observed that, in spite of their complexity, biological systems are highly reliable and fault tolerant. Hence, we are motivated to take inspiration for biological systems in the design of electronic ones. In SABRE (self-healing cellular architectures for biologically inspired highly reliable electronic systems), we have designed a bio-inspired fault-tolerant hierarchical architecture for this purpose. As in biology, the foundation for the whole system is cellular in nature, with each cell able to detect faults in its operation and trigger intra-cellular or extra-cellular repair as required. At the next level in the hierarchy, arrays of cells are configured and controlled as function units in a transport triggered architecture (TTA), which is able to perform partial-dynamic reconfiguration to rectify problems that cannot be solved at the cellular level. Each TTA is, in turn, part of a larger multi-processor system which employs coarser grain reconfiguration to tolerate faults that cause a processor to fail. In this paper, we describe the details of operation of each layer of the SABRE hierarchy, and how these layers interact to provide a high systemic level of fault tolerance.

Assessing medicinal plants from South-Eastern Spain for potential anti-inflammatory effects targeting nuclear factor-Kappa B and other pro-inflammatory mediators.

AIM OF THE STUDY: Identification of plants with anti-inflammatory activity can be successfully based on information gained through knowledge on their traditional use. This is particularly true for biodiversity-rich regions of the world such as the Mediterranean. While such approaches are often single target based, here we used a multitarget, cell-based approach focusing on the pro-inflammatory signaling cascade and especially the NF-kappaB (NF-kappaB) pathway. MATERIALS AND METHODS: The plants from South-Eastern Spain were chosen on the basis that they were recorded as having a traditional use against an indication related to inflammation. The primary target was the transcription factor NF-kappaB (using a luciferase-based assay in HeLa cells). In addition extracts were tested in vitro for effects on cytokines (IL-6, IL-8, TNF-alpha) or PGE(2) in monocytes and for potential cytotoxic/pro-apoptotic action as well as for their influence on the cell cycle. RESULTS: Overall, 64 medicinal plant drugs from 61 species were assessed as potential inhibitors of inflammatory mediators to levels of 100-10 microg/ml. Three plants showed the highest level of activity (50 microg/ml) in inhibiting the activation of NF-kappaB in 5.1 cells: Helichrysum stoechas (Asteraceae), Dorycnium pentaphyllum (Fabaceae, s.l.) and Phlomis almeriensis (Lamiaceae). In the tests against the cytokines it was particularly striking to find that a number of species, Bupleurum fruticosum, Chamaespartium tridentatum, Genista ramosissima, Helichrysum stoechas, Mercurialis tomentosa, Ononis ramosissima, Peganum harmala, Picnomon acarna, Retama sphaerocarpa and Santolina viscosa showed extracts that were active at inhibiting TNF-alpha (10 microg/ml). CONCLUSIONS: Overall, this project has identified a series of species with an activity profile which merits further phytochemical-pharmacological investigation.

In vitro evaluation of effects of two Ghanaian plants relevant to wound healing.

Commelina diffusa and Spathodea campanulata are used as wound-healing agents in Ashanti traditional medicine in Ghana. The methanol extracts of Commelina diffusa herb and Spathodea campanulata bark showed some level of antimicrobial activity with C. diffusa exhibiting selective antifungal activity against Trichophyton species. The extracts reduced the peroxidation of bovine brain extract with an IC(50) value of 1.39 mg/mL and 0.24 mg/mL, respectively. In addition the extracts also exhibited significant antioxidant activity by protecting MRC-5 cells from hydrogen peroxide induced oxidant injury at concentrations between 1 microg/mL and 10 microg/mL. The extracts showed no inhibition of NF-kappaB at 100 microg/mL. The antioxidant activities and antimicrobial activities suggest that the use of the plants in wound healing may be based on antioxidant and antiseptic effects of its constituents.

Cytotoxic activity of a podophyllotoxin-like lignan from Linum tauricum Willd.

The present study describes the preliminary evaluation of the cytotoxic activity of a podophyllotoxin-like compound 4'-demethyl-6-methoxypodophyllotoxin (4'-DM-6-Mptox), isolated as one of the main lignans of Linum tauricum Willd. ssp. tauricum. The cytotoxic effects 4'-DM-6-Mptox were assessed by the MTT-dye reduction assay against the human leukemic cell lines HL-60, BV-173 and LAMA-84. DNA-fragmentation analysis and NF-kB inhibition assay were performed in order to elucidate some of the mechanistic aspects of the cytotoxic action of the investigated compound. 4'-DM-6-Mptox was found to exert prominent cytotoxicity, with IC50 values being several-fold lower than those of the referent antineoplastic agent etoposide. The DNA-fragmentation analysis revealed that 4'-DM-6-Mptox treatment triggered apoptosis in BV-173 and HL-60 cells. In our hands 4'-DM-6-Mptox was found to induce concentration-dependent NF-kB inhibition in HeLa cells as assessed by the IL-6 luciferase gene reporter assay, which though not quite prominent, at least partly contributes to the cytotoxic potential of the tested lignan. On the basis of the results obtained it could be concluded that 4'-DM-6-Mptox necessitates further pharmacological and toxicological evaluation as a possible chemotherapeutic agent. Furthermore due to its relatively high concentrations in the described plant source the possibility for its use as a precursor for the semisynthetic production of lignan-based drugs, could be considered.

Phenylpropanoid NF-kappaB inhibitors from Bupleurum fruticosum.

Two phenylpropanoids from Bupleurum fruticosum (Apiaceae/Umbelliferae) were shown to inhibit the transcriptional activity induced by PMA or TNFalpha of an NF-kappaB-controlled reporter gene. Western blot experiments indicated that the phenylpropanoids did not prevent IkappaBalpha degradation, suggesting that their molecular target is at a post-IKB degradation level. Both compounds prevented cytokine (IL-1, IL-6, TNF, IL-8) release and prostaglandin E2 synthesis.

Antibacterial activity of linoleic and oleic acids isolated from Helichrysum pedunculatum: a plant used during circumcision rites.

The antibacterial activity-guided fractionation of the dichloromethane extract of leaves of Helichrysum pedunculatum resulted in the isolation of linoleic and oleic acids. Linoleic acid inhibited the growth of all the Gram-positive bacterial species tested with the minimum inhibitory concentration (MIC) varying between 0.01 and 1.0 mg/ml. Oleic acid was active against three of the five Gram-positive bacteria at a MIC of 1.0 mg/ml. Both compounds were inactive against the Gram-negative species tested. A synergistic effect between the two fatty acids was observed against Staphylococcus aureus and Micrococcus kristinae.

Comparison of the phenolic composition of fruit juices by single step gradient HPLC analysis of multiple components versus multiple chromatographic runs optimised for individual families.

After minimal sample preparation, two different HPLC methodologies, one based on a single gradient reversed-phase HPLC step, the other on multiple HPLC runs each optimised for specific components, were used to investigate the composition of flavonoids and phenolic acids in apple and tomato juices. The principal components in apple juice were identified as chlorogenic acid, phloridzin, caffeic acid and p-coumaric acid. Tomato juice was found to contain chlorogenic acid, caffeic acid, p-coumaric acid, naringenin and rutin. The quantitative estimates of the levels of these compounds, obtained with the two HPLC procedures, were very similar, demonstrating that either method can be used to analyse accurately the phenolic components of apple and tomato juices. Chlorogenic acid in tomato juice was the only component not fully resolved in the single run study and the multiple run analysis prior to enzyme treatment. The single run system of analysis is recommended for the initial investigation of plant phenolics and the multiple run approach for analyses where chromatographic resolution requires improvement.

Asthma management in adults. Strategies to minimise morbidity.

BACKGROUND: Fundamental changes to the approach in asthma treatment over recent years have resulted in a reduction in asthma mortality in Australia. However, many factors still contribute to asthma morbidity. OBJECTIVE: This article identifies the preventable causes of difficult asthma and identifies those patients at greatest risk of mortality. Recent changes in the use of long acting beta agonists and inhaled corticosteroids are discussed. DISCUSSION: Morbidity due to asthma and quality of life for asthmatic patients can be improved by: identifying preventable causes of persistent asthma symptoms; reviewing inhaler technique; targeting high risk for more intensive monitoring; familiarity with the drugs used to treat asthma.

Respiratory symptoms and lung function in aborigines from tropical Western Australia.

To estimate the prevalence of respiratory symptoms, bronchial hyperresponsiveness, smoking, and atopy in a population of Australians of Aboriginal descent (AAD), to determine the association of these and other factors with lung function, and to compare levels of lung function of AAD with Australians of European descent (AED) according to age and height, and to explore reasons for their differences, we conducted a study of 96 male (41 of whom were under 18 yr of age) and 111 female (48 of whom were under 18 yr of age) AAD living in a single remote tropical community in 1993. This population provided data on age, height, and lung function. A modified British Medical Research Council (MRC) questionnaire on respiratory symptoms and smoking was administered. FEV1, FVC, height, age, and bronchial responsiveness to inhaled methacholine were measured. Atopic status was assessed by skin prick tests for eight common allergens. Age- and sex-adjusted lung function was similar to that of other AAD groups and lower than in AED. For children, lung function increased less with increasing height in AAD than in AED. Lung function was reduced in adult AAD as compared with adult AED, although it was not possible to determine statistically whether lung function started to decline at an earlier age or declined faster with increasing age in AAD. A history of asthma, smoking, dyspnea, cough, or sputum production; atopic status; and increased bronchial responsiveness were all associated with lower levels of lung function. Differences in lung function between AAD and AED appear to be determined by characteristics that may be inherited, as well as by adverse external influences.

Sequence characterisation and expression of homeobox HOX A7 in the multi-potential erythroleukaemic cell line TF-1.

Homeobox gene expression was examined in the erythroleukaemic cell line TF-1. Expression of a number of HOX A, B and C genes, including HOX A7 was detected. Expression of this gene has not previously been reported in erythroleukaemic cell lines. A 2.1 kb full length cDNA of the HOX A7 gene was cloned. The predicted amino acid sequence C-terminal to the homeodomain consists of an alanine-rich region and a strongly negatively charged domain consisting entirely of aspartic and glutamic acid residues.

Fc epsilon R1-beta polymorphism and total serum IgE levels in endemically parasitized Australian aborigines.

Endemic helminthic infection is a major public-health problem and affects a large proportion of the world's population. In Australia, helminthic infection is endemic in Aboriginal communities living in tropical northern regions of the continent. Such infection is associated with nonspecific (polyclonal) stimulation of IgE synthesis and highly elevated total serum IgE levels. There is evidence that worm-infection variance (i.e., human capacity of resistance) and total serum IgE levels may be related to the presence of a major codominant gene. The beta chain of the high-affinity IgE receptor, Fc epsilon R1-beta, has been previously identified as a candidate for the close genetic linkage of the 11q13 region to IgE responses in several populations. We show a biallelic RsaI polymorphism in Fc epsilon R1-beta to be associated with total serum IgE levels (P = .0001) in a tropical population of endemically parasitized Australian Aborigines (n = 234 subjects). The polymorphism explained 12.4% of the total residual variation in serum total IgE and showed a significant (P = .0000) additive relationship with total serum IgE levels, across the three genotypes. These associations were independent of familial correlations, age, gender, racial admixture, or smoking status. Alleles of a microsatellite repeat in intron 5 of the same gene showed similar associations. The results suggest that variation in Fc epsilon R1-beta may regulate IgE-mediated immune responses in this population.

Partial vs full beta-receptor agonism. A clinical study of inhaled albuterol and fenoterol.

STUDY OBJECTIVE: To compare the maximal extrapulmonary effects of the beta-agonists albuterol and fenoterol in eight healthy volunteers. SUBJECTS AND METHODS: In this double-blind study, we have examined the maximum cardiac effects (electromechanical systole [QS2I]--a measure of inotropy, heart rate, BP) and metabolic effects (plasma K+ and cyclic adenosine monophosphate [cAMP]) of repeated inhalation of albuternol and fenoterol. In eight healthy volunteers, 400 microg of each drug was administered every 10 min until QS2I and plasma K+ had reached a plateau (+/- 0.1 mmo l/L for K+, and +/- 10 ms for QS2I). The maximum response (Emax) and the dose of albuterol required to produce 50% of the maximum response to fenoterol (ED50F) were calculated. RESULTS: The Emax for fenoterol was significantly greater than albuterol for plasma K+ (-1.4 vs -1.03 mmol/L; p<0.002), QS2I (-71.8 vs 57.5 ms; p=0.047), and cAMP (33.8 vs 18.1 nmol/L; p<0.002). The dose required to produce the ED50f was significantly greater for albuterol than for fenoterol with potency ratios of 1.75, 1.61, and 2.26 for plasma K+, QS2I, and cAMP, respectively. There were no significant differences between fenoterol and albuterol with respect to heart rate (Emax, 44.9 vs 32.5 beats/min; p=0.19; potency ratio, 1.98; p=0.052). CONCLUSIONS: These findings suggest that albuterol behaves as a partial agonist at beta-receptors when compared with fenoterol, and that when inhaled in doses currently recommended for severe asthma, albuterol will result in lesser maximum cardiac and metabolic effects than fenoterol. These findings are consistent with the hypothesis that the property of full receptor agonism may contribute to the increased risk of death associated with fenoterol.

The effect of hypercapnia and hypoxemia on the cardiovascular responses to isoproterenol.

BACKGROUND: The reason for the increased risk of death with fenoterol and isoproterenol in asthma is unknown but may relate to their cardiovascular effects. Deaths from asthma usually occur outside hospital where hypoxemia, with or without hypercapnia, may exist. Both of these states can influence the cardiovascular system. We investigated whether different gas mixtures modified the cardiovascular effects of isoproterenol. METHOD: Nine healthy men were randomly assigned to receive each of three gas mixtures to achieve (1) normoxia-normocapnia, (2) hypercapnia (end-tidal PaCO2, 50 mm Hg), (3) hypoxemia-hypercapnia (arterial oxygen saturation, 90%; PaCO2, 50 mm Hg). Isoproterenol was administered with each of the gas mixtures. Cardiovascular measurements of heart rate, blood pressure, cardiac index, ejection fraction, fractional shortening, electromechanical systole, and the QTc interval were made before administration of the gases, as well as before and 5 minutes after isoproterenol administration. RESULTS: The changes after hypercapnia were not significantly different from those after normoxia-normocapnia. Hypoxemia-hypercapnia increased heart rate, systolic and diastolic blood pressure, QTc interval, cardiac index, ejection fraction, and fractional shortening. Isoproterenol increased heart rate, systolic blood pressure, QTc interval, cardiac index, ejection fraction, and fractional shortening while the subjects breathed the normoxia-normocapnia gas mixture. It caused similar changes with the other gas mixtures. The changes were additive. CONCLUSION: Isoproterenol and hypoxemia-hypercapnia will increase myocardial oxygen demand and could prove to be detrimental in severe asthma.

A humanized anti-tumor necrosis factor-alpha monoclonal antibody that acts as a partial, competitive antagonist of the template antibody.

We have constructed several humanized versions of a monoclonal antibody (MAb78) against human tumor necrosis factor-alpha (huTNF-alpha) retaining the complementarity-determining regions (CDR) of the original mouse MAb with or without a variable number of original framework region (FR) residues. All versions, except one, showed a loss of binding affinity and neutralizing potency of at least 10-fold compared to the original mouse MAb or its chimeric equivalent. In some cases, however, the decrease in neutralizing potency was significantly greater than the decrease in binding affinity. Two humanized versions showing the greatest dissociation between these two parameters were studied for their capacity to inhibit the neutralizing activity of chimeric or murine MAb78 when used at concentrations that bound but only partially neutralized huTNF-alpha. One humanized version (MAb78D) was indeed able to do so, whereas the other (MAb78C) was not found to exert any inhibitory activity at all concentrations tested. The antagonistic effect of MAb78D was concentration dependent and could be overcome by increasing the concentrations of chimeric or murine MAb78. Two different models of MAb78-huTNF-alpha interaction that may help explain the antagonist activity of humanized MAb78D are discussed.

Nebulized beta 2-adrenoceptor agonists do not affect plasma selenium or glutathione peroxidase activity in patients with asthma.

We investigated whether the beta 2-agonists fenoterol and salbutamol decreased plasma selenium and glutathione peroxidase activity in patients with asthma as this may partially explain the findings of reduced selenium status in asthmatic patients. Nine patients with asthma were studied on 3 occasions and inhaled either fenoterol (5 mg), salbutamol (5 mg) or ipratropium bromide (0.5 mg) administered by nebulization using a randomized, double blind, crossover design. Plasma selenium, glutathione peroxidase activity and potassium were measured prior to drug administration and at 15, 30 and 60 minutes after drug. None of the drugs had any effect on plasma selenium or glutathione peroxidase activity. Ipratropium bromide did not affect plasma potassium. Both beta 2-agonists significantly decreased plasma potassium. The mean (SD) maximum decrease was -0.79 (0-18) mmol/l for fenoterol and -0.26 (0-03) mmol/l for salbutamol (both p < or = 0.01) confirming systemic absorption of the drugs. beta 2-agonists are unlikely to be responsible for the reduced selenium status found in some patients with asthma.

A comparison of the cardiovascular and metabolic effects of formoterol, salbutamol and fenoterol.

The cardiovascular and metabolic effects of the long-acting beta 2-agonist formoterol were compared with those of salbutamol, fenoterol and placebo in 12 healthy volunteers, using a randomised, double-blind, cross-over design. On the study days, the subjects inhaled either formoterol (24 micrograms), salbutamol (400 micrograms), fenoterol (400 micrograms) or placebo, at 30 min intervals for five doses. Heart rate (HR) total electromechanical systole (Q-S2I) (a measure of inotropy), the corrected QT interval (QTc), systolic and diastolic blood pressure, plasma glucose and plasma potassium (K+) were measured prior to drug administration, 10 min after each inhalation and at 30 min intervals for 3 h after the last inhalation. All of the active agents significantly increased HR, QTc and plasma glucose, and decreased Q-S2I, diastolic blood pressure and plasma K+ compared to placebo. Fenoterol had a significantly greater maximum effect on HR, QTc and Q-S2I than either salbutamol or formoterol. Formoterol and fenoterol caused a similar maximum reduction in plasma K+, greater than that due to salbutamol. We conclude that formoterol is a more selective beta 2-agonist than fenoterol, and has similar cardiovascular effects to salbutamol when inhaled repeatedly by normal volunteers.

The extrapulmonary effects of inhaled hexoprenaline and salbutamol in healthy individuals.

We have investigated the cardiovascular and metabolic effects of multiple inhaled doses of salbutamol and hexoprenaline in 12 healthy volunteers. They inhaled 200 micrograms of salbutamol or hexoprenaline at 15 min intervals for 60 min from a metered dose inhaler (total dose 1000 micrograms). We measured heart rate, blood pressure, total electromechanical systole (as a measure of inotropic response), QTc interval on the ECG, and plasma potassium at baseline, 10 min after each inhalation, and 30 and 60 min after the last inhalation. There was no difference in the effects of the two drugs on blood pressure, total electromechanical systole, or QTc interval. Salbutamol significantly increased heart rate compared with hexoprenaline. Hexoprenaline caused a significantly greater fall in plasma potassium compared with salbutamol.

A comparative study of the efficacy of beclomethasone dipropionate delivered from a breath activated and conventional metered dose inhaler in asthmatic patients.

In order to overcome the problem of poor co-ordination with the use of the conventional press and breathe metered dose inhaler, a breath-activated inhaler ('Autohaler' inhalation device) has been developed. The clinical response to equal doses of beclomethasone dipropionate administered from the 'Autohaler' device and the conventional metered dose inhaler was compared in 36 stable asthmatic patients receiving regular inhaled beclomethasone dipropionate. The study was performed using a double-blind, double-dummy crossover design. Each treatment was given for 4 weeks. Objective and subjective measures of asthma severity were compared in the second 14 days of each treatment period, with clinical equivalence defined as a difference of 20% or less in the adjusted mean values for the 30 patients with data from both treatment periods. Equivalence at the +/- 5% level was found in the objective measures of pre-bronchodilator FEV1 (p < or = 0.001); post-bronchodilator FEV1 (p < 0.001); morning and evening peak expiratory flow rate (both p < or = 0.001). Patient diary cards established there was equivalent usage of inhaled bronchodilator, and equivalent symptom scores for daytime disability and daytime and night-time breathlessness. The results show that, in stable asthmatics, treatment with beclomethasone dipropionate is clinically equivalent when delivered by the 'Autohaler' device or the conventional metered dose inhaler used efficiently.

Cardiovascular effects of fenoterol under conditions of hypoxaemia.

BACKGROUND: The reason for the association of increased risk of death with fenoterol in patients with asthma in New Zealand is unknown but may relate to its cardiovascular effects. Most deaths from asthma occur outside hospital, where hypoxaemia is likely to be a complicating factor. The cardiovascular effects of fenoterol have been investigated therefore under conditions of normoxaemia and hypoxaemia. METHOD: Eight healthy men were studied on two occasions. Measurements of heart rate, blood pressure, total electromechanical systole (QS2I), electrocardiographic QTc interval, cardiac index, stroke volume, and ejection fraction were made under conditions of normoxaemia and hypoxaemia (arterial oxygen saturation 90%) before and after administration of 800 micrograms of fenoterol by a metered dose inhaler. The order in which treatments were applied was according to a Latin square design. RESULTS: Before inhalation of fenoterol hypoxaemia was associated with a significant increase in heart rate (8 beats/min) and QTc interval (15.6 ms). Under conditions of normoxaemia fenoterol caused a significant increase in heart rate (14.3 beats/min), systolic blood pressure (7.7 mm Hg), stroke volume (27.7 ml), cardiac index (1.6 1/min/m2), ejection fraction (11.48), and QTc interval (32.9 ms) and a fall in QS2I (-23.2 ms) and diastolic blood pressure (-8.4 mm Hg). Under conditions of hypoxaemia the changes after inhalation of fenoterol were similar to those recorded during normoxaemia; thus the effects of hypoxaemia and fenoterol were additive (heart rate 21.9 beats/min, QTc 43.5 ms with fenoterol and hypoxaemia). CONCLUSION: The chronotropic and electrophysiological effects of fenoterol were enhanced by conditions of hypoxaemia.