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PubMed1986

Additive effects of dobutamine and amrinone on myocardial contractility and ventricular performance in patients with severe heart failure.

The effects of amrinone, dobutamine, and a combination of the two drugs on peak positive left ventricular dP/dt and left ventricular performance were evaluated in 11 patients with chronic congestive heart failure. When administered alone, both dobutamine (10.9 micrograms/kg/min) and intravenous amrinone (1.9 mg/kg/min) significantly increased left ventricular dP/dt and performance. When compared with dobutamine alone, the addition of amrinone resulted in further increases in left ventricular dP/dt and cardiac index (to 1319 +/- 419 from 1202 +/- 376 mm Hg/sec, p less than .002, and to 3.56 +/- 0.78 from 3.04 +/- 0.67 liters/min/m2, p less than .01, respectively). The combination also induced a further reduction in left ventricular end-diastolic pressure (to 15.3 +/- 11.3 from 18.2 +/- 10.3 mm Hg, p less than .05) when compared with amrinone alone. The combination of dobutamine and amrinone increased heart rate slightly when compared with either drug alone, but did not further reduce systemic arterial pressure when compared with amrinone alone. The dose-response curve of left ventricular dP/dt and performance during titration of dobutamine with and without the addition of intravenous amrinone was evaluated in seven patients. The addition of amrinone to any dose of dobutamine produced higher cardiac index and lower systemic vascular resistance than dobutamine or amrinone alone. Thus, when compared with dobutamine alone in patients with chronic congestive heart failure, the addition of intravenous amrinone to dobutamine results in an additive improvement in left ventricular performance throughout the dose range.

Adult↗

PubMed1995

Additive effects of combined angiotensin-converting enzyme inhibition and angiotensin II antagonism on blood pressure and renin release in sodium-depleted normotensives.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors do not decrease plasma angiotensin (Ang) II levels 24 hours after drug intake to the same extent as at peak. This intermittent partial "escape" is explained either by a renin-mediated reactive rise in plasma Ang I or by non-ACE-dependent Ang II generation. We therefore tested the hypothesis that a combination of ACE inhibition and Ang II blockade may have additive biological and hemodynamic effects. METHODS AND RESULTS: In a single-dose, double-blind, randomized, four-way, crossover study, an Ang II antagonist (losartan 50 mg), an ACE inhibitor (captopril 50 mg), their combination, and matched placebos were orally administered to 12 normotensive male volunteers maintained in mild sodium depletion. When captopril 50 mg and losartan 50 mg were given alone, the magnitude of their effects on blood pressure, plasma active renin, Ang I, and aldosterone was similar, whereas the kinetics of their effects were different, reflecting differences in drug pharmacokinetics. The losartan-captopril combination completely suppressed the rise in plasma Ang II induced by losartan 2 hours after drug intake (3.3 +/- 3.6 pg/mL versus 20.3 +/- 19.1 pg/mL, respectively, P < .05). Six hours after drug intake, the losartan-captopril combination induced a significantly greater decrease in mean blood pressure than that produced by either losartan or captopril alone (73 +/- 7 mm Hg versus 79 +/- 8 mm Hg versus 81 +/- 7 mm Hg, respectively, P < .05). The maximum placebo-subtracted falls in mean blood pressure for the losartan-captopril combination, captopril 50 mg, and losartan 50 mg were 14 +/- 5 mm Hg, 10 +/- 3 mm Hg, and 9 +/- 6 mm Hg, respectively (F2.22 = 3.45, P < .05). The duration of the mean blood pressure fall was not prolonged by the combination. After combined losartan-captopril administration, the area under the plasma active renin versus time curve (0 to 24 hours) was significantly increased when compared with either losartan or captopril alone (6404 +/- 2961 pg.h.mL-1 versus 3105 +/- 1461 pg.h.mL-1 versus 2092 +/- 867 pg.h.mL-1, respectively, P < .05). The combination had no additive effects on plasma aldosterone decrease when compared with either losartan or captopril alone (58 +/- 17% versus 51 +/- 20% versus 53 +/- 21%, respectively, NS). CONCLUSIONS: The combined administration of a standard single oral dose of an ACE inhibitor and an Ang II antagonist to mildly sodium-depleted normal subjects (1) had a major additive effect on plasma renin rise, (2) induced an additional mean blood pressure reduction, and (3) had no additive effect on plasma aldosterone fall.

Adolescent↗

PubMed2005

Potential consequences for recruitment, power, and external validity of requirements for additional risk factors for eligibility in randomized controlled trials in secondary prevention of stroke.

BACKGROUND AND PURPOSE: Eligibility criteria determine the external validity (generalizability) of the results of randomized controlled trials. To increase the number of outcome events, and hence statistical power, some recent stroke prevention trials have required additional vascular risk factors for eligibility. METHODS: To assess the merits of additional eligibility criteria in stroke prevention trials, we analyzed data from 3 trials and 1 hospital-referred series of patients with a transient ischemic attack or minor ischemic stroke. Patients were stratified according to 2 sets of additional risk factors similar to those used in recent trials (MATCH, SPORTIF and PRoFESS); risk of stroke, myocardial infarction, or vascular death was calculated in relation to the number of risk factors. RESULTS: Although the observed risk during follow-up did increase with the number of risk factors present (P<0.01 for both sets), the risks in patients with > or =1 risk factors were not substantially greater than those in all patients. Consequently, although the proportions of patients with no risk factors in the 4 cohorts differed substantially between the 2 sets of eligibility criteria (21% to 28% versus 56% to 73%), in neither case could their exclusion be justified on statistical grounds. CONCLUSIONS: The degree of patient selection introduced by use of additional vascular risk factors as eligibility criteria for trials can differ substantially between apparently similar sets of risk factors. Given that the potential for additional eligibility criteria to undermine generalizability and prolong recruitment outweighs any benefits in terms of statistical power, the exclusion of patients with no risk factors is difficult to justify.

Aged↗

PubMed2006

Different additional risk factors for cerebral infarctions associated with the factor V Leiden mutation in a family.

Several cases with cerebral infarctions associated with the factor V Leiden mutation have been reported. However, bearing in mind the large number of asymptomatic individuals with the factor V Leiden mutation, additional risk factors for cerebral infarctions should be considered. In this report, two siblings with cerebral infarctions associated with a combination of heterozygous factor V Leiden mutation and different additional exogenous and endogenous thrombogenic risk factors are described. Respiratory problems in the perinatal period and increased lipoprotein (a) concentrations in the first patient and an episode of gastroenteritis from Shigella infection and persistent high titers of serum anticardiolipin and beta(2)-glycoprotein I antibodies in the second patient were recorded as additional thrombogenic risk factors. Furthermore, both patients were found to be heterozygous for the methylenetetrahydrofolate reductase gene C677T mutation. These findings suggest that even in the same family, different additional thrombogenic risk factors can be present in infants with cerebral infarctions associated with the factor V Leiden mutation. An extensive search of additional circumstantial and genetic thrombogenic risk factors should be useful for prophylaxis and prognosis of these infants with cerebral infarctions associated with the factor V Leiden mutation and of their related family members. To our knowledge, the second patient in this study is the first patient reported to have cerebral infarctions associated with the combination of the factor V Leiden mutation and persistent high titers of serum beta(2)-glycoprotein I antibodies.

Adult↗

PubMed1998

Composition and toxicity of petroleum products and their additives.

1. All petroleum based products are highly complex chemical mixtures. Although almost exclusively composed of hydrocarbons, the composition varies with the crude oil source. 2. Their toxicity for man is generally low but there are exceptions. Although irritancy and sensitization to specific ingredients may be demonstrated in animals, animal experiments are not a reliable indicator of sensitization potential in man. 3. Both product complexity and commercial considerations can make acceptable and meaningful compositional disclosures difficult. A nomenclature system exists which solves these problems. 4. Frame formulations would have some value to poisons centres dealing with petroleum product enquiries. 5. As legislation for the European Union is developed, the balance must be reached between disclosure of the (often confidential) precise chemical composition of products and a practical and useful composition for the guidance of users and medical personnel. This is a key issue with some petroleum products, mainly due to the additives used in them. 6. For several reasons, such as climatic conditions or logistics of supply, the various components, including additives, used in a branded product may vary because the final product composition is determined not by chemistry but by performance in service. 7. Lubricants may contain between 10 and 20% of additives; fuels contain additives only at parts per million levels. However, for both fuels and lubricants, toxicity from additives is rarely a matter of concern.

Animals↗

PubMed2005

Phenotypic error threshold; additivity and epistasis in RNA evolution.

BACKGROUND: The error threshold puts a limit on the amount of information maintainable in Darwinian evolution. The error threshold was first formulated in terms of genotypes. However, if a genotype-phenotype map involves redundancy ("mutational neutrality"), the error threshold should be formulated in terms of phenotypes since there is no unique fittest genotype. A previous study formulated the error threshold in terms of phenotypes, and their results showed that a rather low degree of mutational neutrality can increase the error threshold unlimitedly. RESULTS: We obtain an analytical formulation of the phenotypic error threshold by considering the "additive assumption", in which base substitutions do not influence each other (no epistasis). Our formulation shows that an increase of the error threshold due to mutational neutrality is limited. Computer simulations of RNA evolution are conducted to verify our formulation, and the results show a good agreement between the analytical prediction and the simulations. The comparison with the previous formulation illustrates that it is important for the prediction of the error threshold to consider that the number of base substitutions per replication is rather large near the error threshold. To examine the additive assumption, a detailed analysis of additivity and epistasis in RNA folding of a particular sequence is performed. The results show a high degree of epistasis in RNA folding; furthermore, the analysis also elucidates the reason of the success of the additive assumption. CONCLUSIONS: We conclude that an increase of the error threshold by mutational neutrality is limited, and that the additive assumption achieves a good prediction of the error threshold in spite of a high degree of epistasis in RNA folding because the average number of base substitutions of sequences retaining the phenotype per replication is sufficiently small to avoid of the effect of epistasis.

Algorithms↗

PubMed2001

Macrophages exposed continuously to lipopolysaccharide and other agonists that act via toll-like receptors exhibit a sustained and additive activation state.

BACKGROUND: Macrophages sense microorganisms through activation of members of the Toll-like receptor family, which initiate signals linked to transcription of many inflammation associated genes. In this paper we examine whether the signal from Toll-like receptors [TLRs] is sustained for as long as the ligand is present, and whether responses to different TLR agonists are additive. RESULTS: RAW264 macrophage cells were doubly-transfected with reporter genes in which the IL-12p40, ELAM or IL-6 promoter controls firefly luciferase, and the human IL-1beta promoter drives renilla luciferase. The resultant stable lines provide robust assays of macrophage activation by TLR stimuli including LPS [TLR4], lipopeptide [TLR2], and bacterial DNA [TLR9], with each promoter demonstrating its own intrinsic characteristics. With each of the promoters, luciferase activity was induced over an 8 hr period, and thereafter reached a new steady state. Elevated expression required the continued presence of agonist. Sustained responses to different classes of agonist were perfectly additive. This pattern was confirmed by measuring inducible cytokine production in the same cells. While homodimerization of TLR4 mediates responses to LPS, TLR2 appears to require heterodimerization with another receptor such as TLR6. Transient expression of constitutively active forms of TLR4 or TLR2 plus TLR6 stimulated IL-12 promoter activity. The effect of LPS, a TLR4 agonist, was additive with that of TLR2/6 but not TLR4, whilst that of lipopeptide, a TLR2 agonist, was additive with TLR4 but not TLR2/6. Actions of bacterial DNA were additive with either TLR4 or TLR2/6. CONCLUSIONS: These findings indicate that maximal activation by any one TLR pathway does not preclude further activation by another, suggesting that common downstream regulatory components are not limiting. Upon exposure to a TLR agonist, macrophages enter a state of sustained activation in which they continuously sense the presence of a microbial challenge.

Animals↗

PubMed2003

Survival of Listeria monocytogenes in wilted and additive-treated grass silage.

Grass was field-dried to 3 different dry matter (DM) levels (200, 430 and 540 g/kg) and inoculated with 10(6)-10(7) cfu/g of a Listeria monocytogenes strain sharing a phagovar occasionally involved in foodborne outbreaks of listeriosis. Formic acid (3 ml/kg) or lactic acid bacteria (8 x 10(5)/g) with cellulolytic enzymes were applied only to forages with low and intermediate DM levels. Forages were ensiled in laboratory silos (1700 ml) and were stored at 25 degrees C for 30 or 90 days. After 90 days of storage, L. monocytogenes could not be detected in any silo, except one with the high dry matter grass without additive. After 30 days of storage, between 10(2) and 10(6) cfu L. monocytogenes/g silage were isolated from the untreated silages. Increasing the DM content from 200 to 540 g/kg did not reduce listeria counts possibly because of the lower production of fermentation acids (higher pH). In silages treated with additives, counts of L. monocytogenes were always lower than in silages without additive. In wet silages (DM 200 g/kg) both additives were effective, but in the wilted silages (DM 430 g/kg) only the bacterial additive reduced listeria counts below detection level. Listeria counts were highly correlated to silage pH (r = 0.92), the concentration of lactic acid (r = -0.80) and the pooled amount of undissociated acids (r = -0.83).

Fermentation↗

PubMed1999

Additional value of whole-body positron emission tomography with fluorine-18-2-fluoro-2-deoxy-D-glucose in recurrent colorectal cancer.

PURPOSE: To assess the additional value of the whole-body [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) scan as a staging modality complementing conventional diagnostic methods (CDM) in patients suspected of having recurrent colorectal adenocarcinoma. PATIENTS AND METHODS: In 103 patients, the discordances between FDG-PET and CDM results were identified and related to the final diagnosis obtained by histopathology or clinical follow-up (> 1 year). All FDG-PET studies were reviewed with full knowledge of the CDM findings. RESULTS: In a region-based analysis, discordances between CDM and FDG-PET findings were found in 40 of 412 regions (10%). In these, FDG-PET had additional diagnostic value in 14 of 16 locoregional, six of seven hepatic, seven of eight abdominal, and eight of nine extra-abdominal regions. In a patient-based analysis, CDM categorized a subgroup of 60 patients as having resectable recurrent disease limited to the liver (n = 37) or locoregional region (n = 23). In 13 of these patients, there were discordant FDG-PET findings, detecting additional tumor sites in nine patients and excluding disease in three patients and yielding an additional diagnostic value in 20% of the patients. A second subgroup consisted of 13 patients with inconclusive CDM findings (n = 5) or with elevated plasma carcinoembryonic antigen levels and an otherwise negative conventional work-up (n = 8). In these patients, FDG-PET results were correct in eight of nine discordances, yielding a positive additional diagnostic value in 62% of the patients. CONCLUSION: Whole-body FDG-PET can have a clear impact on the therapeutic management in the follow-up of patients with colorectal cancer.

Abdominal Neoplasms↗

PubMed2001

[Crystalline molecular complexes generated between surfactants and various additive compounds: an attempt to modify sparingly water soluble drugs to easily water soluble drugs].

It has been established that ionic surfactants, whether cationic or anionic, provide crystalline molecular complexes stably with various aromatic compounds as additives. Among various additives phenolic compounds are especially favorable for both surfactant species. Other than these additives, cationic surfactants easily provide crystalline molecular complexes with basic materials and even with non-polar substances such as biphenyl and phenanthrene. The isolated surfactant molecular complexes were analyzed by X-ray. To date the number of the obtained surfactant molecular complexes exceeds two hundred species or more and thirty or more of them were structurally analyzed. These surfactant molecular complexes were shown to be novel surfactant species different from their mother species, supplied with enhanced solubility to the complex additives. We applied these characteristics to sparingly water soluble drugs as the complex additive to modify them into easily water soluble drugs. The obtained complex drugs revealed an improved behavior in solubility and dissolution rate compared with pure drugs.

Crystallization↗

PubMed1994

Enhancement by ascorbic acid 2-glucoside or repeated additions of ascorbate of mitogen-induced IgM and IgG productions by human peripheral blood lymphocytes.

In this study, the effect of ascorbic acid 2-glucoside (AA-2G), a stable derivative of ascorbic acid (AsA), or repeated additions of ascorbate on antibody productions by human peripheral blood lymphocytes (PBLs) was examined, and the physiological function of AsA was evaluated. When human PBLs were stimulated with Staphylococcus aureus Cowan I or pokeweed mitogen, AA-2G remarkably increased the numbers of IgM- and IgG-secreting cells which were detected by enzyme-linked immunospot assay. Although a single addition of ascorbate was without effect, the effect of AA-2G was remarkably inhibited by the addition of castanospermine, an alpha-glucosidase inhibitor; and moreover, repeated additions of AsA to the culture medium during the culture period enhanced the response to the same level as did a single addition of AA-2G. These results indicate that AsA has the ability to stimulate the immunoglobulin productions by AA-2G. The phytohemagglutinin-induced proliferative response of PBLs was also stimulated by AA-2G. The intracellular AsA content in PBLs cultured with AA-2G was maintained at relatively high levels during the culture period, whereas the content with a single dose of AsA reached nearly zero by the end of the experiment. These in vitro findings suggest that AA-2G and AsA function as potent immunostimulators of antibody production in humans and that the intracellular AsA content is a key parameter for establishing the immune response of PBLs.

Antibody Formation↗

PubMed1998

Does additional lubrication affect condom slippage and breakage?

The risk of condom slippage (1.94%) and breakage (0.89%) among 3607 condoms was analysed with respect to the use of additional lubricant. Whether or not lubricant was used, the site at which it was applied and the type of lubricant used were all found to vary significantly with the type of sexual act(s) for which the condoms were used. Little evidence was found for differing effects of type of additional lubricant (water-based, saliva or other) or site of lubricant use (on penis/inside condom, on condom, in vagina/anus). The use of lubricant more than doubles the risk of slippage for vaginal sex. While anal sex is associated with much higher risks of slippage the use of lubricant for this practice actually reduces the risk of slippage to that similar for vaginal sex where lubricant is used. No significant effect of additional lubricant on condom breakage was observed. It is recommended that education messages concerning the use of additional lubricant may need to change to take into account the varied nature of lubricant use practices and the differential effects of lubricant with respect to sexual practices. Specifically, if the use of additional lubricant has little or no impact on condom breakage but increases condom slippage then encouraging its use may be counterproductive if condom users consider slippage to be a reason not to use condoms.

Adult↗

PubMed1986

Small, brief foveal stimuli: an additivity experiment.

In an additivity experiment, increment thresholds were determined for 510 and 660 nm and for 470 and 570 nm. These thresholds were determined for each wavelength separately and for the wavelengths of each pair mixed. These measurements were made against a 1000-Td white background using fields subtending 0.16 degrees and 1.04 degrees visual angles and at 10- and 200-msec durations. For most conditions with the 510- and 660-nm pair, additivity of the reduction type was obtained. Generally, the larger field and longer duration produced larger additivity failures than the smaller field and shorter duration. For the 470- and 570-nm pair, two of the three observers showed additivity for the 0.16 degrees field in both the long- and the short-duration conditions. The larger field with longer durations yielded additivity failure for the three observers, but these failures were smaller than for the 510- and 660-nm pair.

Adult↗

PubMed1990

Additivity of spatially induced blackness.

Tests of additivity of the postreceptoral pathways that mediate the perception of blackness were conducted under conditions of spatial contrast. Observers increased the radiance of a surrounding annulus until a broadband (white) test center appeared completely black. Additivity tests with heterochromatic flicker photometry (HFP) and direct brightness matching were also conducted for each observer. The results indicated that the luminance level of the annulus required to induce blackness did not change with variations in spectral composition. Results consistent with additivity were also obtained for HFP, but the results from brightness matching were not consistent with additivity. The data support the view that the perception of blackness is mediated by neural mechanisms that additively combine the input of middle- and long-wave photoreceptors.

Adult↗

PubMed1998

Sex differences and non-additivity in the effects of genes on personality.

New large-sample data show that non-additive genetic effects, probably epistatic interactions between loci, and sex-limited gene expression are significant features of the genetic architecture of human personality as measured by questionnaire scales of extraversion and neuroticism. Three large data sets--new data on large samples (n = 20,554) of US twins, their spouses, parents, siblings and children, correlations for Australian twins (n = 7,532), and previously published twin data from Finland (n = 14,288)--are subjected to an integrated analysis to test alternative hypotheses about the genetic causes of family resemblance in personality. When allowance is made for differences in reliability of the scales, the combined data are consistent with the same model for variation. There are significant amounts of genetic non-additivity for both dimensions of personality. The evidence favours additive x additive epistatic interactions rather than dominance. In the case of neuroticism, there is especially strong evidence of sex differences in genetic architecture favouring a greater relative contribution of non-additive genetic effects in males. The data confirm previous claims to find no major contribution of the shared environment of twins and siblings to these dimensions of personality. Correlations between spouses are zero, and the correlations for very large samples of siblings and non-identical twins do not differ significantly.

Diseases in Twins↗

PubMed2001

Selection of stabilizing additive for lipase immobilization on controlled pore silica by factorial design.

Candida rugosa lipase was covalently immobilized on silanized controlled pore silica (CPS) previously activated with glutaraldehyde in the presence of several additives to improve the performance of the immobilized form in long-term operation. Proteins (albumin and lecithin) and organic molecules (beta-cyclodextrin and polyethylene glycol [PEG]-1500) were added during the immobilization procedure, and their effects are reported and compared to the behavior of the immobilized biocatalyst in the absence (lacking) of additive. The selection of the most efficient additive at different lipase loadings (150-450 U/g of dry support) was performed by experimental design. Two 22 full factorial designs with two repetitions at the center point were employed to evaluate the immobilization yield. A better stabilizing effect was found when small amounts of albumin or PEG-1500 were added simultaneously to the lipase onto the support. The catalytic activity had a maximum (193 U/mg) for lipase loading of 150 U/g of dry support using PEG-1500 as the stabilizing additive. This immobilized system was used to perform esterification reactions under repeated batch cycles (for the synthesis of butyl butyrate as a model). The half-life of the lipase immobilized on CPS in the presence of PEG-1500 was found to increase fivefold compared with the control (immobilized lipase on CPS without additive).

Albumins↗

PubMed2004

Rational design of solution additives for the prevention of protein aggregation.

We have developed a statistical-mechanical model of the effect of solution additives on protein association reactions. This model incorporates solvent radial distribution functions obtained from all-atom molecular dynamics simulations of particular proteins into simple models of protein interactions. In this way, the effects of additives can be computed along the entire association/dissociation reaction coordinate. We used the model to test our hypothesis that a class of large solution additives, which we term "neutral crowders," can slow protein association and dissociation by being preferentially excluded from protein-protein encounter complexes, in a manner analogous to osmotic stress. The magnitude of this proposed "gap effect" was probed for two simple model systems: the association of two spheres and the association of two planes. Our results suggest that for a protein of 20 A radius, an 8 A additive can increase the free energy barrier for association and dissociation by as much as 3-6 kcal/mol. Because the proposed gap effect is present only for reactions involving multiple molecules, it can be exploited to develop novel additives that affect protein association reactions although having little or no effect on unimolecular reactions such as protein folding. This idea has many potential applications in areas such as the stabilization of proteins against aggregation during folding and in pharmaceutical formulations.

Biophysical Phenomena↗

PubMed2005

Transcriptome analysis and physical mapping of barley genes in wheat-barley chromosome addition lines.

Wheat-barley chromosome addition lines are useful genetic resources for a variety of studies. In this study, transcript accumulation patterns in Betzes barley, Chinese Spring wheat, and Chinese Spring-Betzes chromosome addition lines were examined with the Barley1 Affymetrix GeneChip probe array. Of the 4014 transcripts detected in Betzes but not in Chinese Spring, 365, 271, 265, 323, 194, and 369 were detected in wheat-barley disomic chromosome addition lines 2(2H), 3(3H), 4(4H), 7(5H), 6(6H), and 1(7H), respectively. Thus, 1787 barley transcripts were detected in a wheat genetic background and, by virtue of the addition line in which they were detected, were physically mapped to barley chromosomes. We validated and extended our approach to physically map barley genes to the long and short arms of chromosome 6(6H). Our physical map data exhibited a high level of synteny with homologous sequences on the wheat and/or rice syntenous chromosomes, indicating that our barley physical maps are robust. Our results show that barley transcript detection in wheat-barley chromosome addition lines is an efficient approach for large-scale physical mapping of genes.

Chromosomes, Plant↗