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PubMed2004

From toxin to adjuvant: the rational design of a vaccine adjuvant vector, CTA1-DD/ISCOM.

Mucosally active vaccine adjuvants which will prime a full range of local and systemic immune responses against defined antigenic epitopes are much needed. Cholera toxin (CT) and lipophilic immune stimulating complexes (ISCOMs) containing Quil A can both act as adjuvants for orally administered antigens, but through separate pathways, as evidenced by the dependence on IL-12 for the effect of ISCOMs, whereas CT is independent of this cytokine. Unfortunately the toxicity of CT and recent findings of accumulation of CT in the olfactory nerve and bulb after intranasal administration precludes the clinical use of CT. However, we have been successful in separating the adjuvant and toxic effects of CT, by constructing a gene fusion protein, CTA1-DD, that combines the enzymatically active CTA1-subunit with a B cell targeting moiety, D, derived from Staphylococcus aureus protein A. The present review gives a background to mucosal immunization and the use of -adjuvants in general, followed by a description of a strategy to rationally design a vaccine adjuvant vector that fulfils the criteria of targeting and immunomodulating innate immunity in order to boost a strong adaptive immune response. We have combined CTA1-DD and ISCOMs into a new highly promising vaccine adjuvant vector, CTA1-DD/ISCOMs. The combined vector is immunogenic when given by the subcutaneous, oral or nasal routes, inducing strong cell--mediated and humoral immune responses, including local mucosal IgA. It requires the ADP ribosylating property of the CTA1-enzyme and the effect of the combined vector greatly exceeded the effect of either ISCOMs or CT used alone. Antigens could be incorporated into or just admixed with the new vector. Thus, we have demonstrated that rationally designed vectors consisting of CTA1-DD and ISCOMS may provide a novel strategy for the generation of potent and safe mucosal vaccines.

Adjuvants, Immunologic↗
PubMed2000

[Proposals for a rationale and for rational diagnosis of coughs].

Cough is probably the most frequent symptom in chest diseases. Hence, a rational and economical diagnostic procedure is essential to prevent unnecessary costs to the health services, i.e. acute bronchitis, a self-limiting disease, which is the most frequent cause for cough should not involve extensive per case costs. History, physical examination, chest X-ray and lung function testing--which constitute both the first and second, i.e. the basic level of a stepwise approach--allows to diagnose causes in most patients with cough. Without evidence of the cause after completing this basic diagnostic procedure patients with acute cough may require blood gases analysis, electrocardiography, echocardiography, lung perfusion study, spiral CT angiography, bronchoscopy or laboratory examinations for diagnosis of pulmonary embolism, aspiration or (seldom) pleuritis sicca. Chronic persistent cough (CPC) is diagnosed if the basic standard approach to chronic cough fails to lead to final diagnosis. Patients will then need further subtle diagnostic management, i.e. bronchial provocation testing, 24 hour pH probe, ENT- or neurological examination, high resolution CT of the thorax and bronchoscopy. We present two algorithms for the rational diagnostic approach to acute (figure 1) and chronic (figure 2) cough. Each algorithm considers spectrum and frequency of causes on the one hand, the positive predictive value, costs and patient discomfort due to the examination on the other. Nonetheless, despite extensive examination up to 20% of patients suffering from CPC the cause remains unclear [11]. Frequently, the capsaicin cough challenge test can reveal an idiopathic upregulation of the cough reflex as the hypothesised underlying condition. Psychogenic cough however, a rare condition in adults should not coincide with hypersensitivity of the cough reflex. Inconsistency and low reproducibility of results of the capsaicin challenge in patients with psychogenic cough preclude his routine clinical use. In conclusion, the very common acute bronchitis and the ACE inhibitor-induced cough do not require any other diagnostic procedure except patient history and physical examination. A simple basic diagnostic approach will usually allow to evaluate acute and chronic cough. In the remaining cases the proposed algorithm should be used for best results and to prevent excessive costs.

Acute Disease↗
PubMed1998

[Anticonvulsant combination therapy: rational concepts versus real effectiveness].

Primary drug treatment of epilepsies is usually a monotherapy with an antiepileptic drug. This procedure causes less side effects as polytherapy and probably shows the same efficacy. Two third of patients with focal epilepsies are sufficiently treated with a single antiepileptic drug: 60% of patients with Grand mal and 22-30% of patients with complex focal seizures remain seizures free. An alternative monotherapy will suppress seizures in another 30% of patients. With polytherapy this is achieved in only 12% of the remaining patients, furthermore, side effects increase in polytherapy. Generalized epilepsies are usually treated with valproate monotherapy. Patients remain seizure free from absence in 60-90%, from myoclonic-impulsive seizures in 75-97% and from Grand mal in about 85%. Alternative monotherapy is less common because of the limited efficacy and possible side effects of drugs: ethosuximide does not control Grand mal and phenobarbitone may cause sedation. Thus, polytherapy is commonly initiated when monotherapy fails to control seizures (lamotrigine is often chosen as comedication). Rational polypharmacy is a term suggesting rational concepts in planning antiepileptic polytherapy leading to a superior anticonvulsant effect. However, this consideration is not based on or supported by clinical data. Yet, a combination of drugs which have no or little pharmacokinetic interactions seems to be a clinically relevant recommendation. Thus, newly developed drugs such as vigabatrin, lamotrigine or gabapentin are more frequently used as comedication with standard antiepileptic drugs.

Anticonvulsants↗
PubMed1998

Rational diagnosis of pulmonary embolism (RADIA PE) in symptomatic outpatients with suspected PE: an improved strategy to exclude or diagnose venous thromboembolism by the sequential use of a clinical model, rapid ELISA D-dimer test, perfusion lung scan, ultrasonography, spiral CT, and pulmonary angiography.

A prospective management decision analysis for the exclusion and diagnosis of pulmonary embolism (PE) based on pre-test clinical probability (PCP) estimation for PE, a rapid ELISA D-dimer test, perfusion lungscan (P-scan), CUS, spiral CT, and pulmonary angiography is proposed. The modified PCP model for PE of Wells et al. allows reasonably accurate classification of patients with no, low, moderate, and high probability for PE. The combined rational use of the evidence-based noninvasive imaging techniques P-scan, CUS, and spiral CT with the rapid ELISA D-dimer test and PCP will reduce the need for invasive pulmonary angiography to perhaps 10 to 15% of patients, who initially presented with suspected PE. A Rational Diagnosis of Pulmonary Embolism (RADIA PE) model is proposed for testing in a large multicenter study of patients with suspected PE.

Ambulatory Care↗
PubMed1989

Rational uses of hepatic imaging modalities.

Hepatic imaging studies have been a tremendous benefit in the care of patients with liver diseases. However, uncertainty regarding the rational use of these studies, as with other diagnostic studies, generally promotes overuse. Some principles emerge from the information reviewed here. Generally, duplicative studies with similar test characteristics add little to the diagnostic process, and oftentimes confuse it. Costs are difficult to calculate and usually do not enter into the selection process. The result of each test must be interpreted in light of the clinical process that prompted its use, and when it will not change the diagnostic or therapeutic approach regardless of the result, the test is probably not indicated. Finally, rational use of the studies depends on an understanding of the information that they can and cannot provide.

Diagnostic Imaging↗
PubMed2006

A rationally designed agonist antibody fragment that functionally mimics thrombopoietin.

By using rational design, antibody fragments (Fabs) that mimic thrombopoietin (TPO) were created. A peptide with cMpl receptor-binding capability was grafted into different complementarity-determining regions of a fully human Fab scaffold. Functional presentation of the peptide was optimized by using phage display and cell-based panning. Select antibodies and fragments containing two grafted peptides were assayed for their ability to stimulate the cMpl receptor in vitro. Several candidates demonstrated agonist activity in an in vitro cMpl receptor signaling reporter assay, including Fab59, which was estimated to be equipotent to TPO. Fab59 additionally was able to effectively stimulate platelet production in normal mice. These rationally designed mimetic Fabs may provide a therapeutic intervention for thrombocytopenia while avoiding the potential generation of neutralizing antibodies to endogenous TPO. Furthermore, this study demonstrates a method by which short-lived linear peptides with binding activity may be converted to more stable and potent agonists capable of activating cell surface receptors.

Animals↗
PubMed1997

The rational design and construction of a cuboidal iron-sulfur protein.

Rational protein design is an emerging approach for testing general theories of protein chemistry through the creation of new structures and functions. Here we present the first successful introduction by rational design of a [Fe4S4] cuboidal cluster into the hydrophobic core of Escherichia coli thioredoxin, a protein normally devoid of metal centers. Cuboidal [Fe4S4] is one of the stable forms of self-assembled iron-sulfur clusters that are thought to represent some of the earliest evolved biological redox centers. [Fe4S4] clusters have been recruited for use in a variety of proteins whose functions are central to many of the major biochemical processes ranging from simple soluble electron-transfer agents, to membrane-bound components of electron-transfer chains, to electron reservoirs in complex metalloenzymes such as nitrogenase. By situating an [Fe4S4] cluster into a protein environment not previously adapted by evolution we can explore the factors by which their activity is modulated by the protein matrix.

Algorithms↗
PubMed1997

The rational design of allosteric interactions in a monomeric protein and its applications to the construction of biosensors.

Rational protein design is an emerging approach for testing general theories of structure and function. The ability to manipulate function rationally also offers the possibility of creating new proteins of biotechnological value. Here we use the design approach to test the current understanding of the structural principles of allosteric interactions in proteins and demonstrate how a simple allosteric system can form the basis for the construction of a generic biosensor molecular engineering system. We have identified regions in Escherichia coli maltose-binding protein that are predicted to be allosterically linked to its maltose-binding site. Environmentally sensitive fluorophores were covalently attached to unique thiols introduced by cysteine mutations at specific sites within these regions. The fluorescence of such conjugates changes cooperatively with respect to maltose binding, as predicted. Spatial separation of the binding site and reporter groups allows the intrinsic properties of each to be manipulated independently. Provided allosteric linkage is maintained, ligand binding can therefore be altered without affecting transduction of the binding event by fluorescence. To demonstrate applicability to biosensor technology, we have introduced a series of point mutations in the maltose-binding site that lower the affinity of the protein for its ligand. These mutant proteins have been combined in a composite biosensor capable of measuring substrate concentration within 5% accuracy over a concentration range spanning five orders of magnitude.

ATP-Binding Cassette Transporters↗
PubMed2000

Rational discovery of novel nuclear hormone receptor antagonists.

Nuclear hormone receptors (NRs) are potential targets for therapeutic approaches to many clinical conditions, including cancer, diabetes, and neurological diseases. The crystal structure of the ligand binding domain of agonist-bound NRs enables the design of compounds with agonist activity. However, with the exception of the human estrogen receptor-alpha, the lack of antagonist-bound "inactive" receptor structures hinders the rational design of receptor antagonists. In this study, we present a strategy for designing such antagonists. We constructed a model of the inactive conformation of human retinoic acid receptor-alpha by using information derived from antagonist-bound estrogen receptor-alpha and applied a computer-based virtual screening algorithm to identify retinoic acid receptor antagonists. Thus, the currently available crystal structures of NRs may be used for the rational design of antagonists, which could lead to the development of novel drugs for a variety of diseases.

Algorithms↗
PubMed2005

Rational design of p53, an intrinsically unstructured protein, for the fabrication of novel molecular sensors.

The dominant paradigm of protein engineering is structure-based site-directed mutagenesis. This rational approach is generally more effective for the engineering of local properties, such as substrate specificity, than global ones such as allostery. Previous workers have modified normally unregulated reporter enzymes, including beta-galactosidase, alkaline phosphatase, and beta-lactamase, so that the engineered versions are activated (up to 4-fold) by monoclonal antibodies. A reporter that could easily be "reprogrammed" for the facile detection of novel effectors (binding or modifying activities) would be useful in high throughput screens for directed evolution or drug discovery. Here we describe a straightforward and general solution to this potentially difficult design problem. The transcription factor p53 is normally regulated by a variety of post-translational modifications. The insertion of peptides into intrinsically unstructured domains of p53 generated variants that were activated up to 100-fold by novel effectors (proteases or antibodies). An engineered p53 was incorporated into an existing high throughput screen for the detection of human immunodeficiency virus protease, an arbitrarily chosen novel effector. These results suggest that the molecular recognition properties of intrinsically unstructured proteins are relatively easy to engineer and that the absence of crystal structures should not deter the rational engineering of this class of proteins.

Alkaline Phosphatase↗
PubMed2005

Rational design of intercellular adhesion molecule-1 (ICAM-1) variants for antagonizing integrin lymphocyte function-associated antigen-1-dependent adhesion.

The interaction between integrin lymphocyte function-associated antigen-1 (LFA-1) and its ligand intercellular adhesion molecule-1 (ICAM-1) is critical in immunological and inflammatory reactions but, like other adhesive interactions, is of low affinity. Here, multiple rational design methods were used to engineer ICAM-1 mutants with enhanced affinity for LFA-1. Five amino acid substitutions 1) enhance the hydrophobicity and packing of residues surrounding Glu-34 of ICAM-1, which coordinates to a Mg2+ in the LFA-1 I domain, and 2) alter associations at the edges of the binding interface. The affinity of the most improved ICAM-1 mutant for intermediate- and high-affinity LFA-1 I domains was increased by 19-fold and 22-fold, respectively, relative to wild type. Moreover, potency was similarly enhanced for inhibition of LFA-1-dependent ligand binding and cell adhesion. Thus, rational design can be used to engineer novel adhesion molecules with high monomeric affinity; furthermore, the ICAM-1 mutant holds promise for targeting LFA-1-ICAM-1 interaction for biological studies and therapeutic purposes.

Cell Adhesion↗
PubMed1981

Effect of monensin on the fermentation of basal rations in the Rumen Simulation Technique (Rusitec).

1. A long-term experiment was made with the Rumen Simulation Technique (Rusitec), in which the fermentation of a mixed ration of hay (10 g/d) and bruised barley (5 g/d) was compared with the fermentation of the same diet in the presence of 2, 10 and 50 mg monensin/d. 2. Monensin depressed the production of acetic and butyric acids, markedly increased the production of propionic acid and virtually, eliminated the production of isovaleric acid. The production of methane was decreased in the presence of monensin, but this decrease could be accounted for entirely by the changes in the production of volatile fatty acids and redistribution of metabolic hydrogen. 3. The digestibility of dry matter (DM) in the rations declined in the presence of monensin. Determinations of the rates of digestion showed that the digestion of the readily-fermented food in the initial stages was not affected by monensin, but that at 24 h digestion had been inhibited by monensin. The inhibition was due entirely to its effect on the digestion of the fibrous components. Digestion of non-fibrous material was not affected. 4. The efficiency of microbial growth, expressed as g dry weight/mol ATP formed (YATP) and in terms of DM digested, tended to be increased by monensin. This however occurred only at high, non-practical doses. 5. Urease (EC 3. 5. 1. 5) was induced by the addition of urea of the fermentation, but monensin had no effect on urease activity. Although monensin increased the activity of protease in washed suspensions, more food protein apparently escaped degradation. This may have been due to decreased deaminative activity. 6. Monensin altered the microscopic appearance of the fermentation fluid, and changed the activity of some enzymes in sonicated extracts, including alkaline phosphatase (EC 3. 1. 3. 1), acetate kinase (EC 2. 7. 2. 1) and succinate dehydrogenase (EC 1. 3. 99. 1). These results are discussed in terms of known sensitivities of rumen microbes to monensin and their contribution to the fermentation as a whole.

Animal Feed↗
PubMed1997

Comparison of n-3 fatty acid sources in laying hen rations for improvement of whole egg nutritional quality: a review.

The nutritional manipulation of the diets of laying hens to include sources of n-3 fatty acids promotes the deposition of these nutrients into egg yolk, n-3 Fatty acid-rich eggs may provide an exciting alternative food source for enhancing consumer intake of these proposed healthful fatty acids. Care must be taken when designing n-3 fatty acid-rich poultry rations, however, to assure that the resulting egg fatty acid profile is useful for promoting consumer health yet maintaining egg sensory quality. In study 1 laying hens were fed on diets supplemented with graded levels of menhaden oil (MO), rich in both eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3), for 4 weeks to determine maximal yolk fatty acid deposition attainable without sensory compromise. Yolk fatty acids were analysed for an additional 4 weeks, post-MO removal, to investigate yolk n-3 fatty acid tenacity. Dietary MO levels between 15 and 30 g/kg yielded the greatest yolk n-3 fatty acid content; however, only eggs from birds fed with 15 g MO/kg were considered acceptable by trained flavour panelists. Evaluation of eggs from hens fed with 15 g MO/ kg during storage verified that the shelf-life of enriched eggs was comparable with that of typical eggs. In study 2, graded levels of whole or ground flaxseed were used for the deposition of linolenic acid (LNA; 18:3n-3) and to determine in vivo production of DHA from dietary LNA for yolk deposition. Flaxseed form influenced yolk n-3 fatty acids only when given at 150 g/kg diet. In vivo production of DHA, while significant, was not enhanced by increasing the level of dietary flaxseed nor by grinding the seed. In the third study, a DHA-rich natural marine alga (MA) was investigated as an n-3 fatty acid supplement. Despite similar DHA profiles, dietary MA was found to be more efficient for yolk DHA deposition than dietary MO. These studies suggest that there are numerous viable n-3 fatty acid supplements for poultry rations. It must be realized, however, that the fatty acid profile of the final product varies substantially depending on which supplement is fed.

Animal Feed↗
PubMed2006

High-fibre pelleted rations decrease water intake but do not improve physiological indexes of welfare in food-restricted female broiler breeders.

1. A 3x2 factorial experiment was conducted with three diets and two lines of broiler breeder females to evaluate the contribution of low-energy rations for improving the welfare of feed-restricted birds during rearing. Experimental diets were fed from 6 to 16 weeks of age and were created by diluting a conventional grower (Control) ration containing 11.0 MJ ME/kg with 200 (8.8 MJ ME/kg) or 400 (6.6 MJ ME/kg) g oat hulls/kg using Optimoist to facilitate the pelleting process. Welfare was assessed by changes in behaviour and physiological variables at 8, 12 and 16 weeks of age. Birds were fed restricted quantities of feed to meet recommended body weight targets. 2. There was a decrease in the proportion of observations of drinking and an increase of preening in birds fed on the two experimental diets compared with the control. There was a linear decrease in litter moisture and the number of litter changes with increasing diet dilution, and water intake at 12 weeks was higher in the control than in the two experimental diets. There were no changes in physiological indexes of welfare (heterophil-lymphocyte ratio, plasma corticosterone and antibody responses) associated with the dietary treatments. 3. There were no important differences in the growth, behaviour or physiological responses to dietary treatment between the two lines of broiler breeders. Changes with age were similar to those reported in other experiments. 4. It was concluded that low-energy pelleted diets would improve litter conditions but not improve indexes of welfare in feed-restricted broiler breeders.

Animal Feed↗
PubMed2003

Aflatoxin residues in eggs of laying Japanese quail after long-term administration of rations containing low levels of aflatoxin B1.

The aim was to evaluate the excretion of residues of aflatoxin B(1) (AFB(1)), aflatoxin M(1) (AFM(1)), aflatoxin B(2a) (AFB(2a)) and aflatoxicol (AFL) in eggs of laying Japanese quail fed rations with low levels of aflatoxin B(1) for 90 days. The quail were randomly assigned into four experimental groups and given prepared rations containing either 0 (controls), 25, 50 or 100 microg AFB(1) kg(-1) feed. Thirty-two eggs per treatment were collected on days 1-7, 10, 20, 30, 60 and 90 of the aflatoxin treatment period, and submitted to aflatoxin analysis by high-performance liquid chromatography. Average egg production and feed consumption were not affected ( p > 0.05) by AFB(1). Egg weight was significantly lower ( p<0.05) only for groups exposed to 100 microg AFB(1) kg(-1). Residues of aflatoxins were detected in eggs at levels that ranged from 0.01 to 0.08 microg kg(-1) (AFB(1)), 0.03-0.37 microg kg(-1) (AFM(1)), 0.01-1.03 microg kg(-1)(AFB(2a)) and 0.01-0.03 microg kg(-1) (AFL). Results indicate that the excretion of aflatoxin residues in quail eggs might occur at relatively low concentrations under conditions of long-term exposure of quail to low levels of AFB(1).

Aflatoxin B1↗
PubMedDate not supplied

Rational suicide reconsidered: AIDS as an impetus for change.

At the present time, there does not appear to be an acceptable alternative to intervening to prevent the suicide of persons who display suicidal ideation. This absolutist and, at times, paternalistic view may change, however, as a result of professionals' contact with persons with AIDS. The growing number of persons with AIDS and the incidence of suicide within this population make it increasingly likely that individuals in a number of professions that subscribe to the policy of mandatory suicide intervention will have contact with a suicidal person with AIDS. Given the life circumstances and implications associated with a diagnosis of AIDS, there is the possibility that some of these suicidal persons with AIDS may have made what could be considered to be a rational decision to end their own lives. By taking into account the circumstances that precipitated the suicidal ideation and allowing some individuals to follow through with their plans, professionals will be empowering and returning autonomy to these individuals. Thus, by forcing professionals to think about and deal with the issue of rational suicide, AIDS may provide an impetus to change the traditional absolutist approach of suicide intervention and prevention into a contextual approach in which the intensity of suicide intervention required is viewed as varying along a continuum.

Acquired Immunodeficiency Syndrome↗
PubMed2003

Canned rice products as Philippine military food ration.

Canned prototypes of rice (CR) and rice meal with pork sausage (CRM) were developed as military food ration models for evaluation by personnel in the Bonifacio Naval Station, Fort Bonifacio, Makati, Philippines. The prototypes were produced based on the assumption that a serving size equivalent to 400 g cooked rice and a meat-based viand using a 1:4 (wt/wt) viand to rice ratio was adequate as a single-serve meal for a typical Philippine military personnel. The CR and CRM prototypes were low acid products with pH values of 4.9 and 5.5, respectively. The processed rice portions of the prototypes showed about 200% volume and weight increases, moderate clumpiness and low percentage breakage. More than 90% of the respondents agreed that CR and CRM were suitable military food rations. Majority of the panelists indicated preference for meat-based and poultry-based viands. Bulk and weight portativity problems, however, were raised with the 400 g serving size of cooked products in cans.

Adult↗
PubMed2003

Virtual screening and rational drug design method using structure generation system based on 3D-QSAR and docking.

An efficient virtual and rational drug design method is presented. It combines virtual bioactive compound generation with 3D-QSAR model and docking. Using this method, it is possible to generate a lot of highly diverse molecules and find virtual active lead compounds. The method was validated by the study of a set of anti-tumor drugs. With the constraints of pharmacophore obtained by DISCO implemented in SYBYL 6.8, 97 virtual bioactive compounds were generated, and their anti-tumor activities were predicted by CoMFA. Eight structures with high activity were selected and screened by the 3D-QSAR model. The most active generated structure was further investigated by modifying its structure in order to increase the activity. A comparative docking study with telomeric receptor was carried out, and the results showed that the generated structures could form more stable complexes with receptor than the reference compound selected from experimental data. This investigation showed that the proposed method was a feasible way for rational drug design with high screening efficiency.

Colchicine↗