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PubMed2000

Rational treatment of empyema in children.

HYPOTHESIS: Efficacious and cost-effective treatment of pediatric empyema can be accomplished following a protocol based on its radiographic appearance. Therapeutic modalities include thoracostomy tube drainage (TTD) with or without fibrinolytic therapy (FT) and video-assisted thoracoscopic debridement (VATD). DESIGN: Retrospective case series. SETTING: Tertiary referral center. RESULTS: From 1995 through 1999, 31 children were treated ranging in age from 11 months to 18 years (mean age, 5.1 years). Twenty-seven (87.1%) underwent TTD; of these, 22 (81.5%) received FT with urokinase. The TTD failed in 4 children (14.8%) who required salvage VATD. Primary VATD was performed in another 4 children (12.9%). The mean length of stay was 14.6 days (TTD, 14.1 days; salvage VATD, 20. 0 days; primary VATD, 11.5 days), ranging from 8.0 to 30.0 days. Complications included readmission for fever (2 patients [6.5%]) and gastrointestinal bleeding (1 patient [3.2%]). There were no anaphylactic reactions or bleeding episodes due to urokinase. Two patients (7.4%) treated with TTD and FT developed an air leak that resolved spontaneously. The mean hospital charges were $78,832 (TTD with or without FT, $75,450; salvage VATD, $107,476; primary VATD, $69,634). The procedural charges were highest for salvage VATD. CONCLUSIONS: Most cases of pediatric empyema can be treated by TTD with or without FT. This therapy is safe and effective for children with nascent disease. Primary VATD is preferred in children with advanced disease. Cost-effectiveness could be further improved through better prediction of those patients likely to fail TTD and require salvage VATD. An algorithmic approach based on findings from computed tomography or (better) ultrasonography of the chest may be the best way to make this distinction and rationalize care.

Adolescent↗
PubMed2003

A rational approach to cholelithiasis in bariatric surgery: its application to the laparoscopically placed adjustable gastric band.

BACKGROUND: Gallstones are more common in the obese population and may be formed during rapid weight loss. A rational approach to the management of the gallbladder should be incorporated into bariatric surgical practice. It has been recommended that patients undergoing Roux-en-Y gastric bypass have routine cholecystectomy regardless of gallstone status. We analyzed the outcomes of a noninterventionist policy on 1000 patients undergoing laparoscopic adjustable gastric banding. HYPOTHESIS: Patients scheduled for adjustable gastric banding should undergo investigation for and treatment of gallbladder disease regardless of symptoms. METHODS: Patients were screened preoperatively for symptoms of gallstones. Ultrasound examination was performed only in those with symptoms and, if stones were present, cholecystectomy was performed with gastric banding. The remaining patients were followed up clinically and outcomes were noted. RESULTS: A total of 1000 patients were followed up for 12 to 96 months, a total of approximately 3500 patient-years. Cholecystectomy was performed in 181 patients before and 10 at gastric banding surgery. Of the 809 patients at risk, 55 (6.8%) presented with symptomatic disease during follow-up and proceeded to undergo elective cholecystectomy without complications from the disease or the treatment. CONCLUSIONS: The incidence of cholecystectomy after gastric banding surgery was not different from the expected rate for a nonsurgical obese population. In contrast, after Roux-en-Y gastric bypass, a median of 40% of patients form stones in the postoperative period, and prophylactic cholecystectomy may be justified. Our data indicate that a noninterventionist approach to the gallbladder is appropriate for patients undergoing adjustable gastric banding surgery.

Anastomosis, Roux-en-Y↗
PubMed1999

Variability in quaternary association of proteins with the same tertiary fold: a case study and rationalization involving legume lectins.

Legume lectins constitute a family of proteins in which small alterations arising from sequence variations in essentially the same tertiary structure lead to large changes in quaternary association. All of them are dimers or tetramers made up of dimers. Dimerization involves side-by-side or back-to-back association of the flat six-membered beta-sheets in the protomers. Variations within these modes of dimerization can be satisfactorily described in terms of angles defining the mutual disposition of the two subunits. In all tetrameric lectins, except peanut lectin, oligomerization involves the back-to-back association of side-by-side dimers. An attempt has been made to rationalize the observed modes of oligomerization in terms of hydrophobic surface area buried on association, interaction energy and shape complementarity, by constructing energy minimised models in each of which the subunit of one legume lectin is fitted in the quaternary structure of another. The results indicate that all the three indices favor and, thus, provide a rationale for the observed arrangements. However, the discrimination provided by buried hydrophobic surface area is marginal in a few instances. The same is true, to a lesser extent, about that provided by shape complementarity. The relative values of interaction energy turns out to be a still better discriminator than the other two indices. Variability in the quaternary association of homologous proteins is a widely observed phenomenon and the present study is relevant to the general problem of protein folding.

Biopolymers↗
PubMedDate not supplied

Rational optimization of a HIV-1 Tat inhibitor: rapid progress on combinatorial lead structures.

Lead molecules identified by combinatorial chemistry approaches are preferred starting points for straightforward improvements of compound profiles. Structure-guided rationales can be supported and complemented by systematic variations based on the modular nature of the molecules. A peptoidic compound (CGP 64222), previously identified from a sequential unrandomization process, was shown to specifically inhibit the interaction between the HIV-1 trans-activator Tat and its RNA response element TAR. To improve the compound's pharmaceutical attractiveness an approach to reduce both, size and number of charges was pursued. Because this resulted in activity decrease, parallel synthesis with variations on one rationally defined position aimed at the identification of structural determinants was undertaken to regain in vitro activity in biochemical and cellular Tat-TAR interaction assays. As a result CGP74026 was identified, a drastically simplified but highly active Tat antagonist, which is able to block HIV-1 replication even in primary human cells.

Acridines↗
PubMed1999

Financial efficacy of clinical assessment: rational guidelines and issues for future research.

Whereas the financial efficacy of assessment has been well documented in industrial/organizational settings, there is no comparable literature within the field of clinical assessment. This has become a significant issue due to the increasing cost-consciousness of managed health care organizations. A rational means of increasing the financial efficacy of assessment is outlined, which includes the following: (a) focus on domains most relevant to treatment planning and outcome; (b) use formal assessment for risk management; (c) target problems most likely to result in cost savings (i.e., dissociation, somatization, panic); (d) increase the use of computer-assisted assessment; (e) use time-efficient instruments; (f) more closely link assessment, feedback, and therapy; and (g) integrate treatment planning, monitoring progress, and evaluating outcome. Issues and strategies for developing a research program include clearly defining what should be considered a cost, enumerating possible outcome variables, optimal follow-up time frame, selection of instruments, and the function of assessment.

Cost-Benefit Analysis↗
PubMed1998

A holographic sensor based on a rationally designed synthetic polymer.

A new silver halide-containing holographic recording material has been designed and developed specifically for holographic chemical sensors. The hologram enables very small volume changes to be measured in a polymer layer throughout which the hologram is located. The holographic film is based on a fine-grain silver bromide emulsion suspended in a poly(vinyl alcohol) matrix crosslinked with Cr(III) ions. Cross-linking gives the material sufficient spatial integrity to allow a holographic image to be recorded, while maintaining adequate porosity and elasticity of the polymer matrix for sensing applications. The new material has been characterized with respect to its response to pH and compared with a traditional gelatin holographic film. The response to some ions and small molecules typically found in analytical samples has also been measured. Functional groups introduced covalently into the poly(vinyl alcohol) matrix transform the base matrix into a pH-responsive polymer with predictable swelling properties and which can be further derivatized to incorporate specific ligands. A rationally designed holographic sensor for trypsin has been developed from chemically synthesized artificial polymers. A trypsin substrate, the poly(amino acid) poly(L-lysine), was incorporated into poly(vinyl alcohol) holograms to create a 'designed' holographic material which was degraded in a concentration-dependent manner by trypsin. Extensions of this approach to other hydrolytic enzymes are briefly discussed.

Animals↗
PubMed2000

The photochemistry of 1,3-butadiene rationalized by means of theoretical resonance structures and their weights

A complete active-space self-consistent-field wave function for the pi-electron part of s-trans-1,3-butadiene has been expanded into a set of localized bonding schemes and their weights. These bonding schemes are close to the resonance structures used in organic chemistry. The expansion technique has been applied to both the electronic ground state and the electronically first-excited singlet and triplet pi,pi* states. The manifolds of large-weight bonding schemes represent approximate resonance hybrids for the ground and the singlet and triplet pi,pi* states of s-trans-1,3-butadiene. These resonance hybrids, obtained by theory alone, permit a qualitative rationalization of a significant part of the known singlet and triplet photochemistry.

Journal Article↗
PubMed1977

Lobular carcinoma in situ of the breast. An approach to rational treatment.

A review of 3299 benign breast lesions was carried out. Lobular carcinoma in situ (LCIs) was discovered in 52 cases; and of these, 44 had been treated by biopsy alone. During the follow-up period averaging 15.9 years, 11 patients developed invasive breast cancer (IBC): 9 ipsilateral lesions, and 4 contralateral. This was about 12 times the frequency expected. The development of IBC had no relation to the patient's age, nor could any correlation be drawn between the time periods which elapsed from the time of the diagnosis of the in situ cancer to the development of IBC. The ipsilateral occurrence of IBC was not isgnificantly different from the contralateral. Careful lifelong follow-up seems to be the rational treatment for women whose breast biopsy shows LCIs.

Adult↗
PubMed2001

A rational approach to improving productivity in recombinant Pichia pastoris fermentation.

A Mut(S) Pichia pastoris strain that had been genetically modified to produce and secrete sea raven antifreeze protein was used as a model system to demonstrate the implementation of a rational, model-based approach to improve process productivity. A set of glycerol/methanol mixed-feed continuous stirred-tank reactor (CSTR) experiments was performed at the 5-L scale to characterize the relationship between the specific growth rate and the cell yield on methanol, the specific methanol consumption rate, the specific recombinant protein formation rate, and the productivity based on secreted protein levels. The range of dilution rates studied was 0. 01 to 0.10 h(-1), and the residual methanol concentration was kept constant at approximately 2 g/L (below the inhibitory level). With the assumption that the cell yield on glycerol was constant, the cell yield on methanol increased from approximately 0.5 to 1.5 over the range studied. A maximum specific methanol consumption rate of 20 mg/g. h was achieved at a dilution rate of 0.06 h(-1). The specific product formation rate and the volumetric productivity based on product continued to increase over the range of dilution rates studied, and the maximum values were 0.06 mg/g. h and 1.7 mg/L. h, respectively. Therefore, no evidence of repression by glycerol was observed over this range, and operating at the highest dilution rate studied maximized productivity. Fed-batch mass balance equations, based on Monod-type kinetics and parameters derived from data collected during the CSTR work, were then used to predict cell growth and recombinant protein production and to develop an exponential feeding strategy using two carbon sources. Two exponential fed-batch fermentations were conducted according to the predicted feeding strategy at specific growth rates of 0.03 h(-1) and 0.07 h(-1) to verify the accuracy of the model. Cell growth was accurately predicted in both fed-batch runs; however, the model underestimated recombinant product concentration. The overall volumetric productivity of both runs was approximately 2.2 mg/L. h, representing a tenfold increase in the productivity compared with a heuristic feeding strategy.

Biotechnology↗
PubMed2001

Mapping critical sites in collagen II for rational design of gene-engineered proteins for cell-supporting materials.

Collagen II is the most abundant protein of cartilage and forms a network of fibrils extended by proteoglycans that enables cartilage to resist pressure. The surface of the collagen fibril serves as a platform for the attachment of collagen IX, growth factors, and cells. In this study we examined the mechanism of the interaction of chondrocytes with recombinant versions of procollagen II, in which one of the four blocks of 234 amino acids that define repeating D periods of the collagen triple helix has been deleted. Analysis of the attachment of chondrocytes to collagen II variants with deleted D periods indicated that the collagen II monomer contains randomly distributed sites critical for cell binding. However, as was shown by spreading and migration assays, the D4 period, which is between residues 703 to 936, contains amino acids critical for cell motility. We also showed that binding, spreading, and migration of chondrocytes through three-dimensional nanofibrillar collagenous matrices are controlled by an interaction of the collagen triple helix with beta1 integrins. The results of this study provide a basis for the rational design of a scaffold containing genetically engineered collagen with a high density of specific sites of interaction.

Biocompatible Materials↗
PubMed1983

Modification of irrational ideas and test anxiety through rational stage directed hypnotherapy [RSDH].

Examined the effects of four treatment conditions on the modification of Irrational Ideas and test anxiety in female nursing students. The treatments were Rational Stage Directed Hypnotherapy, a cognitive behavioral approach that utilized hypnosis and vivid-emotive-imagery, a hypnosis-only treatment, a placebo condition, and a no-treatment control. The 48 Ss were assigned randomly to one of these treatment groups, which met for 1 hour per week for 6 consecutive weeks with in-vivo homework assignments also utilized. Statistically significant treatment effects on cognitive, affective, behavioral, and physiological measures were noted for both the RSDH and hypnosis group at the posttest and at a 2-month follow-up. Post-hoc analyses revealed the RSDH treatment group to be significantly more effective than the hypnosis only group on both the post- and follow-up tests. The placebo and control groups showed no significant effects either at post-treatment or at follow-up.

Adolescent↗
PubMed1989

The discrepancy between emotional vs. rational estimates of body size, actual size, and ideal body ratings: theoretical and clinical implications.

Thirty-two asymptomatic college females were assessed on multiple aspects of body image. Subjects' estimation of the size of three body sites (waist, hips, thighs) was affected by instructional protocol. Emotional ratings, based on how they "felt" about their body, elicited ratings that were larger than actual and ideal size measures. Size ratings based on rational instructions were no different from actual sizes, but were larger than ideal ratings. There were no differences between actual and ideal sizes. The results are discussed with regard to methodological issues involved in body image research. In addition, a working hypothesis that differentiates affective/emotional from cognitive/rational aspects of body size estimation is offered to complement current theories of body image. Implications of the findings for the understanding of body image and its relationship to eating disorders are discussed.

Adolescent↗
PubMed2001

Improved enantioselectivity of a lipase by rational protein engineering.

A model based on two different binding modes for alcohol enantiomers in the active site of a lipase allowed rational redesign of its enantioselectivity. 1-Halo-2-octanols were poorly resolved by Candida antarctica lipase B. Interactions between the substrates and the lipase were investigated with molecular modeling. Unfavorable interactions were found between the halogen moiety of the fast-reacting S enantiomer and a region situated at the bottom of the active site (stereoselectivity pocket). The lipase was virtually mutated in this region and energy contour maps of some variants displayed better interactions for the target substrates. Four selected variants of the lipase were produced and kinetic resolution experiments were undertaken with these mutants. Single point mutations gave rise to one variant with doubled enantioselectivity as well as one variant with annihilated enantioselectivity towards the target halohydrins. An increased volume of the stereoselectivity pocket caused a decrease in enantioselectivity, while changes in electrostatic potential increased enantioselectivity. The enantioselectivity of these new lipase variants towards other types of alcohols was also investigated. The changes in enantioselectivity caused by the mutations were well in agreement with the proposed model concerning the chiral recognition of alcohol enantiomers by this lipase.

Binding Sites↗
PubMed2001

Rationally designed strings of promiscuous CD4(+) T cell epitopes provide help to Haemophilus influenzae type b oligosaccharide: a model for new conjugate vaccines.

The age-related and T cell-independent immunological properties of most capsular polysaccharides limit their use as vaccines, especially in children under 2 years of age. To overcome these limitations, polysaccharide antigens have been successfully conjugated to a variety of carrier proteins, such as diphtheria toxoid or tetanus toxoid (TT) and the diphtheria mutant (CRM197) to produce very successful glycoconjugate vaccines. The increasing demand for new conjugate vaccines requires the availability of additional carriers providing high and long-lasting T helper cell immunity. Here we describe the design and construction of three recombinant carrier proteins (N6, N10, N19) constituted by strings of 6, 10 or 19 human CD4(+) T cell epitopes from various pathogen-derived antigens, including TT and proteins from Plasmodium falciparum, influenza virus and hepatitis B virus. Each of these epitopes is defined as universal in that it binds to many human MHC class II molecules. When conjugated to Haemophilus influenzae type b (Hib) oligosaccharide, these carriers elicit a potent anti-Hib antibody response in mice. In the case of the N19-Hib conjugate, this response is at least as good as that observed with CRM197-Hib, a conjugate vaccine currently used for mass immunization. We also show that some of the universal epitopes constituting the recombinant carriers are specifically recognized by two human in vitro systems, suggesting that T cell memory is provided by the selected epitopes. The data indicate that rationally designed recombinant polyepitope proteins represent excellent candidates for the development and clinical testing of new conjugate vaccines.

Amino Acid Sequence↗
PubMed1993

Towards the rational management of the insect pests of tropical legume crops in Asia: review and remedy.

The productivity of legume crops, especially the pulses, has not increased markedly in 30 years. This is a serious matter in this time of exponential human population growth because legume crops provide essential diet components that are not present in cereals at a price that is affordable to the majority. The preferential allocation of research resources to cereal crops is one reason for this stagnation. I suggest that an international effort should be mounted to redress this situation. Most Asian legumes have in common a cadre of insect pests that are reducing yields to levels at which harvesting is not economic. The position is worsening because insecticide resistance in key production areas has rendered many species uncontrollable. The short-term remedy is to persuade farmers to reduce their dependence on insecticides. Long-term solutions should be aimed at a common policy centred on the principal components of integrated pest management (IPM) schemes. Governments should be supplied with information that will permit them to set priorities according to absolute crop loss indicators. These will in turn provide a rational basis for the subsequent development of regional strategies. The establishment of an IPM centre in Asia would support the facilitation of this ideal. Such an organization would become the focal point for collecting, developing and disseminating the information and technology needed to make a quantum leap in legume production.

Animals↗
PubMed1995

Mechanisms of VCAM-1 and fibronectin binding to integrin alpha 4 beta 1: implications for integrin function and rational drug design.

Integrin alpha 4 beta 1 can mediate both cell-cell and cell-extracellular matrix adhesion by binding to either fibronectin or vascular cell adhesion molecule 1 (VCAM-1). Both interactions are important for extravasation of leukocytes from the blood implying that rationally designed inhibitors of alpha 4 beta 1 function may be useful for treating a various inflammatory conditions. The mechanisms of ligand binding by alpha 4 beta 1 are complicated by the fact that alternative splicing can generate different isoforms of the receptor-binding domains in both fibronectin and VCAM-1. Therefore, in addition to developing alpha 4 beta 1 antagonists, we have also been interested in identifying isoform-specific functions. Recombinant ligand variants have been tested in adhesion and direct receptor-binding assays and each molecule was found to have a different inherent affinity for alpha 4 beta 1 that endows them with different adhesive activities. This suggests that alternative splicing may regulate alpha 4 beta 1-dependent motility in vivo. The initial strategy that we have adopted to develop alpha 4 beta 1 inhibitors has been to identify key amino acid residues and peptide sequences participating in the receptor-ligand binding event and to use this information to generate synthetic mimetics. Three active sites have been identified in fibronectin by testing truncated proteins, expressing recombinant fragments and screening synthetic peptides. Two of these sites employ versions of a novel integrin-binding motif, LDVP/IDAP. A key active site in VCAM-1 has been identified by similar approaches as the related sequence IDSP. Since IDSP-like sequences are probably used by other integrin-binding immunoglobulins, derivatives of these peptides may turn out to be the forerunners of a new generation of therapeutic agents with multiple applications.

Amino Acid Sequence↗
PubMed1998

The causes of Parkinson's disease are being unraveled and rational neuroprotective therapy is close to reality.

There has been significant progress in our knowledge of the cause, the pathogenesis, and the nature of the mechanism of cell death in Parkinson's disease (PD). Mutations in single genes have now been shown to be able to cause PD but likely only account for a small number of cases. Alternatively, there is evidence that environmental factors play a large role in the majority of cases of sporadic PD. Most likely, genetic factors predispose patients to develop PD if combined with other gene mutations or environmental toxins. Interest has thus focused on factors that contribute to the pathogenesis of neurodegeneration and the mechanism of cell death in an attempt to design a neuroprotective therapy. Oxidant stress, mitochondrial dysfunction, excitotoxicity with excess nitric oxide formation, and glia and inflammatory processes are all thought to contribute to the cell death process and agents that interfere with these events may be neuroprotective. It is now generally held that the final culmination of these events is the induction of apoptosis in nigral dopaminergic neurons and this too offers opportunities for providing neuroprotection. A rational argument can be made for investigating a large number of different approaches or combination of approaches in the hope of developing a meaningful neuroprotective therapy, using clinically relevant indices and neuroimaging markers of nigral dopaminergic neurons. It is evident that conventional approaches to trials that utilize large numbers of patients in search of small incremental effects are costly and time consuming. As such, it will be virtually impossible to test all of the potentially valuable neuroprotective agents that are now at hand, let alone those that will likely soon emerge. We suggest that it may be more profitable to test a large number of agents in a small number of selected patients in search of a more robust neuroprotective effect. In this way, we will reduce the risk of missing a powerful neuroprotective treatment with a treatment that might not otherwise have been studied because of a lack of time, money, or patients.

Cell Death↗
PubMed2006

Polymeric sensor materials: toward an alliance of combinatorial and rational design tools?

Increased selectivity, response speed, and sensitivity in the chemical and biological determinations of gases and liquids are of great interest. Particular attention is paid to polymeric sensor materials, which are applicable to sensors exploiting various energy transduction principles, such as radiant, electrical, mechanical, and thermal energy. Ideally, numerous functional parameters of sensor materials can be tailored to meet specific needs using rational design approaches. However, increasing the structural and functional complexity of polymeric sensor materials makes it more difficult to predict the desired properties. Combinatorial and high-throughput methods have had an impact on all areas of research on polymer-based sensor materials including homo- and copolymers, formulated materials, polymeric structures with engineered morphology, and molecular shape-recognition materials. Herein we report on the state-of-the-art, the development trends, and the remaining knowledge gaps in the area of combinatorial polymeric sensor materials design.

Journal Article↗