Examining the exhaled levels of hydrogen peroxide in rheumatoid arthritis: a pilot study.
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Adult↗
Biomedical subjects
D A Bergman
Publications and source records attributed to D A Bergman.
Diagnostic accuracy of fine-needle aspiration and frozen section in nodular thyroid disease.
OBJECTIVE: To assess the diagnostic accuracy of fine-needle aspiration (FNA) and frozen section (FS) in nodular thyroid disease. SETTING: Tertiary care academic medical center. STUDY DESIGN: Retrospective review of 139 consecutive patients undergoing surgery for nodular thyroid disease. FNA and FS sensitivity, specificity, and accuracy were calculated with respect to permanent section histology. RESULTS: Among 63 patients with an FNA interpreted as either benign (n = 38) or malignant (n = 25), FNA was accurate (sensitivity 89%, specificity 97%, accuracy 94%). FS identified only one case of carcinoma missed by FNA. Among 76 patients with a "suspicious" FNA, FS was reasonably accurate (sensitivity 67%, specificity 100%, accuracy 89%), but was deferred in 50% of cases. CONCLUSION: Given high FNA accuracy, more selective use of FS is suggested. SIGNIFICANCE: The study results will assist with intra-institutional patient counseling and intraoperative decision-making with respect to FNA and FS results in patients with nodular thyroid disease.
Adenoma↗
The influence of intraoperative parathyroid hormone monitoring on the surgical management of hyperparathyroidism.
OBJECTIVE: To examine the role of intraoperative rapid parathyroid hormone (PTH) monitoring in the surgical management of hyperparathyroidism. DESIGN: Thirty-eight-month retrospective review. SETTING: Tertiary care academic medical center. PATIENTS: One hundred consecutive patients undergoing surgery for primary hyperparathyroidism. INTERVENTION: All patients underwent preoperative technetium Tc 99m sestamibi scan localization and intraoperative blood PTH monitoring by means of a rapid (12-minute) immunochemiluminometric assay. MAIN OUTCOME MEASURES: The influence of intraoperative PTH levels on extent of surgical dissection and achievement of postoperative normocalcemia. RESULTS: Intraoperative PTH levels dropped an average of 64%, 75%, and 83% at 5, 10, and 20 minutes, respectively, after excision of all hyperfunctioning parathyroid tissue. A PTH decrease of 46% or more at 10 minutes and 59% or more at 20 minutes after excision of hyperfunctioning tissue was predictive of postoperative normocalcemia. In 79 patients (79%), the sestamibi scan provided accurate preoperative localization; all but 1 of these patients were treated successfully, most often with a limited, gland-specific dissection. In 24 patients with inaccurate, negative, or misleading preoperative sestamibi scans, 23 (96%) were treated successfully with the use of the intraoperative PTH assay. CONCLUSIONS: The rapid intraoperative PTH assay accurately predicts postoperative success in patients with primary hyperparathyroidism. The rapid PTH assay allows for greater confidence in performing limited dissections in well-localized uniglandular disease. In cases of inaccurate preoperative localization, the rapid PTH assay directly affects surgical decision making and provides greater confidence in determining when surgical success has been achieved.
Adult↗
Synthesis, stability, antiviral activity, and protease-bound structures of substrate-mimicking constrained macrocyclic inhibitors of HIV-1 protease.
Three new peptidomimetics (1-3) have been developed with highly stable and conformationally constrained macrocyclic components that replace tripeptide segments of protease substrates. Each compound inhibits both HIV-1 protease and viral replication (HIV-1, HIV-2) at nanomolar concentrations without cytotoxicity to uninfected cells below 10 microM. Their activities against HIV-1 protease (K(i) 1.7 nM (1), 0.6 nM (2), 0.3 nM (3)) are 1-2 orders of magnitude greater than their antiviral potencies against HIV-1-infected primary peripheral blood mononuclear cells (IC(50) 45 nM (1), 56 nM (2), 95 nM (3)) or HIV-1-infected MT2 cells (IC(50) 90 nM (1), 60 nM (2)), suggesting suboptimal cellular uptake. However their antiviral potencies are similar to those of indinavir and amprenavir under identical conditions. There were significant differences in their capacities to inhibit the replication of HIV-1 and HIV-2 in infected MT2 cells, 1 being ineffective against HIV-2 while 2 was equally effective against both virus types. Evidence is presented that 1 and 2 inhibit cleavage of the HIV-1 structural protein precursor Pr55(gag) to p24 in virions derived from chronically infected cells, consistent with inhibition of the viral protease in cells. Crystal structures refined to 1.75 A (1) and 1.85 A (2) for two of the macrocyclic inhibitors bound to HIV-1 protease establish structural mimicry of the tripeptides that the cycles were designed to imitate. Structural comparisons between protease-bound macrocyclic inhibitors, VX478 (amprenavir), and L-735,524 (indinavir) show that their common acyclic components share the same space in the active site of the enzyme and make identical interactions with enzyme residues. This substrate-mimicking minimalist approach to drug design could have benefits in the context of viral resistance, since mutations which induce inhibitor resistance may also be those which prevent substrate processing.
Anti-HIV Agents↗
Conformational selection of inhibitors and substrates by proteolytic enzymes: implications for drug design and polypeptide processing.
Inhibitors of proteolytic enzymes (proteases) are emerging as prospective treatments for diseases such as AIDS and viral infections, cancers, inflammatory disorders, and Alzheimer's disease. Generic approaches to the design of protease inhibitors are limited by the unpredictability of interactions between, and structural changes to, inhibitor and protease during binding. A computer analysis of superimposed crystal structures for 266 small molecule inhibitors bound to 48 proteases (16 aspartic, 17 serine, 8 cysteine, and 7 metallo) provides the first conclusive proof that inhibitors, including substrate analogues, commonly bind in an extended beta-strand conformation at the active sites of all these proteases. Representative superimposed structures are shown for (a) multiple inhibitors bound to a protease of each class, (b) single inhibitors each bound to multiple proteases, and (c) conformationally constrained inhibitors bound to proteases. Thus inhibitor/substrate conformation, rather than sequence/composition alone, influences protease recognition, and this has profound implications for inhibitor design. This conclusion is supported by NMR, CD, and binding studies for HIV-1 protease inhibitors/substrates which, when preorganized in an extended conformation, have significantly higher protease affinity. Recognition is dependent upon conformational equilibria since helical and turn peptide conformations are not processed by proteases. Conformational selection explains the resistance of folded/structured regions of proteins to proteolytic degradation, the susceptibility of denatured proteins to processing, and the higher affinity of conformationally constrained 'extended' inhibitors/substrates for proteases. Other approaches to extended inhibitor conformations should similarly lead to high-affinity binding to a protease.
Amino Acid Sequence↗
Beclomethasone for asthma in children: effects on linear growth.
BACKGROUND: Inhaled steroids play a central role in the management of childhood asthma. There is concern about their side effects, especially on growth. However asthma may also cause growth retardation. Growth rates are not stable, so randomised controlled parallel group studies are needed to assess the impact of inhaled steroids on growth. This review is confine to one inhaled steroid, beclomethasone, that is known to have significant levels of systemic absorption. OBJECTIVES: To determine whether inhaled beclomethasone cause significant delay in the linear growth of children with asthma. SEARCH STRATEGY: The Cochrane Airways Group asthma register was searched. Bibliographies from included studies, and known reviews were searched for additional citations. Personal contact with colleagues and researchers working in the field of asthma were made to identify potentially relevant trials. SELECTION CRITERIA: Randomized, controlled trials comparing the effects of beclamethasone to non-steroidal medication (placebo or non-steroidal therapy) on the linear growth of children with asthma. DATA COLLECTION AND ANALYSIS: Data related to the clinical outcome "change in growth" were extracted by two reviewers working independently MAIN RESULTS: One hundred and fifty-nine citations were identified by the search strategy and bibliography review. Three studies met the inclusion criteria. All used beclomethasone 200 mcg twice daily delivered by dry powder Diskhaler to treat children with mild-moderate asthma. Study duration was 7-12 months. In all three studies, a significant decrease in linear growth occurred in children treated with beclomethasone compared to those receiving placebo or non-steroidal asthma therapy. The average decrease, calculated through meta-analysis, was -1.54 cm per year (95% CI -1.15, -1.94). REVIEWER'S CONCLUSIONS: In children with mild-moderate asthma, beclomethasone 200 mcg twice daily caused a decrease in linear growth of -1.54 cm per year. These studies lasted a maximum of 54 weeks, so it remains unclear whether the decrease in growth is sustained or whether it reverses with 'catch up' after therapy is discontinued. We are unable to comment on growth effects of other inhaled steroids that have potentially less systemic effects. If inhaled steroids are required to control a child's asthma, we recommend using the minimum dose that effectively controls the child's asthma and closely following growth.
Age Factors↗
The effect of inhaled steroids on the linear growth of children with asthma: a meta-analysis.
OBJECTIVE: To determine whether inhaled steroid therapy causes delayed linear growth in children with asthma. DATA SOURCES: Medline (1966-1998), Embase (1980-1998), and Cinahl (1982-1998) databases and bibliographies of included studies were searched for randomized, controlled trials of inhaled steroid therapy in children with asthma that evaluated linear growth. STUDY SELECTION: Studies were included if they met the following criteria: subjects 0 to 18 years of age with the clinical diagnosis of asthma; subjects randomized to inhaled beclomethasone, budesonide, flunisolide, fluticasone, or triamcinolone versus a nonsteroidal inhaled control for a minimum of 3 months; single- or double-blind; and outcome convertible to linear growth velocity. English- and non-English-language trials were included. DATA EXTRACTION: Data were extracted using a priori guidelines. Methodologic quality was assessed independently by both authors. Outcome was extracted as linear growth velocity. RESULTS: Included trials were subgrouped by inhaled steroid. The beclomethasone subgroup, with 4 studies and 450 subjects, showed a decrease in linear growth velocity of 1.51 cm/year (95% confidence interval: 1.15,1.87). The fluticasone subgroup, with 1 study and 183 subjects, showed a decrease in linear growth velocity of.43 cm/year (95% confidence interval:.01,.85). Sensitivity analysis in the beclomethasone subgroup, which evaluated study quality, mode of medication delivery, control medication, and statistical model, showed similar results. CONCLUSIONS: This meta-analysis suggests that moderate doses of beclomethasone and fluticasone in children with mild to moderate asthma cause a decrease in linear growth velocity of 1.51 cm/year and.43 cm/year, respectively. The effects of inhaled steroids when given for >54 weeks, or on final adult height, remain unknown.
Administration, Inhalation↗
Molecular recognition of macrocyclic peptidomimetic inhibitors by HIV-1 protease.
High-resolution crystal structures are described for seven macrocycles complexed with HIV-1 protease (HIVPR). The macrocycles possess two amides and an aromatic group within 15-17 membered rings designed to replace N- or C-terminal tripeptides from peptidic inhibitors of HIVPR. Appended to each macrocycle is a transition state isostere and either an acyclic peptide, nonpeptide, or another macrocycle. These cyclic analogues are potent inhibitors of HIVPR, and the crystal structures show them to be structural mimics of acyclic peptides, binding in the active site of HIVPR via the same interactions. Each macrocycle is restrained to adopt a beta-strand conformation which is preorganized for protease binding. An unusual feature of the binding of C-terminal macrocyclic inhibitors is the interaction between a positively charged secondary amine and a catalytic aspartate of HIVPR. A bicyclic inhibitor binds similarly through its secondary amine that lies between its component N-terminal and C-terminal macrocycles. In contrast, the corresponding tertiary amine of the N-terminal macrocycles does not interact with the catalytic aspartates. The amine-aspartate interaction induces a 1.5 A N-terminal translation of the inhibitors in the active site and is accompanied by weakened interactions with a water molecule that bridges the ligand to the enzyme, as well as static disorder in enzyme flap residues. This flexibility may facilitate peptide cleavage and product dissociation during catalysis. Proteases [Aba67,95]HIVPR and [Lys7,Ile33,Aba67,95]HIVPR used in this work were shown to have very similar crystal structures.
Aminobutyrates↗
Evidence-based guidelines and critical pathways for quality improvement.
Clinical practice guidelines have a long and distinguished tradition in pediatrics. Currently, the American Academy of Pediatrics has developed more than 15 practice guidelines and more than 250 clinical policy statements. In the past, practice guidelines have been used to improve care through the dissemination of evidence-based, clinically effective practices to pediatric practitioners. In the current environment this purpose has been broadened to include cost reduction, standardization of practice, and reduction of medical liability. This has led to both confusion and distrust on the part of the pediatrician. Practice guidelines are best understood as a tool to insure that children receive evidence-based care. They are best used in association with a set of outcome and performance measures that provide feedback to clinicians and allow for modification of the guidelines to meet the needs of the local patient population. The quality of practice guidelines is directly dependent on the quality of the medical evidence supporting the recommendation. Unfortunately only a small percentage of the evidence supporting practice guidelines comes from randomized clinical trials with the majority of the evidence coming from expert clinical panels. The success of practice guidelines in improving care for children has yet to be convincingly demonstrated. Currently, there is a dearth of well designed studies that document the effectiveness of practice guidelines. Their ultimate effectiveness will depend on both an improved evidence base and effective strategies for rapid dissemination of the recommendations. The development of evidence-based practice guidelines does not insure that it will have a major impact on physician practice. In the past, effective dissemination of new knowledge has been a long process, often taking years. This cycle time can be dramatically shortened through the development of networks of practice sites that share knowledge and experience in the implementation of practice guidelines and the use of strategies that take advantage of key groups in the dissemination process. When used appropriately, practice guidelines can provide an important adjunct to clinical research by facilitating the dissemination of new clinical findings and can provide an important platform for encouraging innovations in patient care.
Critical Pathways↗
Clinical practice guidelines in pediatric and newborn medicine: implications for their use in practice.
Clinical practice guidelines are becoming pervasive in pediatrics and newborn medicine. They have spanned a wide range of primary care practice parameters from treating otitis media with effusion, to performing complex surgery for congenital heart disease, and management of respiratory distress syndrome and coordinating discharge from the neonatal intensive care unit. Administrators believe that using clinical practice parameters reduces health care costs, improves quality of care, and limits malpractice liability. Practice parameters and guidelines have grown in use because powerful interests-third-party payers, insurers, and health maintenance organizations, as well as hospital administrators bent on reducing variable costs of care and contracting for capitated care-champion their development, implementation, and monitoring. Economic credentialing of physicians with excessive variances without risk-adjusting for other than average patients is problematic and remains unchecked partly because of the fundamental characteristics of the evolving health care industry in which costs are more easily measured than quality. For highly autonomus physicians this standardization of medical decision making may represent a difficult transition into corporate practice by realigning traditional values of the doctor-patient relationship. However, because guidelines are almost certainly here to stay, pediatricians and neonatologists need to think critically about how their content and method of implementation, monitoring, and modification may influence medical teaching and decision making in the future. If guidelines are introduced primarily as a cost savings or containment tool that ignores the impact on the quality of care and restricts necessary care for infants and children, especially those with chronic illness or who are developmentally at risk, then neonatologists and pediatricians must be quick and determined to challenge the potentially damaging use of practice parameters or guidelines. Furthermore, there are many medicolegal implications of guideline implementation that may not favor physicians and leave to hospitals, insurers, and ultimately the courts decisions regarding evidence-based practice. In this review article, we pay special attention to the guidelines developed in newborn medicine. We discuss why and how guidelines are developed and critically evaluate the available evidence describing potential benefits and drawbacks of guidelines in general. There are legal implications to the implementation of guidelines, and guidelines may increase provider susceptibility to malpractice allegations. Neonatologists and pediatricians should critically analyze the following questions when guidelines are being developed: Are clinical practice parameters the most effective means to reduce the costs of health care, or improve the quality of health care services while reducing the need for and protecting physicians from malpractice suits? Or do clinical practice guidelines more closely resemble an audit system developed by health care organizations, insurers, and others including government-sponsored health care to appease powerful interests-with limited evidence for promise and perhaps potential negative cost, quality, and malpractice liability implications? In pediatric and newborn medicine there is limited evidence that guidelines have achieved the desired goals and further analysis of their process of care and the costs of implementation is warranted.
Health Services↗
Hospital-based quality management: a program at the crossroads.
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Hospital Administration↗
Localization and quantification of the dopamine transporter: comparison of [3H]WIN 35,428 and [125I]RTI-55.
Transport into the presynaptic terminal by the dopamine transporter is the primary mechanism for removing dopamine from the synaptic cleft. This transporter is a specific marker for dopamine terminals and is a primary site for CNS actions of cocaine. Several radioligands have been developed for analysis of the dopamine transporter. The ligands vary in affinity and specificity, leading to differences in reported transporter density in brain regions. We compared two of the most commonly used ligands, [3H]WIN 35,428 and [125I]RTI-55, analyzing the localization and density of sites in the rat brain using serial sections and quantitative autoradiography. Citalopram at 50 nmol/l was used to block [125I]RTI-55 binding to serotonin transport sites. Transporter density was highest in the striatum and both ligands labeled equivalent numbers of sites, with lateral to medial and anterior to posterior gradients. In most areas the density of sites measured with the two ligands was similar. However, [125I]RTI-55 binding was significantly higher than [3H]WIN 35,428 binding in the substantia nigra zona compacta, ventral tegmental area, subthalamic nucleus and a number of other subcortical nuclear groups while [3H]WIN 35,428 binding was higher in lateral striatum and in olfactory tubercle. These differences could reflect different forms of the transporter, perhaps due to post-translational modifications, and they may provide a basis for differential pharmacological regulation of transporter function in discrete brain regions and disease states.
Animals↗
Thriving in the 21st century: outcome assessment, practice parameters, and accountability.
The past two decades have brought about major health care changes that have been driven by an ever-increasing cost of health care, practice variability, and medical malpractice litigation. These changes pose a challenge to pediatricians to contain costs, to reduce inappropriate use of health care services, and to demonstrate improved health care outcomes. To meet this challenge, a new "clinical tool kit" is required, one that will allow the pediatrician to analyze current practices and to document effective interventions. Two of the major tools in this kit are practice guidelines and outcomes assessment instruments. Practice guidelines are optimal care specifications that provide an analytic framework for defining high-quality care and measuring health care outcomes. Ideally, these guidelines should be developed from scientific evidence. In practice, however, scientific evidence to support the majority of recommendations made in guidelines is insufficient. Consequently, these recommendations are instead developed by expert consensus. Measurement of health outcomes includes clinical outcomes, patient satisfaction, cost and use, and quality of life. Health care organizations have become very sophisticated in measuring cost and use, but considerably less work has been done in the patient-centered areas of satisfaction and quality of life. This is particularly true for children, because measures are dependent on the viewpoint chosen (parent, child, or teacher), the age of the child, and the adjustment for severity of illness. Analyzing practice patterns and improving health outcomes will not be easy tasks to accomplish. For the pediatrician to use these tools in an efficient and effective manner, a new research agenda and new skills will be required.
Guidelines as Topic↗
Localization of nicotinic cholinergic receptors in rat brain: autoradiographic studies with [3H]cytisine.
There is a great deal of interest in the role of nicotinic acetylcholine receptors in the central nervous system, although their function is not well understood at present. Currently, central nicotinic receptors can be classified broadly as either alpha-bungarotoxin binding sites with low affinity for acetylcholine agonists, or as high-affinity agonist binding sites with low affinity for alpha-bungarotoxin. Neuronal nicotinic receptors with a high affinity for agonists are distributed widely in the central nervous system. Evidence from molecular biology and electrophysiology suggests that multiple nicotinic receptor types exist in the brain. In this study we have used the agonist [3H]cytisine as a ligand for autoradiography to generate a detailed quantitative map of the high-affinity agonist binding nicotinic receptor in the rat brain. Optimized binding conditions, characterization of the kinetic and equilibrium binding properties, and demonstration of the nicotinic pharmacology of this binding site in tissue sections confirm the usefulness of [3H]Cytisine as a ligand for nicotinic receptor autoradiography. [3H]Cytisine autoradiography provides excellent anatomic resolution with very low non-specific binding. This property has allowed us to describe variations in receptor density within subnuclei and gradients of receptor density in larger brain regions. Data from several studies suggest that the predominant high-affinity agonist binding nicotine receptor in the central nervous system is composed of the alpha 4 and beta 2 subunits. The data in the current study are consistent with the suggestion that [3H]cytisine labels only the alpha 4 beta 2 nicotinic receptor with high affinity, offering the possibility of localizing a specific nicotinic receptor subtype in the central nervous system. In summary, we characterize the optimum experimental conditions for the use of [3H]cytisine in tissue section autoradiography. [3H]Cytisine proves to be an excellent marker for nicotinic cholinergic receptors with a very high affinity and very low background. We provide a detailed quantitative characterization of nicotinic receptor density in the rat central nervous system and we find there are significant variations and gradients in receptor density within specific brain regions, including subregions previously thought to be homogeneous.
Alkaloids↗
Quality improvement: buzz words or boon?
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Costs and Cost Analysis↗
Thyroid physiology and immunology.
The thyroid gland, like the paintings of Chagall, has forced us to look at our traditional understanding of things in a new way and to gain fresh insight into ancient concepts of human physiology.
Humans↗
Thermodynamic nonideality in enzyme catalysis. Effect of albumin on the reduction of pyruvate by lactate dehydrogenase.
The enhanced catalytic reduction of pyruvate by rabbit muscle lactate dehydrogenase that results from the addition of serum albumin [Nichol, L. W., Sculley, M. J., Ward, L. D. & Winzor, D. J. (1983) Arch. Biochem. Biophys. 222, 574-581] is shown to emanate solely from an increase in maximal velocity, there being no discernible effect of this inert space-filling macromolecular solute on the Michaelis constant for either pyruvate or NADH. As part of the search for a mechanistic explanation of this kinetic phenomenon, the space-filling effects of albumin have been used to eliminate the possibility that the increase in sedimentation coefficient of lactate dehydrogenase effected by inclusion of oxamate with enzyme-NADH complex reflects preferential binding of this pyruvate analog to a more compact isomeric state of the binary complex. The enzyme kinetic results are therefore considered in terms of a reaction scheme entailing gross conformational changes during the formation of ternary enzyme-NADH-pyruvate complex and its isomerization to an activated transition state. The experimentally observed insensitivity of the Michaelis constant for pyruvate to albumin concentration is in keeping with theoretical prediction, but incorporation of the measured extent of maximal velocity enhancement into the kinetic model leads to a predicted volume for the fully saturated transition-state complex that is far too small to be experimentally feasible. A more complex mechanistic model involving additional isomerizations of enzyme-substrate species is thus required to achieve quantitative description of the albumin effect solely in terms of thermodynamic nonideality.
Kinetics↗
Space-filling effects of inert solutes as probes for the detection and study of substrate-mediated conformational changes by enzyme kinetics: theoretical considerations.
From expressions derived for the space-filling effects of small inert solutes on kinetic parameters for univalent enzymes undergoing isomerizations that are substrate-induced and pre-existing, it is concluded that experimental observation of an enhanced maximal velocity in the presence of inert solute can only reflect the existence of the former type of conformational change; and that the isomerization must be governed by a relatively small equilibrium constant. Similar conclusions apply to multivalent enzymes exhibiting Michaelis-Menten kinetics. Extension of the theory to provide quantitative expressions for multivalent enzymes has made possible the numerical simulation of thermodynamic non-ideality effects on systems conforming with the Monod and Koshland models of allostery. In that regard the simulated Scatchard plots for the two models differ sufficiently in form to suggest that detailed examination of the space-filling effects of small solutes on the kinetics of an allosteric enzyme may, under favourable circumstances, allow identification of the appropriate allosteric mechanism. Finally, these considerations of thermodynamic non-ideality in relation to the kinetics of allosteric enzymes have revealed formal similarities between the consequences of space-filling by inert solutes and the specific effects of allosteric activators or inhibitors. Attention is drawn to the possible implications of this observation in relation to the functioning of allosteric enzymes in vivo, where catalytic performance may be modified by factors no more specific than the ability of unrelated solutes to occupy space in the highly concentrated cellular environment.
Chemical Phenomena↗