The hypergraph regularity method and its applications.

Szemeredi's regularity lemma asserts that every graph can be decomposed into relatively few random-like subgraphs. This random-like behavior enables one to find and enumerate subgraphs of a given isomorphism type, yielding the so-called counting lemma for graphs. The combined application of these two lemmas is known as the regularity method for graphs and has proved useful in graph theory, combinatorial geometry, combinatorial number theory, and theoretical computer science. Here, we report on recent advances in the regularity method for k-uniform hypergraphs, for arbitrary k > or = 2. This method, purely combinatorial in nature, gives alternative proofs of density theorems originally due to E. Szemeredi, H. Furstenberg, and Y. Katznelson. Further results in extremal combinatorics also have been obtained with this approach. The two main components of the regularity method for k-uniform hypergraphs, the regularity lemma and the counting lemma, have been obtained recently: Rodl and Skokan (based on earlier work of Frankl and Rodl) generalized Szemeredi's regularity lemma to k-uniform hypergraphs, and Nagle, Rodl, and Schacht succeeded in proving a counting lemma accompanying the Rodl-Skokan hypergraph regularity lemma. The counting lemma is proved by reducing the counting problem to a simpler one previously investigated by Kohayakawa, Rodl, and Skokan. Similar results were obtained independently by W. T. Gowers, following a different approach.

Improving prescribing patterns for the elderly through an online drug utilization review intervention: a system linking the physician, pharmacist, and computer.

CONTEXT: Pharmacotherapy is among the most powerful interventions to improve health outcomes in the elderly. However, since some medications are less appropriate for older patients, systems approaches to improving pharmacy care may be an effective way to reduce inappropriate medication use. OBJECTIVE: To determine whether a computerized drug utilization review (DUR) database linked to a telepharmacy intervention can improve suboptimal medication use in the elderly. DESIGN: Population-based cohort design, April 1, 1996, through March 31, 1997. SETTING: Ambulatory care. PATIENTS: A total of 23269 patients aged 65 years and older throughout the United States receiving prescription drug benefits from a large pharmaceutical benefits manager during a 12-month period. INTERVENTION: Evaluation of provider prescribing through a computerized online DUR database using explicit criteria to identify potentially inappropriate drug use in the elderly. Computer alerts triggered telephone calls to physicians by pharmacists with training in geriatrics, whereby principles of geriatric pharmacology were discussed along with therapeutic substitution options. MAIN OUTCOME MEASURES: Contact rate with physicians and change rate to suggested drug regimen. RESULTS: A total of 43007 alerts were triggered. From a total of 43007 telepharmacy calls generated by the alerts, we were able to reach 19368 physicians regarding 24 266 alerts (56%). Rate of change to a more appropriate therapeutic agent was 24% (5860), but ranged from 40% for long half-life benzodiazepines to 2% to 7% for drugs that theoretically were contraindicated by patients' self-reported history. Except for rate of change of beta-blockers in patients with chronic obstructive pulmonary disease, all rates of change were significantly greater than the expected baseline 2% rate of change. CONCLUSIONS: Using a system integrating computers, pharmacists, and physicians, our large-scale intervention improved prescribing patterns and quality of care and thus provides a population-based approach to advance geriatric clinical pharmacology. Future research should focus on the demonstration of improved health outcomes resulting from improved prescribing choices for the elderly.

Pharmacotherapy: strategies to control drug costs in managed care.

Pharmacotherapy remains one of the most cost-effective interventions physicians can provide to manage the medical conditions of older patients. Because many older Americans have multiple diseases, the practitioner's goal is to maximize appropriate drug use while avoiding duplicative or interacting medications. Medicare managed care plans seek to provide appropriate medication for the older patient at a reasonable cost through such strategies as formularies, prior authorization, generic and therapeutic substitution, and drug utilization review. Yet, like the medications themselves, these strategies require careful attention to their risks and benefits to the individual patient.

Assessing health-related quality of life in elderly outpatients: telephone versus face-to-face administration.

OBJECTIVE: While health-related quality of life (HRQOL) is increasingly being used as an outcome in clinical trials, it is unknown whether HRQOL assessments are influenced by the method of administration. Within the context of a randomized, controlled trial evaluating a pharmacist intervention for elderly outpatients prescribed at least five medications, we compared telephone and face-to-face administration of the SF-36, a widely used HRQOL measure. DESIGN: Survey. SETTING: General Medicine Clinic, Veterans Affairs Medical Center. PATIENTS: At entry, participants in the randomized trial received continuous care from a general medicine clinic physician, were > or = 65 years of age, and were prescribed > or = 5 regularly scheduled medications. Patients were excluded if they were cognitively impaired and had no caregiver available to participate in the study as a proxy or if they resided in a nursing home. MEASUREMENTS: Subjects completed the SF-36 by telephone at closeout and face-to-face at clinic visits within 1 month (mean = 16.7 days). MAIN RESULTS: Telephone administration required significantly less time than face-to-face interviews (10.2 vs 14.0 minutes, P < 0.001). Although systematic differences between modes of administration were generally small, there were substantial nonsystematic discrepancies for all eight SF-36 scales (mean absolute difference scores ranged from 10.8 to 30.1). Discrepancies were greatest for emotional role functioning, physical role functioning, social functioning, and bodily pain; these four scales also demonstrated low to moderate correlations (.33 to .58). CONCLUSIONS: The two modes of administration may not produce interchangeable results. Researchers should be cautious when mixing modes of administration to elderly patients.

Treatment Investigational New Drug experience with Survanta (beractant).

From September 1989 through July 1991, before commercial availability, Survanta (beractant intratracheal suspension), a modified bovine-derived surfactant used for prevention and treatment of neonatal respiratory distress syndrome, was made available to 231 neonatal intensive care units in the United States and Canada under a Treatment Investigational New Drug protocol. Results of this open clinical experience are reported. Investigators could give one dose of Survanta soon after birth to neonates weighing 600 to 1250 g (prevention strategy). Neonates weighing 600 to 1750 g who were not treated at birth could begin Survanta therapy if respiratory distress syndrome developed within 8 hours of birth (rescue strategy). All neonates could receive up to three more doses over the first 48 hours of life at minimum intervals of 6 hours if they met retreatment criteria. Qualifications for enrollment closely matched those used in previous randomized controlled clinical trials. This report includes results from 8168 neonates who completed the study. Treatment Investigational New Drug rates for intracranial hemorrhage, patent ductus arteriosus, pulmonary hemorrhage, pulmonary air leaks, bronchopulmonary dysplasia, death or bronchopulmonary dysplasia, pulmonary interstitial emphysema, pretreatment sepsis, and posttreatment sepsis were less than for treated neonates in the controlled trials and survival was equivalent across studies. Problems with treatment administration were reported with 30.4% of doses, while adverse events were reported in 0.5% of neonates. The results of the Treatment Investigational New Drug protocol revealed no new safety concerns associated with the widespread use of Survanta and confirmed the safety profile established in earlier controlled trials.

The teleost cone cytoskeleton. Localization of actin, microtubules, and intermediate filaments.

This laboratory has been using the teleost retinal cone as a model for studying the mechanisms and regulation of retinal cell motility. In previous inhibitor studies, the authors have shown that dark-induced cone elongation requires microtubules, whereas light-induced contraction requires actin filaments. This study examines the distributions of actin filaments, microtubules, and intermediate filaments in the cone cytoskeleton. Actin filaments have been localized in isolated cones by labeling with fluorescent derivatives of phalloidin; microtubules were localized by immunofluorescent labeling with anti-tubulin. Actin, microtubule, and intermediate filament distributions have also been examined in detergent-lysed motile cell models of cones fixed with a new method that enhances preservation of the cytoskeleton. Longitudinal bundles of actin filaments extend from the cone's calycal processes through the ellipsoid and into the myoid. No actin filaments are detectable in the perinuclear region and axon, but filaments are present in both pre- and post-synaptic components of the synapse. Intermediate filaments are numerous in the perinuclear region and cone axon but relatively sparse in the myoid. In contrast, microtubule distribution is more uniform: numerous longitudinally oriented microtubules are present throughout the length of the cell. Thus the cone cytoskeleton reflects the highly polarized shape and function of the cell, with actin filaments localized to the distal movable part of the cell and intermediate filaments localized to the proximal part of the cell, which is anchored in the retina.

Calmodulin-binding proteins in teleost retina, rod inner and outer segments, and rod cytoskeletons.

125I-calmodulin gel overlay techniques have been used to identify calmodulin-binding proteins in teleost retina, in a rod fragment preparation which contains rod inner and outer segments (RIS-ROS), and in RIS-ROS cytoskeletons. We have previously shown that teleost rods change length in response to changes in light conditions, that rod movement is mediated by the actin filaments in the rod inner segment, and that both Ca2+ and cAMP appear to be involved in regulating rod movement. We report here the development of a rod fragment preparation (RIS-ROS), which retains the movable part of the rod, for use in biochemical analysis of rod motility. Gel overlay studies indicate that isolated whole retinas have six prominent calmodulin-binding proteins, migrating at 240 K, 190 K, 150 K, 61 K and a doublet at 18/19 K. In contrast, detached RIS-ROS have three different prominent calmodulin-binding proteins, migrating at 330 K, 33 K, and 31 K. RIS-ROS cytoskeletons have been produced by extraction with Triton X-100; they contain both actin filament bundles and microtubules associated with the connecting cilium. RIS-ROS cytoskeletons have 3 prominent calmodulin-binding proteins migrating at 240 and 18/19 K. These proteins produce faint bands in gel overlays of intact RIS-ROS, but prominent bands in overlays of whole retina. The 240 K protein of RIS-ROS cytoskeletons co-migrates with the 240 K calmodulin-binding subunit of rat brain fodrin. We suggest that the rod 240 K calmodulin-binding protein may be a spectrin-like protein which participates in Ca2+- and calmodulin-regulation of rod motility.

Scanning electron microscope study of herpes simplex virus experimental disciform keratitis.

Scanning electron microscopy of the endothelium of experimental disciform keratitis revealed corneal endothelial changes which distinguished disciform oedema from the more progressive stages of disciform keratitis. The endothelium of corneas with disciform oedema were wholly intact and characterised by subtle morphological alterations. In contrast, the more progressive stages of disciform keratitis were characterised by massive destruction and denudation of the endothelium. The significance of these observations is discussed.

Scanning electron microscopic observation of two retinoblastoma cell lines.

Two continuous retinoblastoma cell lines were observed by scanning electron microscopy. Both cell lines spontaneously grow as a suspension of round cells in clusters, chains, and unique ring (rosette) formations. Scanning electron microscopy of suspension cells reveals some variation in the number and frequency of surface adornments such as blebs, lamellipodia, and microvilli. Although the cell lines are nonadherent to substratum and therefore assume a spherical form, highly villous cells are not characteristic of the entire cell populations. When WERI-Rb1 and Y79 are seeded onto a polyornithine-treated substrate, attachment and growth as adherent cultures are evident. With selective attachment on a positively charged substrate, we observe alteration of membrane architecture with the extension of cytoplasm and filopidia. In addition, WERI-Rb1 cell-to-substratum adhesion induces morphological changes suggestive of neuronal cell differentiation.

Secretion of drugs by the parotid glands of rats and human beings.

The following drugs have been demonstrated to be secreted by the parotid glands of rats and human beings: amobarbital, chlorpromazine, codeine, glutethimide, meprobamate, pentobarbital, phenobarbital, and secobarbital. Methadone could not be detected in the parotid saliva of either rats or human beings, and morphine has been demonstrated only in parotid saliva of rats.