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Site visits for the review of grant applications to the National Institutes of Health: Views of an applicant and a scientist administrator.

The review of applications to the National Institutes of Health for individual research projects and complex programs of research may involve a visit to the applicant institution. The site visit is a review technique that is used only when information necessary for the scientific and technical review cannot be obtained satisfactorily by other means. The agenda for the visit must be carefully planned, particularly in the case of large research programs, since adequate time must be allowed for the presentation and discussion of the more complex components of the proposed research. All of the participating investigators associated with the proposal should get together for a thorough and critical rehearsal a few days before the visit. The impressions conveyed to the site visitors are transmitted to the initial review group usually through a site-visit report. The final recommendation of the visitors, which is based on the scientific merit of the proposed research, the competence of the investigators, and the suitability of the institutional setting, results from a thorough discussion of the strengths and weaknesses of the proposed program. The initial review group, in turn, uses the information obtained at the site visit in arriving at their recommendation to the appropriate National Advisory Council.

Administrative Personnel↗

[Application of the immunofluorescente (fluorescent antibody technique) in clinical immunology.--II. Application and significance (author's transl)].

The fluorescent antibody technique is nowadays mainly a technique, which is routinely carried out in all clinical-immunological laboratories. The main fields of application in clinical immunology are the determination of autoantibodies (e.g. ANA, AMA, smooth muscle antibodies, parietal cell antibodies), detection of B-lymphocytes as well as bacterial antigens (e.g. Treponema pallidum). Furthermore the demonstration of deposits of immune complexes in tissues (e.g. glomerulonephritis, periarteriitis nodosa). The presented paper shows the different fields of application of the fluorescent antibody technique. It is pointed out that the FAT could be only one out of the variety of methods in clinical-immunological investigations.

Adrenal Glands↗

[Lecture of principles and applications of capillary electrophoresis (V) Applications of capillary electrophoresis in pharmaceutical analysis and clinical chemistry].

A review with 68 references is presented on the application and new developments of CE in pharmaceutical analysis, clinical chemistry and single cell analysis etc. The pharmaceutical analysis includes main component assay, determination of drug-related impurities, stoichiometric determination and quantitative determinations. The Chinese herb analysis includes determinations of main components and prescriptions of Chinese herb. The chiral separation includes separation mechanism and some new chiral selectors. The application of CE in clinical chemistry includes determinations of serum and protein, monitoring of drug metabolism, etc. Single cell analysis includes determinations of component in neurocells and human erythrocyte.

Animals↗

Clinical application of percutaneous transluminal angioscopy. Comparison of findings in percutaneous transluminal angioplasty, thrombolysis, thrombus-extraction and stent-application.

Since the introduction of ultrathin angioendoscopes into clinical application, it has been possible to subject the findings of conventional or digital angiography to objective verification. In dogs and in patients, this new angioscopic method for visualization of arteries without surgical intervention has been carried out. The approach is transfemoral. Endoscopy is combined with angiography and, when indicated, percutaneous transluminal angioplasty (PTA), thrombolysis, thrombus extraction and insertion of a new type of stent. An ultrathin endoscope with an outer diameter of 1.6 mm and a working channel of 0.35 mm is used. Guidewires, contrast media and drugs for local thrombolysis can be employed through this channel. The endoscope is placed in the region of interest under fluoroscopy and direct visualization is obtained by using 0.9% NaCl for decreasing blood flow. Image recording is achieved by video or high-speed camera. With this method, the intraluminal events of dilatation, recanalization, local lysis, stent application and thrombus extraction can be visualized.

Angioplasty, Balloon↗

Pharmacokinetic concepts and applications affecting the clinical laboratory: I. General concepts and applications.

This article (the first in a series of two papers on pharmacokinetic concepts and applications for the clinical laboratory) presents a general review of pharmacokinetic principles used in conjunction with assays of drug plasma concentrations to assist in developing safer and more efficacious drug dosage regimens for patients. The pharmacokinetic factors influencing drug therapy are discussed, followed by a consideration of the indications for, and limitations of, using drug plasma concentrations as a guide to treatment. Drugs commonly assayed by the clinical laboratory are noted and applications are presented.

Adult↗

High-resolution particle analysis--its application to platelet counting and suggestions for further application in blood cell analysis.

The characteristics of an instrument for high-resolution particle analysis in flow are discussed. It employs a combination of hydrodynamic focusing, fluid resistors, and electronic techniques to achieve precision and ease of use heretofore unobtainable in a moderate-cost clinical instrument. Its application to whole blood platelet counting is discussed, and suggestions are made for its possible application to a wide variety of blood cell measurements.

Animals↗

Update on proliferation-associated antibodies applicable to formalin-fixed paraffin-embedded tissue and their clinical applications.

This review provides an update on proliferation-associated antibodies applicable to immunohistochemical techniques in formalin-fixed paraffin-embedded tissue. New insights into proliferating cell nuclear antigen (PCNA) and antibodies to PCNA are presented. The characterization of the protein recognized by the Ki-67 antibody has enabled production of a new range of antibodies (monoclonal and polyclonal) which have immunostaining profiles similar to those of the original antibody. A new proliferation-associated antibody, KiS1, is described. The clinical applications of antibodies to PCNA in human material are summarized, and the limitations of these studies are discussed.

Animals↗

Application of modeling and simulation to integrate clinical pharmacology knowledge across a new drug application.

Typical drug development includes few studies to find the right dose/dosing regimen and several other bridging studies evaluating various prognostic factors (e.g.: co-administration of other drugs, organ failure). The drug sponsors and the regulators use this information to formulate labeling instructions for safe and effective use of the drug. In the current article, modeling and simulation are proposed as tools to integrate the knowledge from the effectiveness/safety studies and the bridging studies. Simulations allow exploring the impact of various prognostic factors on the effectiveness and safety. The concept is exemplified using the new drug application of an anti-migraine drug. The exercise aids in integrating all the knowledge across the drug development to suggest rationale dosing strategies; effectively communicating the impact of the prognostic factors to the clinicians/regulators; and protect against any intellectual losses due to development team changes.

Computer Simulation↗

Relevance and applicability of a simple earthworm biomarker of copper exposure. II. Validation and applicability under field conditions in a mesocosm experiment with Lumbricus rubellus.

Earthworms Lumbricus rubellus were exposed to a range of increasing soil copper concentrations in a mesocosm experiment for 17, 40, 70, and 110 days, respectively. Neutral-red retention times were measured along with earthworm tissue copper residues and earthworm growth and survival. The neutral-red retention assay demonstrated a clear dose-response threshold preceding a copper exposure value where increased regulatory activity had resulted in the copper bioconcentration factor (BCF) decreasing from 1 to 0.5. Effects on earthworm growth and survival occurred only at soil copper concentrations where the earthworm BCFs were lowered to ca. 0.5. Thus, the position of the neutral-red threshold could potentially make it possible to differentiate between copper exposure and actual toxicity. In terms of field applicability it was demonstrated that natural and seasonal variations in climatic parameters had little or no effect on the neutral-red response. Neutral-red retention assay has a potential role in environmental risk assessment and routine monitoring, as it is likely to provide a sufficiently accurate warning of impending ecological damage at a level below that found to cause actual physiological damage to the earthworms.

Analysis of Variance↗

Application of automatic image analysis for morphometric studies of peroxisomes stained cytochemically for catalase. I. Electron-microscopic application.

The feasibility of the application of an electronic image analyzer, the Texture Analysis System (TAS) (Leitz Wetzlar, FRG), for fast automatic ultrastructural morphometric studies of hepatic peroxisomes has been investigated. Rat liver peroxisomes were stained selectively with the alkaline DAB procedure for localization of catalase in order to obtain sufficient contrast for automatic detection by TAS. Electron micrographs of ultrathin sections from this material were analyzed both automatically by TAS and manually by using a digitizer tablet connected with an Apple IIe microcomputer. The results showed negligible differences. As far as the speed of the operation is concerned, the image analysis was 4-5 times faster than the manual technique. In further studies, the importance of using DAB-stained sections for accurate morphometric studies of peroxisomes was demonstrated by comparing the results of such DAB-stained preparations with unstained material. This revealed that the numerical density was lower and the average profile diameter higher in unstained sections. The value for volume density was also affected, being about 30% lower in such preparations. It is likely that in unstained preparations small peroxisomes without crystalline nucleoids were frequently not identified as such and were not taken into account in morphometric calculations. These observations establish that computer-controlled electronic image analysis in conjunction with selective cytochemical staining of peroxisomes for catalase provides a fast, accurate and reliable method for ultrastructural morphometric studies of this organelle in rat liver.

Animals↗

Application of automatic image analysis for morphometric studies of peroxisomes stained cytochemically for catalase. II. Light-microscopic application.

The feasibility of the application of a television-based image analyzer, the Texture Analysis System (TAS, Leitz Wetzlar, FRG) in conjunction with a light microscope for morphometric studies of hepatic peroxisomes has been investigated. Rat liver peroxisomes were stained with the alkaline-DAB method for localization of catalase and semithin (0.25 and 1 micron) sections of plastic-embedded material were examined under an oil immersion objective. The TAS detected the peroxisomal profiles selectively and determined their morphometric parameters automatically. The same parameters were obtained also by morphometric analysis of electron micrographs from the same material. The volume density of peroxisomes determined by TAS in semithin sections of normal liver, after correction for section thickness, is quite close to the corresponding value obtained by morphometry of electron micrographs. The difference is approximately 20%. In animals treated with the hypolipidemic drug bezafibrate, which causes proliferation of peroxisomes, TAS detected readily the increase in volume density of peroxisomes in semithin sections. In comparison with electron microscopy, however, the light-microscopic approach seems to underestimate the proliferation. The lower resolution of the light microscope and overlapping of neighbouring particles in relatively thick sections used for light-microscopic analysis may account for the differences. The present study has demonstrated the usefulness of automatic image analysis in conjunction with selective cytochemical staining of peroxisomes for morphometry of this organelle in rat liver. The light-microscopic approach is not only faster but is also extremely economical by obviating the use of an electron microscope.

Animals↗

Applications of biological monitoring in occupational health practice: practical application of urinary 2-ethoxyacetic acid to assess exposure to 2-ethoxyethyl acetate in large format silk-screening operations.

A practical application of urinary 2-ethoxyacetic acid (EAA) to assess occupational exposure to 2-ethoxyethyl acetate (EGEE-Ac) during a large format silk-screening operation is described. Industrial hygiene air monitoring of employees of a silk-screen shop producing large aircraft interior panel coverings revealed a broad range of exposures to EGEE-Ac. Time weighted exposures averaged 12 ppm (range 2.9-34 ppm) in press operators during production press runs, exceeding the 5 ppm Washington State permissible exposure limit. Employees were instructed to use organic vapor respirators until engineering controls could be developed. Urinary monitoring of EAA was conducted on 30 employees by the company medical department to aid in exposure risk assessment and to assess compliance. Results obtained ranged from 1.1-27 mg EAA/g creatinine which compares favorably with the proposed Biological Exposure Index (BEI) of 100 mg EAA/g creatinine. Results of representative air and biological monitoring, and observations of work practices for different exposure groups indicated that inhalation exposure was the predominant route of exposure. Follow-up testing to assess the efficacy of a newly installed ventilation upgrade is planned.

Acetates↗

[Effect of high frequency application on the tongue base. In vitro results of "radiofrequency application" on the porcine tongue base].

BACKGROUND AND OBJECTIVE: A newly developed radio-frequency monopolar needle electrode was evaluated in vitro on porcine tongues. PATIENTS AND METHODS: Porcine tongues with different tissue temperatures (20+/-1) degrees C and (32+/-2) degrees C were coagulated for 90 s. In a second step, 23 coagulations at 7 W were applied (34+/-2) degrees C. RESULTS: The volume of the lesion correlated well with increasing temperature. In step two, the mean energy was 238 J and the mean volume of the lesion was 507 mm(3) (100+/-15)%. Prolonged energy application did not correlate with a larger volume of the lesion. CONCLUSION: The new radio-frequency needle electrode can reduce tongue volume in a precise and controlled manner (SD+/-15%).

Animals↗

The application of a 3D-QSAR (autoMEP/PLS) approach as an efficient pharmacodynamic-driven filtering method for small-sized virtual library: application to a lead optimization of a human A3 adenosine receptor antagonist.

We have recently reported that the combination of molecular electrostatic potential (MEP) surface properties (autocorrelation vectors) with the conventional partial least squares (PLS) analysis can be used to produce a robust ligand-based 3D structure-activity relationship (autoMEP/PLS) for the prediction of the human A3 receptor antagonist activities. Here, we present the application of the 3D-QSAR (autoMEP/PLS) approach as an efficient and alternative pharmacodynamic filtering method for small-sized virtual library. For this purpose, a small-sized combinatorial library (841 compounds) was derived from the scaffold of the known human A3 antagonist pyrazolo-triazolo-pyrimidines. The most interesting analogues were further prioritized for synthesis and pharmacological characterization. Remarkably, we have found that all the newly synthetized compounds are correctly predicted as potent human A3 antagonists. In particular, two of them are correctly predicted as sub-nanomolar inhibitors of the human A3 receptor.

Adenosine A3 Receptor Antagonists↗

[The use of clomiphene citrate in ambulatory medicine practice in the Midi-Pyrénées area: compliance to national guidelines applicable to infertility diagnosis and to prescription and monitoring rules applicable to clomiphene citrate treatments].

OBJECTIVE: Evaluate the compliance to the national guidelines from ANDEM (1996) and AFSSAPS (2003) concerning the diagnosis of infertility, the prescription of clomiphene and the monitoring of these treatments. PATIENTS AND METHODS: Retrospective study of female patients from 16 to 50 y.o. having benefited from reimbursement of clomiphene citrate treatment between 1st April 2002 and 30th June 2002. After random sampling stratified on age, data on diagnosis procedures and treatments were extracted from the Social Security reimbursement database. These data were validated and completed by patients' interviews. RESULTS: A total of 283 women were included. 30% were subject to the basic hormonal tests (FSH, LH, estradiol). The proportion of patients explored by hysterosalpingogram, post-coital test and echography were respectively 50%, 35% and 68%. A semen analysis was found in 60% of the partners. The complete set of recommended tests before start of treatment was realised in 1.5% of women. In 7% of cases, women were treated without prior exploration. The proportion of tests performed was comparable below and above the age of 35. 77% of treatments were initiated after at least one year of waiting for a spontaneous conception. 69% of women were monitored during treatment by other methods than clinical follow-up. CONCLUSION: Prescription of clomifene citrate is too frequently realised without compliance to guidelines applicable to infertility investigations and therefore without persuasive diagnosis. These practices can lead to loss of childbearing opportunities and complications.

Adult↗

Repetitive low-energy shock wave application without local anesthesia is more efficient than repetitive low-energy shock wave application with local anesthesia in the treatment of chronic plantar fasciitis.

BACKGROUND: It remains unclear whether application of local anesthesia (LA) interferes with clinical efficacy of extracorporeal shock wave therapy (ESWT) for chronic plantar fasciitis. AIMS: To evaluate the effect of local anesthesia on the clinical outcome after repetitive low-energy ESWT for chronic plantar fasciitis. METHODS: Eighty-six patients with chronic plantar fasciitis were randomly assigned to receive either low-energy ESWT without LA, given weekly for three weeks (Group I, n=45; 3 x 2000 pulses, total energy flux density per shock 0.09 mJ/mm2) or identical ESWT with LA (Group II, n=41). Primary outcome measure was: Reduction of pain from baseline to month 3 post-treatment in a pain numeric rating scale [0-10 points] during first steps in the morning, evaluated by an independent blinded observer. Calculations were based on intention-to-treat. RESULTS: No difference was found between the groups at baseline. At 3 months, the average pain score was 2.2+/-2.0 points for patients of Group I, and 4.1+/-1.5 points for patients of Group II. The mean between-group difference was 1.9 points (95% CI: [1.1-2.7 points]; P<.001). Significantly more patients of Group I achieved 50% reduction of pain compared to Group II (67% vs 29%, P<.001). CONCLUSION: ESWT as applied should be done without LA in patients suffering from chronic heel pain. LA applied prior treatment reduced the efficiency of low-energy ESWT.

Adult↗

An overview of the development, validation, and application of neurobehavioral and neuromolecular toxicity assessment batteries: potential applications to combustion toxicology.

Currently, there are few alternatives to the use of animals in toxicology for human risk assessment. Neurobehavioral toxicology is an emerging area in which complex performance capacity is evaluated during or following toxicological exposure. While a number of single tests and a few more complex neurobehavioral batteries exist, no fully validated and comprehensive neurobehavioral toxicity assessment battery has yet been developed. The Neurobehavioral Toxicity Assessment Battery (NTAB) is a multi-test battery being developed by the Naval Medical Research Institute Detachment (Toxicology) (NMRI/TD) to categorize the potential neurobehavioral toxicity of compounds of Navy interest, especially those found in combustion atmospheres. The NTAB is intended to identify specific areas of deficit (e.g. motivational, sensory, motor, and cognitive) from complex changes in performance induced by toxic exposures, as well as to provide a mechanism to evaluate recovery of neurobehavioral integrity. Portions of the NTAB have been successfully used to assess the risk of brief exposure to low concentrations of combustion gases, including smoke from electrical aircraft fires, ozone-depleting substances and their replacements, and the novel neuroconvulsant trimethylolpropane phosphate. The goal of the NMRI/TD Neurobehavioral Toxicology Group and the Tri-Service Toxicology Consortium's neurobehavioral toxicology program is the incorporation of more molecular techniques involving neurophysiology, neuropharmacology, in vivo electrochemistry, and real-time microdialysis for correlative use with the neurobehavioral battery in human risk assessment. This overview discusses the application of neurobehavioral and neuromolecular endpoint test batteries to combustion toxicology.

Animals↗