A Critical Reappraisal of the Bleeding Time.

Seminars in Thrombosis and Hemostasis (STH) celebrates 50 years of publishing in 2024. To celebrate this landmark event, STH is republishing some archival material. This manuscript represents the second most highly cited paper ever published in STH. The manuscript published without an abstract, and essentially represented a State of the Art Review on the bleeding time, a relatively invasive procedure that required an incision on the skin or earlobe of a patient, and timing how long it took for the incision to stop bleeding. The bleeding time test was first described in 1901 by the French physician Milian, who presented three studies of bleeding from stab wounds made in the fingertips of healthy and diseased subjects. In 1910, Duke observed the duration of bleeding from small incisions of the ear lobe, and pointed out that the duration of bleeding was increased in instances of reduced platelet counts. The test was subsequently repeatedly modified, and numerous variants of the test, including semiautomated methods, were described by several workers. The most frequently utilised test reflected one described by Ivy and coworkers, who shifted the location of the incision to the volar aspect of the forearm and applied a blood pressure cuff to the arm to maintain a standard venous pressure. The bleeding time has been proposed for use as a diagnostic test for platelet-related bleeding disorders, a measure of efficacy in various forms of therapy, and as a prognosticator of abnormal bleeding. The authors to the current review reevaluated the bleeding time literature using methods to assess the performance of the test in 1990, locating 862 printed documents that discussed the bleeding time, the majority in peer-reviewed professional journals. As this is a republication of archival material, transformed into a modern format, we apologise in advance for any errors introduced during this transformation.

Characteristics of orphan drug applications that fail to achieve marketing approval in the USA.

The US Orphan Drug Act has fostered the development of drugs for patients with rare diseases by granting 'orphan designations', although several orphan drugs for which a marketing application has been submitted to the FDA have failed to obtain approval. This study identified the clinical trial design, the level of experience of the sponsor and the level of interaction with the FDA to be associated with non-approval. Sponsors, therefore, should engage in dialogue with the FDA and thoughtfully design pivotal clinical trials in accordance with FDA guidance documents.

Fourier transform ion cyclotron resonance: state of the art.

This short review summarizes recent and projected advances in Fourier transform ion cyclotron resonance mass spectrometry instrumentation and applications, ranging from petroleomics to proteomics. More details are available from the cited primary literature and topical reviews.

Creating a clinical video-conferencing facility in a security-constrained environment using open-source AccessGrid software and consumer hardware.

The Department of Laboratory Medicine at the University of California, San Francisco (UCSF) has been split into widely separated facilities, leading to much time being spent traveling between facilities for meetings. We installed an open-source AccessGrid multi-media-conferencing system using (largely) consumer-grade equipment, connecting 6 sites at 5 separate facilities. The system was accepted rapidly and enthusiastically, and was inexpensive compared to alternative approaches. Security was addressed by aspects of the AG software and by local network administrative practices. The chief obstacles to deployment arose from security restrictions imposed by multiple independent network administration regimes, requiring a drastically reduced list of network ports employed by AG components.

ICPC Multilingual Collaboratory: a Web- and Unicode-based system for distributed editing/translating/viewing of the multilingual International Classification of Primary Care.

The International Classification of Primary Care (ICPC) is a clinical classification containing 726 clinical concepts, available in over 20 languages, augmented by links to ICD-10 concepts. It is employed in clinical information systems in several European countries, Israel, Japan, and Australia. In translating ICPC, it has been challenging to manage the flow of multilingual information, maintain its quality, and optimize its portability, particularly in light of the numerous character encodings used to represent its content. The ICPC Multilingual Collaboratory (IMC) is a World Wide Web-based environment, created to allow the viewing, maintenance, and translation of ICPC content by a dispersed international editorial staff. Based upon open-source software, it represents ICPC content using the Unicode standard for character encoding. The system implements three interfaces to ICPC data: 1) a password-protected editorial interface which instantiates a hierarchical authority model and communication channels for review and control of content, including a means of up-loading new candidate translations; 2) an openly accessible read-only interface, with e-mail access to the editors (providing another level of content review); and, 3) a management interface for the system administrator. The completed system powerfully demonstrates the ability of the World Wide Web, open-source software, and Unicode to expedite and simplify international multilingual collaboration, even in a world in which Unicode support is incomplete on existing computing platforms.

Kendrick mass defect spectrum: a compact visual analysis for ultrahigh-resolution broadband mass spectra.

At currently achievable Fourier transform ion cyclotron resonance broadband mass spectrometry resolving power (m/deltam50% > 350,000 for 200 < m/z < 1,000), it would be necessary to spread out a conventional mass spectrum over approximately 200 m in order to provide visual resolution of the most closely resolved peaks. Fortunately, there are natural gaps in a typical mass spectrum, spaced 1 Da apart, because virtually no commonly encountered elemental compositions yield masses at those values. Thus, it is possible to break a broadband mass spectrum into 1-Da segments, rotate each segment by 90 degrees, scale each segment according to its mass defect (i.e., difference between exact and nominal mass), and then compress the spacing between the segments to yield a compact display. For hydrocarbon systems, conversion from IUPAC mass to "Kendrick" mass (i.e., multiplying each mass by 14.00000/14.01565) further simplifies the display by rectilinearizing the peak patterns. The resulting display preserves not only the "coarse" spacings (e.g., approximately 1 Da between odd and even masses, corresponding to either even vs odd number of nitrogens or 12C(c) vs 12C(c-1)13C1 elemental compositions of the same molecule; approximately 2-Da separations, corresponding to a double bond or ring; approximately 14 Da separations, corresponding to one CH2 group) but also the "fine structure" (i.e., different mass defects for different elemental compositions) across each 1-Da segment. The method is illustrated for experimental electrospray ionization FTICR ultrahigh-resolution mass spectra of a petroleum crude oil. Several thousand elemental compositions may be resolved visually in a single one-page two-dimensional display, and various compound families-class (NnOoSs), type (Z in C(c)H2(c+z)NnOoSs), and alkylation series-may be identified visually as well.

Compositional analysis for identification of arson accelerants by electron ionization Fourier transform ion cyclotron resonance high-resolution mass spectrometry.

Elemental compositions of each of 100 to 500 different constituents (i.e., every peak in a mass-to-charge ratio range, 50 < m/z < 300) of lighter fluid, kerosene, turpatine, gasoline, diesel fuel, and two brands of mineral spirits (and their weathered analogs) make possible direct identification of each accelerant in a experimental fire, based on electron ionization 6.0 Tesla Fourier transform ion cyclotron resonance (EI FT-ICR) ultrahigh resolution mass spectrometry. Septum injection of as little as 500 nL of accelerant into an all-glass heated inlet system yields definitive elemental compositions (molecular formulas) based on accurate (< +/-1 ppm average error) mass measurement alone. Extraction and EI FT-ICR mass analysis of fire debris from a controlled burn of a couch with simple (lighter fluid) and complex (turpatine) ignitable liquid yielded dozens of elemental compositions serving as a unique "fingerprint" for each petroleum product, despite the presence of up to 249 additional extracted matrix and pyrolysis components. Forty-five of 56 lighter fluid constituents and 126 of 133 turpatine constituents (not counting 13C-containing species) were identified in the debris from a fire staged for each respective accelerant.

Stable isotope incorporation triples the upper mass limit for determination of elemental composition by accurate mass measurement.

By comparing electrospray ionization Fourier-transform ion cyclotron resonance (FT-ICR) mass spectra and collision-induced dissociation (CID) FT-ICR mass spectra of a phospholipid (851 Da) extracted from natural abundance and 99% 13C bacterial growth media, we are able to reduce its number of possible elemental compositions (based on +/-10 ppm externally calibrated mass accuracy and biologically relevant compositional constraints) from 394 to 1. The basic idea is simply that the mass of a molecule containing N carbon atoms increases by N Da when 12C is replaced by 13C. Once the number of carbons is known, the number of possible combinations of other atoms in the molecule is greatly reduced. We demonstrate the method for a stored-waveform inverse Fourier transform-isolated phospholipid from an extract of membrane lipids from Rhodococcus rhodochrous hydrocarbon-degrading bacteria grown on either natural abundance or 99% 13C-enriched mixtures of n-hexadecane and n-octadecane. We project that this method raises the upper mass limit for unique determination of elemental composition from accurate mass measurement by a factor of at least 3, thereby extending "chemical formula" determination to identification and sequencing of larger synthetic and bio-polymers: phospholipids, oligopeptides of more than three to four amino acids, DNA or RNA of more than two nucleotides, oligosaccharides of more than three sugars, etc. The method can also be extended to determination of the number of other atoms for which heavy isotopes are available (e.g., 15N, 34S, 18O, etc.).

Searching for biomedical information on the World Wide Web.

The rapid growth of biomedical information available via the Internet and its most popular retrieval system, the World Wide Web, has fostered active research and development directed toward locating resources that are appropriate for answering specific queries. The goal is to create tools that optimize information retrieval (as measured by two quantities, precision and recall) while minimizing the effort required by the user. Existing Web retrieval tools can be divided into the following groups: manually maintained topical lists; automatically generated word-based indices; software agents and multi-index searching aids; network cataloging methods; and miscellaneous hybrid and newer approaches. Improvements in current methods should arise from further research into: methods of describing objects on the Web; improved ways of searching for (and within) collections of documents as opposed to single documents; the ability to search for fielded documents; and ways to describe resources that span intra- and interdisciplinary as well as cross-cultural linguistic differences. For this last problem, the U.S. National Library of Medicine's Unified Medical Language System (UMLS) will be of great help. As online information retrieval improves, efforts are underway to improve the online information itself; quality control over content is being addressed as the peer-review systems of traditional printed journals migrate into the realm of electronic publication.

Java and its future in biomedical computing.

Java, a new object-oriented computing language related to C++, is receiving considerable attention due to its use in creating network-sharable, platform-independent software modules (known as "applets") that can be used with the World Wide Web. The Web has rapidly become the most commonly used information-retrieval tool associated with the global computer network known as the Internet, and Java has the potential to further accelerate the Web's application to medical problems. Java's potentially wide acceptance due to its Web association and its own technical merits also suggests that it may become a popular language for non-Web-based, object-oriented computing.

A critical reappraisal of the bleeding time.

Since its initial invention by the French worker Milian in 1901, the bleeding time has been put forward as a clinically useful test in three contexts: diagnosis (particularly of platelet disorders), prediction of clinically important bleeding, and assessment of the adequacy of various forms of therapy. Attempting a complete review of the published experience with this test, we assessed 862 articles. Original bleeding time data appeared in 664 of these articles, from which we tabulated 1083 distinct studies in humans. ROC analysis, which characterizes the sensitivity and specificity of the test, was applied in every instance in which published data were adequate (34 studies). ROCs from 27 studies of the bleeding time in association with aspirin ingestion reveal high variability in the ability of the bleeding time to detect aspirin intake, and provide evidence against claims that recently devised bleeding time methods have improved discriminatory ability based on improved reproducibility. Two ROCs from surgical studies, in which the bleeding time was used to try to predict abnormal bleeding, were statistically indistinguishable from that of a completely noninformative test. In ROCs from five studies of abnormal bleeding in uremia, the test performed approximately the same as the platelet count or hematocrit (taken singly); in one of these studies, prothrombin consumption was determined and was a better predictor of bleeding than bleeding time, hematocrit, or platelet count. In the settings of renal biopsy (one study) and massive transfusion (one study), data allowed estimation of predictive value: in no instance was there evidence that the bleeding time significantly altered a priori estimates (based on prevalence) of the risk of bleeding. Linear regression analysis was applied to data from 23 studies relating platelet count to bleeding time, to assess published claims that the bleeding time and platelet count follow a predictively useful linear relationship. In 22 of 23 instances, the inverse relationship between bleeding time and platelet count was associated with broad statistical scatter, making it impossible to predict precisely one variable given the other. The pathophysiology of an abnormal bleeding time remains poorly understood. The bleeding time is affected by a large number of diseases, drugs, physiologic factors, test conditions, and therapeutic actions, not all of them platelet-related. The test is likely to remain widely used for the diagnosis of inherited disorders of platelet function, such as von Willebrand's syndrome, despite the lack of clear criteria for its use in this context.(ABSTRACT TRUNCATED AT 400 WORDS)

Persistent immune complexes and abnormal CD4/CD8 ratios in HIV infection.

We assessed the immunopathologic role of circulating immune complexes in human immunodeficiency virus infection by evaluating the data base and the serum bank of the San Francisco Men's Health Study, a longitudinal clinical and epidemiological investigation conducted since 1983. A group of 4,276 sera from 1,023 (including 811 homosexual/bisexual) men were tested for circulating immune complexes. We used a modification of the commercially available enzyme immunoassay test, based on monoclonal anti-C1q antibodies coupled to the solid phase, for capturing circulating immune complexes from the test serum, followed by detection of circulating immune complexes with either anti-IgG or with anti-IgM probes. Although persistent IgM and IgG circulating immune complexes were most frequently encountered in human immunodeficiency virus-seropositive homosexual/bisexual men, they were not an indicator of disease progression as assessed by abnormalities in the absolute numbers or ratios of CD4- and CD8-positive T cells, or clinical signs and symptoms of AIDS/ARC.

(PLOT79): a comprehensive portable Fortran scientific line graphics system, as applied to biomedical research.

Scientific results are often most succinctly presented in graphical form. We describe a system for computer-generated scientific line graphics known as (PLOT79), named to commemorate the SIGGRAPH CORE graphics standard proposal of 1979. (PLOT79) is a widely used and actively evolving graphics system, written primarily in SFTRAN3, a structured procedural computer language which can be translated readily into Fortran. The package embodies concepts of sound software engineering, having been designed from the outset to be portable, maintainable and hardware-independent; much of the effort required to implement the system was directed toward the development of software engineering tools to ensure these goals. A modular design strategy has allowed a wide variety of graphics output devices to be supported. (PLOT79) has been installed under numerous operating systems, and software tools provided by UNIX have allowed particularly efficient installation and use of the system. Access to (PLOT79) is available through three avenues: (1) linking (PLOT79) routines with a user-written high-level program; (2) use of pre-written high-level applications programs which perform certain frequently-required tasks such as the plotting of simple two or three-dimensional data; or (3) the use of an interactive graphics command parser known as slides. (PLOT79) has proven popular among workers in the physical sciences and engineering both for its easy availability, openness (all source code is provided), and powerful capability. The system presents an equally important (though lesser known) resource for biomedical research, as demonstrated by examples from ongoing biomedical research projects. It also provides a focus for discussion of the practical limitations inherent in existing graphics standards and programming languages.

Interrelations of lymphocyte subset values, human immunodeficiency virus antibodies, and HIV antigen levels of homosexual males in San Francisco.

Serum and leukocytes from a cohort of homosexual males were analyzed to determine the interrelationships of antibodies to human immunodeficiency virus (HIV), serum HIV antigen levels, and phenotypical differences in lymphocyte subpopulations of HIV antibody-positive (HIV Ab+) and HIV antibody-negative (HIV Ab-) homosexual males. Significant reductions were observed in the percentages of B lymphocytes, CD4+ and CD4+ kappa lambda- T lymphocytes and the CD4+/CD8+ ratios of HIV Ab+ homosexual males in comparison to HIV Ab- homosexual males. Significant increases were observed in the percentages of CD8+, CD8+ CD11b-, CD8+ kappa lambda-, CD8+ DR+, CD8+Leu7+, and Leu7+ lymphocytes of HIV Ab+ study subjects. Statistical analysis revealed that among the immunological variables tested, decreases in the CD4+/CD8+ ratio and in the percentage of CD4+ kappa lambda- lymphocytes showed the strongest associations with HIV-sero-positivity in asymptomatic homosexual males. Only 44 (16.5%) of 267 HIV Ab+ homosexual males had detectable levels of HIV antigen (HIV Ag) in their serum. The percentages of CD4+ or CD4+ kappa lambda- lymphocytes and the CD4+/CD8+ ratios of HIV Ab+ males differed significantly between HIV Ag-positive (HIV Ag+) and--negative (HIV Ag-) homosexual males. These variables, however, did not correlate well with HIV Ag levels,indicating that no clear associations can be drawn between levels of HIV antigen and lymphocyte subset abnormalities of HIV-infected individuals.