Iliad: diagnostic tools for general medicine. Interview by Bill W. Childs.
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Diagnosis, Computer-Assisted↗
Biomedical subjects
H R Warner
Publications and source records attributed to H R Warner.
Does genotypic sex have a direct effect on longevity?
Females of the human species live longer than males, and the longevity differential is probably not entirely explained by reasons which are presently obvious. Genotypic sex has long been suspected to affect longevity to the advantage of the female. Several recent findings about the X and Y chromosomes must be reckoned with in considering determinants of longevity which derive from genotypic sex. The advantages of having two X chromosomes are apparent, notwithstanding X-chromosome inactivation. Not only can some cells compensate for biosynthetic deficiencies of others, but also cell selection according to which X chromosome is active can occur during development according to cell viability and proliferative capacity. It has recently been observed that at least some genes on inactive X chromosomes are reactivated late in life. Details of the reactivation process must be studied to determine its significance and the effects of the process on late life survival. The recent mapping of the catalytic polypeptide of DNA-polymerase-alpha to the X chromosome calls attention to a new property of the genotype which could affect the basic ability of cells to proliferate. It is likely that this enzyme, perhaps in concert with DNA-polymerase-delta, is required for DNA replication, suggesting that two alleles for this enzyme and cell selection within the female phenotypic mosaic for DNA replication may provide a sex-linked determinant of cell proliferation which could be advantageous in late life. Much remains to be learned about the Y chromosome, although there are early results consistent with a determinant of longevity on that chromosome which operates to the male disadvantage and probably does not involve sex hormones. The genotype may be a significant determinant of longevity in humans even if it does not appear to be so in non-human animals, because causes of death are different. Determinants of longevity are based on susceptibility or vulnerability to the causes and diseases of mortality, and these differ in different species.
Female↗
Control of cell proliferation in senescent cells. Introduction.
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Aging↗
Involvement of DNA repair in cancer and aging.
The theory of aging which proposes that DNA repair capacity declines with age and/or DNA damage accumulates with age, resulting in increasingly aberrant gene expression, is attractive but still unproven. Most results that do not support the theory are at least neutral. We propose that much of the ambiguity produced by work so far is due to (a) the difficulty of controlling all relevant variables, including particularly the proliferation state of the cells used and the location and nature of the damage being repaired, and (b) the existence of multiple and overlapping DNA repair pathways. A better knowledge of the critical, rate-limiting events in DNA repair in vivo, and the application of more sophisticated approaches for studying these events, may ultimately resolve the ambiguities. The causal relationship between DNA damage and cancer seems more secure. Declining DNA repair capacity with age would be expected to accelerate the increased incidence of cancer with age, but it is not known how important this is compared to other genetic and environmental variables. Results with genetic diseases generally support this view. Diseases characterized by DNA repair deficiencies are accompanied by phenomena that are also characteristic of normal aging, but a causal relationship has not been established. However, some of these diseases do constitute a strong risk factor for cancer. Even less convincing is a causal link between DNA repair deficiencies and aging in the so-called premature aging syndromes.
Aging↗
Iliad: moving medical decision-making into new frontiers.
If the essence of clinical practice is a process of sequential problem-solving, whereby a physician works with a patient to formulate a series of decisions about diagnostic treatment, then it would naturally follow that the essence of medical education should evolve around the training of would-be clinicians in the difficult art of diagnostic decision-making. Yet this is not often the case.
Clinical Clerkship↗
Integrated Academic Information Management Systems (IAIMS). Part III. Implementation of integrated information services. Clinical linkages: IAIMS at the University of Utah.
The IAIMS project at the University of Utah has focused on clinical linkages to facilitate the research, teaching, and service mission of the Medical Center. The planning phase focused on the relationship among ther users and providers of the system and developed a scenario describing the professor and clinical clerk making rounds in the bedside setting. The prototype Health Evaluation through Logical Processes (HELP) system brings together three sources necessary to solve a medical problem: the patient database, the medical literature, and an expert in the subject. Microcomputers provide access to the HELP system and a complementary literature knowledge database.
Academic Medical Centers↗
What you don't know can hurt you.
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Evaluation Studies as Topic↗
A decision-driven system to collect the patient history.
We have developed a computer-administered history designed to directly interview hospitalized patients with pulmonary disease. A frame-based decision system is used to direct the history and to generate a one- to five-member differential diagnostic list based on this history. This system incorporates a cognitive model of question selection and a Bayesian scoring algorithm. Structures to control the choice of questions are embedded in the diagnostic frames and in a QUERY program that makes the final choice of questions. We have compared the behavior of this decision-driven approach with a history taken using a paper questionnaire. The paper-based history presents 182 questions to every patient and captured 75% of 85 pulmonary diseases in its differential lists. The decision-driven system asks 50.7 +/- 31.0 (mean +/- standard deviation) and captured 74% of 61 pulmonary diseases. Our experience suggests that the use of a computerized diagnostic knowledge base to direct the selection of pertinent questions can substantially reduce the number of questions necessary to collect a diagnostically useful patient history.
Artificial Intelligence↗
The Partial Purification and Characterization of Nuclear and Mitochondrial Uracil-DNA Glycosylase Activities from Zea mays Seedlings.
Uracil-DNA glycosylase activities from etiolated Zea mays seedling nuclei and mitochondria were partially purified and characterized. Nuclei and mitochondria were separated using sucrose differential and step gradient centrifugation. Experiments with osmotically shocked organelles indicated that enzyme activity from mitochondria was soluble, whereas nuclear enzyme activity was only partially soluble under the conditions tested. Purification using DEAE-cellulose and Affigel Blue column chromatography yielded distinct elution profiles from both columns for each of the organellar enzyme activities. Final purification was 490- and 850- fold for the nuclear and mitochondrial uracil-DNA glycosylase, respectively. Characterization studies demonstrated significant differences between the nuclear and mitochondrial uracil-DNA glycosylase with respect to K(m), temperature, and pH activity optimum, the effect of salts, and substrate preference. Molecular weight as determined by gel filtration was 18,000 for enzymes from both sources. Both were also sensitive to the sulfhydryl group-blocking agent N-ethylmaleimide. A number of uracil analogs were tested for their ability to inhibit nuclear and mitochondrial uracil-DNA glycosylase activities. 5-Azauracil, uracil, 6-aminouracil, 6-azauracil, 5-aminouracil, and 5-fluorouracil all inhibited both activities to variable degrees.
Journal Article↗
Partial Purification and Characterization of Uracil-DNA Glycosylase Activity from Chloroplasts of Zea mays Seedlings.
A uracil-DNA glycosylase activity has been purified about 750-fold from the chloroplasts of light-grown Zea mays seedlings. This report represents the first direct demonstration of a DNA-glycosylase repair activity in chloroplasts. The activity, in part, was associated with a chloroplast Triton X-100 sensitive membrane. Its apparent K(m) was 1.0 micromolar for a poly(dA-dT/U) substrate, and its molecular weight, as determined by gel filtration, was 18,000. The enzyme exhibited optimal activity at pH 7.0 with an atypically narrow pH tolerance. Activity was inhibited greater than 60% by 10 millimolar NaCl, 5 millimolar MgCl(2), or 5 millimolar EDTA. Enzyme activity was inhibited 80% by 10 millimolar N-ethylmaleimide, a sulfhydryl group-blocking agent. The activity removed uracil more rapidly from single-stranded DNA than from double-stranded DNA. With this report, uracil-DNA glycosylase activity has now been attributed to all three DNA-containing organelles of eucaryotic cells.
Journal Article↗
Bringing HELP to the clinical laboratory--use of an expert system to provide automatic interpretation of laboratory data.
In domains where the types of data which are to be interpreted are relatively constrained (as in the case of specific laboratory test results), our modular data-driven approach can be very productive and well received by the clinical recipient of the data. The computer rarely surpasses the knowledge of an experts result from lack of communication, imperfect memory, oversight or multiple decision-makers caring for the same patient. In such cases, most of the alerts are immediately recognized as valid, so the need for elaborate explanations is not a high priority. On the other hand, a non-specialist is alerted to the need for additional investigation, tests or collaborative support, by the fact that a reminder or diagnosis that s/he had not previously considered, appears. In other words, for the expert, a data-driven system provides unceasing oversight in high-volume low-yielded situations where a small number of mistakes may uncommonly occur for reasons which are not related to the lack of knowledge of the provider. For the non-specialist the system suggests that the patient may have problems in a domain for which the physician needs additional support. In the present state of the art, we do not think that total reliance on the computer-contained knowledge is the ultimate source of this additional support; providing the awareness of the need may be the most important contribution. Once you know that you need help, it is usually obtainable. In a discussion about how computer systems have failed, Friedman and Gustafson made the following observation.(ABSTRACT TRUNCATED AT 250 WORDS)
Decision Making, Computer-Assisted↗
Cell-free transcription and translation of isolated restriction fragments localize bacteriophage T5 pre-early genes.
In vitro transcription and translation of isolated restriction fragments containing all or part of the terminal redundancies of bacteriophage T5 localized virtually every pre-early gene to a small 6.3-kilobase BglI fragment. Among these genes were those encoding the A1 and A2 proteins, which are responsible for complete entry of the viral genome into its host, and the deoxynucleoside 5'-monophosphatase. A 3.9-kilobase BglI fragment containing the remainder of the pre-early region induced no proteins under these same conditions. Proteins induced by fragments including the right and left terminal redundancies were also compared and found to be identical. DNA immediately flanking the pre-early regions induced few proteins in vitro. Thus, this technique has allowed the overall gene organization of the pre-early region of T5 to be described.
Cell-Free System↗
Development of a computerized infectious disease monitor (CIDM).
At the LDS Hospital in Salt Lake City, an interface was developed between the microbiology laboratory computer system and the HELP integrated central hospital computer system. The HELP system includes medical information from most clinical care support areas. The microbiology data are translated from the laboratory computer file structure to a hierarchical data structure on the HELP system. A knowledge base was created with the help of infectious disease experts, and became part of a Computerized Infectious Disease Monitoring system (CIDM). The knowledge base is automatically activated when specific microbiology data are entered into a patient's computer file (data driven), thus decisions are made automatically with no additional effort required of medical personnel. The CIDM was designed to inform infectious disease personnel when a patient has one of the following conditions: a hospital-acquired infection, an infection at a normally sterile body site, an infection due to a bacteria with an unusual antibiotic sensitivity pattern, an infection for which the patient is not receiving an antibiotic to which the offending bacteria is sensitive, an infection that could be treated with a less expensive antibiotic, an infection which is required by law to be reported to state and national health authorities, and those patients receiving prophylactic antibiotics longer than is medically indicated. All of the microbiology data are now extensively reviewed by nurses and physicians from terminals at nursing stations or intensive care units. The CIDM is currently being used for hospital-acquired infection surveillance at LDS Hospital.
Anti-Bacterial Agents↗
Isolation and partial characterization of a bacteriophage T5 mutant unable to induce thymidylate synthetase and its use in studying the effect of uracil incorporation into DNA on early gene expression.
A mutant of phage T5 which is unable to induce thymidylate synthetase was isolated. T5 thy mutants synthesized less DNA than did wild-type T5, and the burst size of progeny phage was correspondingly reduced two- to threefold in thy+ Escherichia coli. No DNA or progeny phage were made in E. coli thy hosts grown in the absence of exogenous thymine. When the T5 thy mutation was recombined with a T5 dut mutation (unable to induce dUTPase), replication resulted in progeny which contained significant amounts of uracil in their DNA, and these phage failed to produce plaques unless the plating host was deficient in uracil-DNA glycosylase. T5 phage containing various amounts of uracil in their DNA were prepared and used to determine the effect of uracil on the induction of the early enzyme dTMP kinase. The presence of uracil in the parental DNA increased the rate of induction of this enzyme by about 2.5-fold. The T5 thy gene was mapped and is located near the T5 frd gene on the B region of the T5 genome.
Chromosome Mapping↗
Base excision repair in the thermophile Thermus sp. strain X-1.
The thermophile Thermus sp. strain X-1, grown at 70 degrees C, contains uracil-DNA glycosylase and apurinic endonuclease activities, both of which are known to have roles in the repair of DNA damaged by heat. Both of these activities have temperature optima of about 70 degrees C. However, neither of these activities is present in quantities significantly greater than that found in Escherichia coli grown at 37 degrees C. Therefore, it appears that thermophilic organisms may not contain greatly elevated levels of the enzymes thought to be involved in the repair of DNA damaged by heat.
DNA Glycosylases↗
Computer-based ICU data acquisition as an aid to clinical decision-making.
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Computers↗