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Biomedical subjects

D L Hudson

Publications and source records attributed to D L Hudson.

35 records · Page 2Linked to original sources
PubMed1994

Information integration in a decision support system.

Electronic medical records pose a challenge because of the complex types of data which are included. Decision support systems must be able to deal effectively with these data types. In the expert system demonstrated here, a diversity of data types are included. These data are processed by three different methods. However, the different methods of processing are transparent to the user. An overall rule-based interface integrates the different methods into one comprehensive system.

Artificial Intelligence↗
PubMed1993

Towards gene therapy for haemophilia B using primary human keratinocytes.

Haemophilia B might be permanently cured by gene therapy--the introduction of a correct copy of the factor IX gene into the somatic cells of a patient. Here, we have introduced a recombinant human factor IX cDNA into primary human keratinocytes by means of a defective retroviral vector. In tissue culture, transduced keratinocytes were found to secrete biologically active factor IX and after transplantation of these cells into nude mice, human factor IX was detected in the bloodstream in small quantities for one week. This is the first demonstration of a therapeutic protein reaching the bloodstream from transduced primary keratinocytes. This may have implications for the treatment of haemophilia B and other disorders.

Animals↗
PubMed1993

Evidence against a major role for integrins in calcium-dependent intercellular adhesion of epidermal keratinocytes.

It is well established that integrins mediate keratinocyte adhesion to extracellular matrix proteins, but, in addition, there is some evidence that they mediate intercellular adhesion. We have investigated the role of integrins in keratinocyte-keratinocyte adhesion by adding anti-integrin antibodies to cells in three assays that differ according to the calcium ion concentration of the medium, the presence or absence of an adhesive substrate (glass or tissue culture plastic) and the timing of antibody addition. As previously reported by Larjava et al., (J. Cell Biol. 110:803-815), a monoclonal antibody to the beta 1 subunit perturbed cell-cell adhesion when added to adherent monolayers in low calcium medium (0.1 mM calcium ions), but did not prevent cell-cell adhesion or stratification induced by raising the level of calcium ions to 1.8mM (the concentration in standard medium). Monoclonal antibodies to both the alpha 3 and beta 1 subunits inhibited the attachment, spreading and motility of keratinocytes in low or standard calcium medium when added at the time of plating; however, they had only a modest effect on the accumulation of cells in adherent clusters. Aggregation of keratinocytes in suspension required a calcium ion concentration of greater than 0.1mM and was not inhibited by any of a large panel of anti-integrin antibodies, including three new antibodies that recognise alpha 2 beta 1. We conclude that any inhibitory effects of individual anti-integrin antibodies on cell-cell adhesion are abrogated by a calcium ion concentration above 0.1mM and that in low calcium medium at least some of the inhibition of cell-cell adhesion is a consequence of the inhibition of cell-substrate adhesion and motility.

Antibodies, Monoclonal↗
PubMed1992

Characterisation of eight monoclonal antibodies to involucrin.

Involucrin is a precursor of the insoluble protein envelope that is assembled in the outermost layers of the epidermis. The coding sequence of the protein contains a number of short tandem repeats that have been greatly altered during mammalian evolution. We have characterised eight mouse monoclonal antibodies raised against human involucrin, all of which bind to the protein in immunoprecipitation, immunoblot and immunohistochemical preparations. Each antibody was screened for cross-reactivity with gorilla, owl monkey, dog and pig involucrin and with a fragment of the human protein, expressed in lambda gt 11, that includes the entire early region of the modern segment of repeats. Three antibodies recognised involucrin in all of these assays. Four antibodies recognised primate involucrins and the lambda gt 11 fragment. One antibody, which showed cross-reactivity with lower molecular weight proteins, only recognised primate involucrins and therefore bound outside the early region of the modern segment. Since the antibodies can be used to detect involucrin both biochemically and histologically, in a range of species, they will have applications in further studies of the expression, function and evolution of the protein.

Amino Acid Sequence↗
PubMed1991

Mitogens induce calcium transients in both dividing and terminally differentiating keratinocytes.

During terminal differentiation, keratinocytes lose the ability to divide. One indicator of responsiveness to certain growth factors is a transient rise in the intracellular concentration of free calcium ions ([Ca2+]i). The aim of our experiments was to discover whether or not terminally differentiating keratinocytes have lost the ability to exhibit an increase in [Ca2+]i in response to factors that stimulate [3H]thymidine incorporation and increase [Ca2+]i in undifferentiated keratinocytes. [Ca2+]i was measured with the calcium indicator dye FURA-2 and by a ratio imaging method. Expression of involucrin, a precursor of the keratinocyte cornified envelope, was used as a marker of terminal differentiation. Measurements were made on stratified colonies of cells grown in standard medium (containing 1.8 mM calcium ions) and on cell monolayers in low calcium medium (0.1 mM). Treatment of serum-starved monolayers with substance P, bombesin or complete growth medium containing 10% fetal calf serum resulted in increased [3H]thymidine incorporation. A switch from low calcium to standard medium also stimulated [3H]thymidine incorporation whether or not the cells had been serum-starved. In each experiment some cells showed an increase in [Ca2+]i while others did not. However, the heterogeneity in the [Ca2+]i response did not reflect the terminal differentiation status of individual cells: both involucrin-positive and -negative cells were found in the responding and nonresponding populations. Involucrin-positive and -negative areas of stratified cultures also underwent a transient increase in [Ca2+]i in response to serum-containing medium. Our data therefore indicate that both proliferating (involucrin-negative) and post-mitotic, terminally differentiating (involucrin-positive) keratinocytes can respond to mitogenic stimuli by an increase in [Ca2+]i.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood↗
PubMed1991

Neural network approach to detection of metastatic melanoma from chromatographic analysis of urine.

Chromatographic analysis of sera or urine is important in medicine for the evaluation of patients whose clinical status is associated with the presence of specific biochemical markers. Malignant melanoma has been a model for such studies due to the elaboration of melanin precursors and pigment as the tumor metastasizes. Computer-assisted methods for categorizing chromatographic data and clinical status are imperative due to the large number of detectable compounds and possible correlations. In addition, computer-based analysis of the data can readily extract patterns that are not obvious by visual inspection. In this paper, we present a neural network analysis of melanoma chromatographic and clinical data that categorizes subjects into normals, NED patients (No Evidence of Disease), and metastatic patients. The set of marker compounds for metastatic disease represents a significant advance over the correlations derived by visual inspection.

Algorithms↗
PubMed1990

DNA amplification is rare in normal human cells.

Three types of normal human cells were selected in tissue culture with three drugs without observing a single amplification event from a total of 5 x 10(8) cells. No drug-resistant colonies were observed when normal foreskin keratinocytes were selected with N-(phosphonacetyl)-L-aspartate or with hydroxyurea or when normal mammary epithelial cells were selected with methotrexate. Some slightly resistant colonies with limited potential for growth were obtained when normal diploid fibroblast cells derived from fetal lung were selected with methotrexate or hydroxyurea but careful copy-number analysis of the dihydrofolate reductase and ribonucleotide reductase genes revealed no evidence of amplification. The rarity of DNA amplification in normal human cells contrasts strongly with the situation in tumors and in established cell lines, where amplification of oncogenes and of genes mediating drug resistance is frequent. The results suggest that tumors and cell lines have acquired the abnormal ability to amplify DNA with high frequency.

Breast↗
PubMed1989

Onset of expression of peanut lectin-binding glycoproteins is correlated with stratification of keratinocytes during human epidermal development in vivo and in vitro.

During gestation the epidermis develops from a single layer of ectoderm into a layer of keratinocytes overlaid by a layer of periderm; this is followed by a progressive increase in the number of layers of keratinocytes, until finally the distinct granular and cornified layers characteristic of mature epidermis are formed. As part of our investigation into the function of the peanut lectin-binding glycoproteins of cultured human keratinocytes, we have examined their expression at different stages of human epidermal development. We found that the onset of expression of the glycoproteins coincided with the transition from a two- to a three-layered epidermis, both in vivo and in organ culture. In adult epidermis, the patterns of binding of peanut lectin and Limax flavus lectin are complementary, with peanut binding more strongly to suprabasal keratinocytes and Limax flavus lectin binding more strongly to cells in the basal layer. We found that the complementary pattern of binding of the two lectins was established at, or shortly after, the onset of stratification and retained throughout development. In contrast, expression by keratinocytes of involucrin, a protein precursor of the cornified envelope, occurred after stratification had begun. Finally, we identified the peanut lectin-binding glycoproteins of adult epidermis by immunoblotting with an antiserum raised against the glycoproteins of cultured neonatal keratinocytes. In conclusion, expression of the peanut lectin-binding glycoproteins is an early event in epidermal development, and this would be consistent with a role for the glycoproteins in stratification.

Embryonic and Fetal Development↗
PubMed1989

Exercise training bradycardia: the role of autonomic balance.

We used an algebraic model of resting heart rate (HRr), HRr-mn (HRo), to compare resting parasympathetic (n) and sympathetic (m) influence, intrinsic heart rate (HRo), and resting autonomic balance (Abal) in ten endurance-trained (ET) and ten nontrained (NT) men. The values of m, n, and Abal were determined by selective pharmacological blockade with atropine and metoprolol. HRo was obtained during double blockade with atropine and metoprolol. HRo and HRr were significantly lower (P less than or equal to 0.04 and P less than or equal to 0.01, respectively) in the ET subjects (79.5 +/- 2.8 beats.min-1 and 54.7 +/- 3.0 beats.min-1, respectively) when compared to the NT subjects (86.6 +/- 2.5 beats.min1 and 70.2 +/- 3.1 beats.min-1, respectively). Parasympathetic influence (n) was greater in the ET subjects (P less than or equal to 0.04), while sympathetic influence (m) was slightly (P less than or equal to 0.05) less in the ET subjects. Consequently, the value of Abal was significantly less in the ET subjects (P less than or equal to 0.02), indicating that resting parasympathetic predominance was significantly greater in the ET subjects. We concluded that the exercise training bradycardia, observed in this group of subjects, was due to both a lower HRo and an Abal with an augmented parasympathetic dominance.

Adult↗
PubMed1988

Effect of changes in cardiac autonomic balance on blood pressure regulation in man.

The role of cardiac autonomic balance in fitness-related differences in blood pressure regulation was evaluated by comparing the cardiovascular responses to lower body negative pressure (LBNP) in 10 trained and 10 untrained men. Cardiac autonomic balance was quantified as the ratio of resting heart rate to intrinsic heart rate, and was significantly lower in the trained subjects (0.68 +/- 0.03) than the untrained subjects (0.81 +/- 0.03) indicating a greater parasympathetic dominance at rest in the trained subjects. Arterial pressure decreased significantly more during LBNP in the trained subjects and was due to lower chronotropic and vasoconstrictor responses in these trained subjects. 'Cardiac autonomic balance' was equilibrated between the groups by partial parasympathetic blockade with atropine sulfate in the trained subjects and partial sympathetic blockade with metoprolol tartrate in the untrained subjects. Equilibration of cardiac autonomic balance eliminated the group differences in blood pressure maintenance, and chronotropic and vasoconstrictor responsiveness during LBNP. It was hypothesized that the elevated tone of parasympathetic control of the heart rate of the trained subjects resulted in an attenuation of blood pressure regulation.

Adult↗
PubMed1988

Baroreflex function in endurance- and static exercise-trained men.

The effect of exercise training mode on reflex cardiovascular control was studied in a cross-sectional design. We examined the cardiovascular responses to progressive incremental phenylephrine (PE) infusion to maximal rates of 120 micrograms/min and the delta heart rate/delta blood pressure responses to lower body negative pressure (LBNP) to -50 Torr in 30 men who were either endurance exercise trained (ET), untrained (UT), or weight trained (WT). During PE infusion, measures of blood pressures, forearm blood flow, heart rate and cardiac output, and calculations of forearm vascular resistance, stroke volume, and peripheral vascular resistance were made at each infusion rate when steady-state blood pressure was attained. No significant differences (P less than 0.05) in forearm blood flow or resistance were observed between the groups at any dose of PE, suggesting that the vasoconstrictor response was similar among the groups. Regression analyses of heart rate against mean blood pressure during the PE infusion were performed to evaluate baroreflex function. A linear model was used and correlation coefficients ranging from 0.82 to 0.96 were obtained (P less than 0.05). The slope of the line of best fit for the ET subjects (-0.57) was significantly less (P less than 0.05) than the slopes obtained for either the UT (-0.91) or WT (-0.88) subjects. In addition, the delta heart rate/delta blood pressure measurements obtained during LBNP reflected a similarly significant attenuation of reflex chronotropic control in the ET subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Blood pressure regulation during cardiac autonomic blockade: effect of fitness.

The purpose of this study was to determine the role of the autonomic nervous system's control of the heart in fitness-related differences in blood pressure regulation. The cardiovascular responses to progressive lower-body negative pressure (LBNP) were studied during unblocked (control) and full blockade (experimental) conditions in 10 endurance-trained (T) and 10 untrained (UT) men, aged 20-31 yr. The experimental conditions included beta 1-adrenergic blockade (metoprolol tartrate), parasympathetic blockade (atropine sulfate), or complete blockade (metoprolol and atropine). Heart rate, blood pressure, forearm blood flow, and cardiac output were measured at rest and -16 and -40 Torr LBNP. Forearm vascular resistance, peripheral vascular resistance, and stroke volume were calculated from these measurements at each stage of LBNP. Blood pressure was maintained, primarily by augmented vasoconstriction, equally in T and UT subjects during complete and atropine blockade. The fall in systolic and mean pressure from 0 to -40 Torr was greater (P less than 0.05) in the T subjects during the unblocked and metoprolol blockade conditions. This reduced blood pressure control during unblocked condition was attributable to attenuated vaso-constrictor and chronotropic responses in the T subjects. We hypothesize that an autonomic imbalance (elevated base-line parasympathetic activity) in highly trained subjects restricts reflex cardiac responses, which accompanied by an attenuated vasoconstrictor response, results in attenuated blood pressure control during a steady-state hypotensive stress.

Adult↗
PubMed1987

Physical fitness and hemodynamic response of women to lower body negative pressure.

Aerobic fitness as assessed by maximal aerobic capacity (VO2max) has been shown to be associated with an attenuated baroreflex function during lower body negative pressure (LBNP) in men. Sixteen women (mean age = 24.7 yrs) were evaluated during progressive LBNP to -50 torr. Each subject's VO2max was determined using indirect calorimetry during the Bruce protocol exercise test. Eight subjects [mean VO2max = 56.8 (ml O2 X min-1) X kg-1] were designated as trained, and eight subjects [mean VO2max = 39.4 (ml O2 X min-1) X kg-1] were designated as untrained. During LBNP, heart rate, blood pressure, cardiac index, forearm blood flow, and leg circumference were measured. All subjects completed the LBNP protocol without clinical symptoms of pre-syncope. The over-all hemodynamic responses of both groups to LBNP were qualitatively similar to previous findings reported for males. However, no significant differences in response of hemodynamic variables were observed between trained and untrained subjects during LBNP to -50 torr (P greater than 0.05) except for vascular resistance and diastolic blood pressure at -50 torr where the untrained value was greater than the trained value. This would suggest that a fitness-related difference may have been present at higher levels of LBNP. Furthermore, in contrast to previous reports in males, the index of baroreflex responsiveness (delta heart rate/delta systolic blood pressure) was similar for both groups (P greater than 0.05). When these data were compared with a similar subject pool of males, the females displayed a significantly greater (P less than 0.05) tolerance of LBNP to -50 torr regardless of fitness.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Effect of muscle tension on the cardiovascular responses to lower body negative pressure in man.

The purpose of this investigation was to evaluate the effect of moderate (non-hypertensive) levels of muscle tension on the cardiovascular responses to progressive lower body negative pressure (LBNP) in eight healthy male volunteers. Subjects were presented with progressive LBNP to -50 torr or the occurrence of vasovagal symptoms during three different levels of electromyographic activity in the lower limbs represented by the relaxed state, 5 and 10% maximal voluntary contraction. The same procedure was also performed at the same three levels of electromyographic activity in the arms with concomitant relaxation of the abdomen and lower extremities. In 75% of the subjects, pre-syncopal reactions were observed during the relaxed state while no pre-syncopal responses occurred during the elevated muscle tension levels. Both levels of muscle tension in the legs attenuated the LBNP-induced decrease in blood pressure (P less than 0.05). The effect of the 5% maximal voluntary contraction tension level appeared to be due to a compressive effect on the vascular tree, because similar levels of tension in the forearm had minimal effect on the blood pressure response to LBNP. In addition to a compressive effect, the 10% maximal voluntary contraction tension level appeared to induce a reflex stimulation of the heart as evidenced by an augmented heart rate response to LBNP and an increase in cardiac output. The muscle tension appeared to induce a mechanical compression of the vascular tree which was accompanied by somatopressor reflex responses, resulting in a maintenance of blood pressure that was primarily mediated by a maintained cardiac output.

Adult↗
PubMed1984

Derivation of rule-based knowledge from established medical outlines.

The purpose of this paper is to describe the derivation of a rule base for an expert system from an existing medical auditing method called a criteria map. The criteria map represents the physician's logic in the specialty involved. The system described, EMERGE, is written in the standard Pascal programming language, operates on a microcomputer, and provides a convenient user-interface. All medical knowledge in EMERGE is contained in an independent set of production rules, which are derived from the criteria map.

Diagnosis, Computer-Assisted↗
PubMedDate not supplied

Development of decision making rules for transportable, microcomputer-based expert systems in medicine.

Computerized decision making aids have been developed for use in certain medical specialties over the last decade. These programs are designed to give expert-level advice within their limited domains. Two major components are required in the design of these systems: development of software and development of a knowledge base to handle the specific medical application. The advantage of the knowledge-based approach is that the application can be changed by replacement of the knowledge base, without requiring changes to the software. In this paper, EMERGE, a medical decision making system, originally developed for analysis of chest pain in the emergency room environment, is described. EMERGE uses production rules for representation of its knowledge base. The method by which this system can accommodate new rule bases for other applications is emphasized, as well as the transportability of the system.

Computers↗