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Biomedical subjects

F Lau

Publications and source records attributed to F Lau.

14 recordsLinked to original sources
PubMed1997

Phenytoin-induced teratogenesis: a molecular basis for the observed developmental delay during neurulation.

PURPOSE: We wished to determine whether chronic phenytoin (PHT) exposure could impair neural development and if any morphological alterations could be linked to changes in gene expression. METHODS: Pregnant SWV mice were chronically administered PHT 40 mg/kg/day from gestational day (GD) 0:12 (day:h) until they were killed at various timepoints throughout neural tube closure (NTC). At each timepoint, embryos from both treated and control dams were collected and scored for their progression through NTC. The neural tubes were then isolated and subjected to in situ transcription (IST) and antisense RNA amplification procedures. Using these techniques, we examined the expression of 10 genes: N-cadherin (Ncad), collagen type IV (col-IV), bcl-2, c-jun, PAX-3, collular retinol binding protein-2 (CRBP-2), retinoic acid receptor alpha (RAR alpha), transforming growth factor(beta2) (TGF(beta2)), wee-1, and EMX-2. RESULTS: Chronic PHT exposure not only caused a delay in NTC whereby exposed embryos lagged behind the controls at each collection timepoint, but also significantly altered the expression of specific genes at distinct times during NTC. Early in NTC, PHT induced a significant reduction in the expression of N-cad, col-IV, and c-jun in exposed embryos as compared with controls. In contrast, during the midstages of NTC, the only significant molecular alterations observed in the PHT-exposed embryos was the continued decreased expression of col-IV and an increase in CRBP-2 expression. Finally, in the latter stages of NTC, PHT caused a significant reduction in the expression of bcl-2, RAR alpha, TGF(beta2), EMX-2, and PAX-3. CONCLUSIONS: These results show that although the effects of PHT are morphologically subtle, causing a delay in the development of the neural tube, this delay is accompanied by alterations in critical genes at crucial times of neural development that may account for the observed neurological deficits often associated with PHT exposure.

Abnormalities, Drug-Induced↗
PubMed1996

Imaging inflammation with 99Tcm-labeled chemotactic peptides: analogues with reduced neutropenia.

Two 99Tcm-labelled analogues of the chemotactic peptide ForMLF were evaluated as potential agents for imaging inflammation and infection, in the hope that they would be simple to use and would give diagnostically useful images shortly after injection. The peptides differed in the chelation site for 99Tcm and the presence of a hydrophilic spacer. The sequences of RP050 and RP056 were ForNleLFNleYK(G)G-C(Acm)-GPic and ForNleLFNleYKK(DG)GC(Acm)SPic respectively, where Pic is picolinic acid. In in vitro tests of binding to the ForMLF receptor on polymorphonuclear neutrophils and potency for release of myeloperoxidase, RP056 was similar in potency to ForMLF, whereas RP050 was 10 times more potent. When administered in 5-nmol doses to rats, RP050 produced less extensive neutropenia than ForMLF, whereas RP056 produced very little neutropenia. Following labelling by ligand exchange from tartrate or glucoheptonate at 100 degrees C and purification using a C-18 solid-phase extraction cartridge, 4-MBq doses were administered to rats bearing infectious (Escherichia coli) or sterile (zymosan) inflammation sites in the thigh. The inflammation-to-normal muscle ratios at 30 min after injection were 3.9 +/- 0.4 for RP050 and 4.7 +/- 0.3 for RP056 (mean +/- S.E.M., n = 4), and the ratios were maintained for up to 3 h. These peptides are promising agents for imaging inflammation and infection.

Amino Acid Sequence↗
PubMed1995

Bradykinin potentiates acetylcholine induced responses in native endothelial cells from rabbit aorta.

Membrane potential and intracellular [Ca2+] were measured in freshly isolated rabbit aortic endothelial cells. Acetylcholine (10 microM) induced transient membrane hyperpolarization and increased [Ca2+]i. Bradykinin (4 microM) had no direct effect on membrane potential or [Ca2+]i on its own, but potentiated the subsequent ACh response. It changed the usual transient ACh response to a maintained hyperpolarization. The maintained hyperpolarization was blocked by NiCl2 and TEA, indicating an involvement of receptor-operated-Ca2+ channel and Ca2+ -dependent K+ -channel activity. This potentiating effect on bradykinin in isolated cells was confirmed in organ bath studies using isolated aortic rings.

Acetylcholine↗
PubMed1995

Acetylcholine-sensitive intracellular Ca2+ store in fresh endothelial cells and evidence for ryanodine receptors.

In a freshly isolated endothelial cell preparation from rabbit aorta, the regulation of the acetylcholine (ACh)-sensitive intracellular Ca2+ store and the effects of the Ca(2+)-induced Ca2+ release agonists ryanodine and caffeine were studied using fura 2 imaging fluorescence microscopy. ACh (10 mumol/L) caused a transient release of Ca2+ from an intracellular store, presumably via an inositol tris-phosphate-sensitive mechanism. This ACh response could be repeated in the presence of extracellular Ca2+ but was obtained only once in Ca(2+)-free bathing solution, which shows that a depleted intracellular Ca2+ store can be rapidly refilled from the extracellular space. Refilling can be prevented by the endoplasmic reticulum Ca(2+)-ATPase inhibitor cyclopiazonic acid (10 mumol/L), implying that Ca2+ enters the cytoplasm before accumulation in the endoplasmic reticulum. Ionomycin (10 mumol/L) caused a large Ca2+ release even after the ACh-releasable store had been emptied, indicating the existence of other ACh-insensitive stores, perhaps including the mitochondria. In one third of the cells studied, ACh induced oscillations in [Ca2+]i that were dependent on extracellular Ca2+. Also investigated were the effects of caffeine and ryanodine. In this cell preparation neither caffeine nor ryanodine induced a Ca2+ transient but instead slowly increased [Ca2+]i. It was observed that both caffeine and ryanodine were able to slowly deplete the ACh-sensitive store. These results indicate the presence of functional ryanodine receptors in native endothelial cells and demonstrate overlap between the caffeine and agonist-sensitive Ca2+ stores. We also found that caffeine was able to directly inhibit the process of ACh-induced Ca2+ release.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1995

A knowledge-based care protocol system for ICU.

There is a growing interest in using care maps in ICU. So far, the emphasis has been on developing the critical path, problem/outcome, and variance reporting for specific diagnoses. This paper presents a conceptual knowledge-based care protocol system design for the ICU. It is based on the manual care map currently in use for managing myocardial infarction in the ICU of the Sturgeon General Hospital in Alberta. The proposed design uses expert rules, object schemas, case-based reasoning, and quantitative models as sources of its knowledge. Also being developed is a decision model with explicit linkages for outcome-process-measure from the care map. The resulting system is intended as a bedside charting and decision-support tool for caregivers. Proposed usage includes charting by acknowledgment, generation of alerts, and critiques on variances/events recorded, recommendations for planned interventions, and comparison with historical cases. Currently, a prototype is being developed on a PC-based network with Visual Basic, Level-Expert Object, and xBase. A clinical trial is also planned to evaluate whether this knowledge-based care protocol can reduce the length of stay of patients with myocardial infarction in the ICU.

Alberta↗
PubMed1994

A clinical decision support system prototype for cardiovascular intensive care.

This paper describes the development and validation of a decision-support system prototype that can help manage hypovolemic hypotension in the Cardiovascular Intensive Care Unit (CVICU). The prototype uses physiologic pattern-matching, therapeutic protocols, computational drug-dosage response modeling and expert reasoning heuristics in its selection of intervention strategies and choices. As part of model testing, the prototype simulated real-time operation by processing historical physiologic and intervention data on a patient sequentially, generating alerts on questionable data, critiques of interventions instituted and recommendations on preferred interventions. Bench-testing with 399 interventions from 13 historical cases showed therapies for bleeding and fluid replacement proposed by the prototype were significantly more consistent (p < 0.0001) than those instituted by the staff when compared against expert critiques (80% versus 44%). This study has demonstrated the feasibility of formalizing hemodynamic management of CVICU patients in a manner that may be implemented and evaluated in a clinical setting.

Alberta↗
PubMed1993

Modularity of protein function: chimeric interleukin 1 beta s containing specific protease inhibitor loops retain function of both molecules.

Although it is widely recognized that many proteins contain discrete functional domains, it is less certain whether smaller, less obviously discrete, units of structure will retain their specific function when transplanted into a different context. The observation that the potent inflammatory cytokine human interleukin 1 beta has the same overall structure as soybean trypsin inhibitor (STI) (Kunitz) prompted us to replace a tight turn in the cytokine sequence with the large loop in soybean trypsin inhibitor that binds to the active site of trypsin. Wild-type interleukin 1 beta (IL-1 beta) is highly resistant to proteolysis, but the chimeric STI/IL is specifically cleaved by trypsin, apparently in the inserted loop. Other chimeric interleukins have also been constructed, by replacing the same tight turn with inhibitory loops from other protein protease inhibitors: turkey ovomucoid inhibitor (TOI), a chymotrypsin inhibitor, and alpha 1-antitrypsin (AT), an elastase inhibitor. Although these loops come from proteins not related structurally to interleukin 1, they confer specific protease sensitivity or inhibition on the chimeric cytokine. The cytokine properties of these chimeric interleukins have also been evaluated. The chimeras formed from human IL-1 beta and all inhibitory loops tested bind to the interleukin 1 receptor with reasonable affinity. The typical cellular effects of IL-1, however, are not observed with all the recombinant proteins, thus confirming that receptor binding and signal transduction can be uncoupled. When these results are taken together with the results of site-directed mutagenesis of IL-1, reported in this paper and elsewhere, they allow the receptor and intracellular transduction sites on the protein to be mapped in detail.

Amino Acid Sequence↗
PubMed1993

Formalized decision support for cardiovascular intensive care.

The massive volume of hemodynamic data routinely available within the Cardiovascular Intensive Care Unit (CVICU) can adversely affect the quality, relevance, and timing of hemodynamic management decisions on patients after cardiac surgery. Yet, at the same time, the lack of appropriate treatment-outcome data and access to prior CV case histories deprives the clinician of any opportunity to improve personal decision-making skill and assess the effectiveness of various treatment methods. This paper presents a formalized decision-support model for CVICU that incorporates expert and quantitative knowledge, as well as prior outcome and case experience to augment the clinician's decision-making capability. This includes the use of optimal hemodynamic patterns derived from outcome analysis as therapy goals, expert rules and trend analysis to interpret incoming data, standardized protocols based on predefined hemodynamic patterns from clinical cases, and access to the database for similar case comparison. Most importantly, the model suggests an integrated approach where the clinical database not only is a documentation source for the patient, but also can serve as an outcome research database where clinical experience can be formalized and combined with expert knowledge to influence future therapy decisions. At present, a prototype is being developed at the CVICU of the University of Alberta Hospitals on a Unix platform using ART-IM, C and Ingres. Once implemented, the prototype will be evaluated on a small group of CV patients for its effectiveness and acceptability to clinicians.

Artificial Intelligence↗
PubMed1992

Formalized decision-support for cardiovascular intensive care.

The massive volume of hemodynamic data routinely available within the Cardiovascular Intensive Care Unit (CVICU) can adversely affect the quality, relevance and timing of hemodynamic management decisions on patients after cardiac surgery. Yet, at the same time, the lack of appropriate treatment-outcome data and access to prior CV case histories deprives the clinician of any opportunity to improve personal decision-making skill and assess the effectiveness of various treatment methods. This paper presents a formalized decision-support model for CVICU that incorporates expert and quantitative knowledge, as well as prior outcome and case experience to augment the clinician's decision-making capability. This includes the proposed use of optimal hemodynamic patterns derived from outcome analysis as therapy goals, expert rules and trend analysis to interpret incoming data, standardized protocols based on predefined hemodynamic patterns from clinical cases, and access to the database for similar case comparison. Most importantly, the model suggests an integrated approach where the clinical database is not only a documentation source for the patient, but can also serve as an outcome research database where clinical experience can be formalized and combined with expert knowledge to influence future therapy decisions. At present, a prototype is being developed at the CVICU of the University of Alberta Hospitals on a Unix platform using ART-IM, C and Ingres. Once implemented, the prototype will be evaluated on a small group of CV patients for its effectiveness and acceptability to clinicians.

Cardiovascular Diseases↗
PubMed1991

Designing an outcome-oriented computer decision-support system for cardiovascular ICU--a preliminary report.

This paper describes the conceptual framework and preliminary results of an outcome-oriented decision-support system prototype for the cardiovascular intensive care unit (CVICU). The major characteristics of this design include: (1) its problem-based approach to solving clinical problems; (2) an integrated structure with the hospital information system in terms of its data, model and knowledge bases; (3) proposed alternative modes of interaction that include monitoring and critiquing; (4) and research modules that design, manage, and analyze outcome-based clinical studies. At present, an initial prototype has been implemented on a PC as a set of modules accessible from a main menu. The structural framework of the overall system is fairly well defined but only limited quantitative, statistical and expert knowledge has been captured. The second phase of the project involves porting the prototype to a Unix workstation environment, refining and adding models to the model base, expanding its knowledge bases, reasoning capability, and testing the prototype with actual clinical cases in a real-time fashion.

Alberta↗
PubMed1979

R--pulse wave timing: a technique for continuous cardiovascular monitoring in obstetrics--preliminary report.

A simple, noninvasive technique for continuous cardiovascular monitoring in obstetrics using R--pulse wave timing is described. This preliminary study suggests that different maternal heart rate/R pulse patterns are found in different clinical circumstances. A significant decrease in the R pulse interval occurred in the third trimester in both normal and diabetic women in the left lateral position when compared to the supine position. The R pulse intervals were all prolonged in the standing position in both gravid and nongravid women. During labor R pulse interval usually shortened during uterine contraction. Prolongation of R pulse interval was observed during thiopental injection, hypotension, and excessive bleeding at cesarean section. Exercise testing in healthy male subjects suggested that the change in R pulse interval becomes constant when the oxygen consumption rate reaches a plateau at 100% maximal work load. Further extensive clinical study appears worthwhile since it may add another dimension to cardiovascular monitoring and give an early indication of cardiovascular reserve.

Anesthesia, Obstetrical↗