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PubMed2001

AI in medicine on its way from knowledge-intensive to data-intensive systems.

The last 20 years of research and development in the field of artificial intelligence in medicine (AIM) show a path from knowledge-intensive systems, which try to capture the essential knowledge of experts in a knowledge-based system, to data-intensive systems available today. Nowadays enormous amounts of information is accessible electronically. Large datasets are collected continuously monitoring physiological parameters of patients. Knowledge-based systems are needed to make use of all these data available and to help us to cope with the information explosion. In addition, temporal data analysis and intelligent information visualization can help us to get a summarized view of the change over time of clinical parameters. Integrating AIM modules into the daily-routine software environment of our care providers gives us a great chance for maintaining and improving quality of care.

Artificial Intelligence↗
PubMed2001

Where do selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) now fit into breast cancer treatment algorithms?

The agents used for endocrine therapy in patients with breast cancer have changed markedly over the past decade. Tamoxifen remains the anti-oestrogen of choice, but could be replaced by the oestrogen receptor down-regulator ICI 182780 or by the fixed ring triphenylethylene arzoxifene (previously SERM III) soon. Whilst aminoglutethimide and 4-OH androstenedione were the aromatase inhibitors of choice, they have been replaced by non-steroidal (anastrozole and letrozole) and steroidal (exemestane) inhibitors of high potency and low side effect profile. Previously, often used treatments such as progestogens (megestrol acetate and medroxyprogesterone acetate) and androgens are now rarely used or confined to fourth or fifth line treatments. The LHRH agonist, goserelin, remains the treatment of choice for pre-menopausal patients with advanced breast cancer although recent randomised trials indicate a response, time to progression and survival advantage for the combination of goserelin and tamoxifen compared with goserelin alone. The newer treatments have led to questions concerning the optimum sequence of agents to use in advanced breast cancer and as neo-adjuvant and adjuvant therapy in relation to surgery. Two trials of anastrozole compared with tamoxifen and one trial of letrozole compared with tamoxifen indicate that the new triazole aromatase inhibitors have a significant advantage over the anti-oestrogen with respect to time to progression and survival. Similarly, triazole aromatase inhibitors give faster and more complete responses compared with tamoxifen when used in post-menopausal women before surgery. Major research questions remain with respect to the aromatase inhibitors used as adjuvant therapy. Anastrozole is being tested alone or in combination with tamoxifen compared with tamoxifen in the 'so-called' ATAC trial. Over 9000 patients have been randomised to this important study: the results will be available late-2001. A similar study comparing letrozole and tamoxifen started recently under the auspices of the Breast International Group. Importantly, this trial is also comparing the sequence of tamoxifen followed by letrozole (or vice versa). A similar trial of exemestane given after 2-3 years of tamoxifen compared with 5 years of tamoxifen is recruiting well as is a study comparing letrozole (or placebo) for 5 years after 5 years of adjuvant tamoxifen. These studies may show that aromatase inhibitors are superior to tamoxifen or that a sequence is preferable.ICI 182780 causes complete oestrogen receptor down-regulation leading to a the lack of agonist activity of the drug. Two trials of ICI 182780 compared with anastrozole for advanced disease will report later this year and a comparison with tamoxifen next year. Arzoxifene (SERM III) is being tested against tamoxifen. These studies are likely to result in new anti-oestrogens being introduced into the clinic. Most of our endocrine treatments deprived the tumour cell of oestradiol. In vitro experiments with MCF-7 cells indicate that tumour cells can adapt and then grow in response to low oestrogen concentrations in the tissue--culture medium. Importantly, the cells were shown to apoptose in response to high oestrogen concentrations. A recent clinical trial has demonstrated a high response rate to stilboestrol given after a median of four previous oestrogen depriving endocrine therapies. These data and the newer treatments available indicate a need to re-think our general approach to endocrine therapy and endocrine prevention.

Adaptation, Physiological↗
PubMed2000

Salicylate-selective electrodes based on AI(III) and Sn(IV) salophens

New salicylate-selective electrodes based on aluminum-(III) and tin(IV) salophens are described. The electrodes were prepared by incorporating the ionophores into plasticized poly(vinyl chloride) (PVC) membranes, which were directly coated on the surface of graphite electrodes. These novel electrodes display high selectivity for salicylate with respect to many common inorganic and organic anions. The influence of membrane composition and pH and the effect of lipophilic cationic and anionic additives on the response properties of the electrodes were investigated. The electrode based on aluminum salophen, with 32% PVC, 65.8% plasticizer, and 2.2% ionophore, shows the best potentiometric response characteristics and displays a linear log [Sal-] vs EMF response over the concentration range 1 x 10(-6) - 1 x 10(-1) M in phosphate buffer solutions of pH 7.0, with a Nernstian slope of -59.2 mV/decade of salicylate concentration. Highest selectivity was observed for the membrane incorporating 38.8% PVC, 57.3% plasticizer, 2.6% Sn(salophen), and 1.3% sodium tetraphenylborate. The electrodes exhibit fast response times and micromolar detection limits (approximately 1 x 10(-6) M salicylate) and could be used over a wide pH range of 3-8. Applications of the electrodes for determination of salicylate in pharmaceutical preparations and biological samples are reported.

Journal Article↗
PubMed1988

Alterations of the glutamine residues of human apolipoprotein AI propeptide by in vitro mutagenesis. Characterization of the normal and mutant protein forms.

We have used site-directed mutagenesis to independently alter the Gln residues at positions -1 and -2 of the human apoAI propeptide to Arg residues. The normal and mutated genes were placed under the control of the mouse metallothionein 1 promoter in a bovine papilloma virus (BPV) vector which also carries a copy of the human metallothionein 1A gene. Following transfection of mouse C127 cells [corrected] with the vectors, cell clones resistant to CdCl2 were selected and analyzed for production of apoAI mRNAs and protein. The RNA blotting analysis showed that the steady-state apoAI mRNA levels of cell clones expressing either the normal or the mutant apoAI gene are 3-5-fold higher than that of the liver or HepG2 cells. Two-dimensional gel electrophoresis of radiolabeled apoAI showed that the apoAI-expressing clones secreted mainly the proapoAI form. Furthermore, both mutant proapoAI's differed by one positive charge from the normal apoAI. Secretion of apoAI into the culture medium follows apparent first-order kinetics and gives similar rate constants for the normal and mutant apoAI forms. Separation of secreted apoAI by density gradient ultracentrifugation in the presence of human plasma or HDL shows identical distribution of plasma and nascent (normal and mutant) apoAI. The findings indicate that in the cell system used the modification of either of the two glutamines of the apoAI prosegment does not affect the intracellular transport and secretion of apoAI, and its ability to associate with HDL.

Animals↗
PubMed2004

An apolipoprotein AI mimetic peptide: membrane interactions and the role of cholesterol.

The 18-amino acid amphipathic helical peptide Ac-DWFKAFYDKVAEKFKEAF-NH(2) promotes the separation of cholesterol from the phospholipid, resulting in the formation of cholesterol crystallites, even at mole fractions of cholesterol as low as 0.3. The peptide exerts a greater degree of penetration into membranes of pure phosphatidylcholine in the absence of cholesterol than into bilayers of phosphatidylcholine and cholesterol. The circular dichroism spectrum of the peptide in buffer indicates that it self-associates, leading to the formation of structures with higher helical content. However, in the presence of lipid, the peptide remains helical over a larger concentration range. The peptide undergoes a thermal transition on heating. Cholesterol has little effect on the secondary structure of the peptide; however, increased Trp emission intensity in the absence of cholesterol indicates a deeper penetration of the helix upon removal of cholesterol from the membrane. The results with these model systems demonstrate changes in peptide-lipid interactions that may be related to the observed biological properties of this peptide.

Amino Acid Sequence↗
PubMed1999

Apolipoprotein AI efficiently binds to and mediates cholesterol and phospholipid efflux from human but not rat aortic smooth muscle cells.

Aortic smooth muscle cells (SMC) from several animal species have been reported to resist depletion of cellular cholesterol by the major apolipoprotein of HDL, apoAI. Resistance of SMC to this protective action of apoAI, if present in humans, could contribute to the overaccumulation of arterial wall cholesterol seen in atherosclerosis. We investigated the ability of human aortic medial SMC to bind and be depleted of cholesterol and phospholipids by apoAI. In contrast to rat aortic SMC, but similar to human fibroblasts, human SMC were readily depleted of cholesterol by apoAI, measured by a marked depletion of intracellular cholesterol available for esterification, and an increase in cholesterol efflux to the medium. Human SMC were also actively depleted of the phospholipids phosphatidylcholine and sphingomyelin by apoAI. In contrast, rat SMC released only a small fraction of these cellular phospholipids to apoAI-containing medium. (125)I-labeled apoAI bound with high affinity and specificity to human SMC, but failed to bind to rat SMC. Similar levels of expression of class B, type I scavenger receptor (SR-BI) and caveolin in human and rat SMC suggested these proteins do not account for the differences in apoAI binding or lipid efflux seen in these cells. An enhancer of apolipoprotein-mediated cholesterol efflux, tyrosyl radical-oxidized HDL, markedly amplified the depletion of cholesterol available for esterification in human SMC compared to HDL, but had no enhanced effect in rat SMC. These results show that human SMC bind and are readily depleted of cellular lipids by apoAI, and suggest that apoAI-mediated cholesterol efflux from arterial SMC may contribute significantly to the circulating pool of HDL cholesterol in vivo. The marked difference in apoAI binding to human and rat arterial SMC provides an excellent model to study the nature of the apoAI-cell binding interaction.

Animals↗
PubMed2001

Inhibition of oxalate nephrolithiasis with Ammi visnaga (AI-Khillah).

We investigated the effect of Ammi visnaga seeds on experimentally - induced kidney stones - in male Wistar albino rats. Oxalate nephrolithiasis was experimentally induced by 3% glycolic acid (added in their diet) given for the period of four weeks. A highly significant amount of deposits were found in the kidneys, which were analyzed quantitatively. These deposits were mainly of calcium oxalate in composition. Daily oral (gavage) treatment with Ammi visnaga (500 mg/kg) highly reduced the incidence of nephrolithiasis (calcium oxalate deposition in the kidneys). Ammi visnaga seeds extract showed highly potent diuretic activity. The reduction in body weight, increase in kidneys weight, increase in water intake, decrease in urine output found in glycolic acid control group were prevented to various extent on Ammi visnaga treatment; and the values became to insignificant difference with control group. The changes in weights of liver, heart and lungs of the three groups were insignificant. Uraemia and hyperbilirubinaemia observed in glycolic acid control group were found to be ameliorated by Ammi visnaga seed extract treatment.

Ammi↗
PubMed2001

Ultraviolet AI exposure of human skin results in Langerhans cell depletion and reduction of epidermal antigen-presenting cell function: partial protection by a broad-spectrum sunscreen.

BACKGROUND: Ultraviolet (UV) B-induced effects on the skin immune system have been extensively investigated, but little is known regarding the immunological changes induced by UVA exposure of human skin. Recent data assessing the protection afforded by sunscreens against photoimmunosuppression stress the need for broad-spectrum sunscreens with an adequate UVA protection. OBJECTIVES: The purpose of this study was first to determine the changes observed in epidermal Langerhans cells (ELC) density and epidermal antigen-presenting cell (APC) activity after exposure of human skin to UVAI (340-400 nm) radiation, and secondly to assess the immune protection afforded in vivo by a sunscreen formulation containing a long wavelength UVA filter with a low UVA protection factor (UVA-PF = 3). METHODS: Epidermal cell (EC) suspensions were prepared from skin biopsies 3 days after exposure to a single dose of UVAI (either 30 or 60 J cm(-2)). RESULTS: Flow-cytometric analysis of EC suspensions revealed that exposure to 60 J cm(-2) UVAI resulted in a decreased number of ELC without infiltration of CD36+ DR+ CD1a- antigen-presenting macrophages into the epidermis, and a significant reduction of HLA-DR expression on viable ELC. In vivo exposure to both 30 and 60 J cm(-2) resulted in a decreased allogeneic CD4+ T-cell proliferation induced by UVAI-irradiated ECs. The sunscreen application partially prevented (57 +/- 9%) the decrease in epidermal allogeneic APC activity induced by 60 J cm(-2) UVAI. CONCLUSIONS: In vivo UVAI exposure of human skin results in a decreased number of ELC and in a downregulation of epidermal APC activity. This last effect is partially prevented by prior application of a sunscreen with a low UVAI-PF value. These results indicate that increasing the absorption of UV filters for long UVA wavelengths may lead to an improved immune protection.

Adult↗
PubMedDate not supplied

Relationship between peri-oestrus progesterone levels and time of ovulation by echography in pigs and influence of the interval between ovulation and artificial insemination (AI) on litter size.

Two methods for the determination of ovulation were compared to one ultrasonography performed 5 times a day. Time of ovulation by echography was 40 +/- 5.8 h (mean +/- SD) after the onset of oestrus. Preovulatory LH rise (two blood samples per day) began near the onset of oestrus but, in our conditions, this parameter could not be used to predict ovulation. The basal level of progesterone (two blood samples per day) was determined with a non-linear model, the timing when progesterone rose more than one SD (0.3 ng x mL(-1)) coincided with the timing of ovulation determined by echography (R2 = 0.98). This method was efficient and was used in a field trial to measure the consequences of the variability of the interval between Al and ovulation on litter size. The interval between Al and ovulation had an effect on litter size; litter size decreased by one piglet when this interval increased by 10h.

Animals↗