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2.
Andreassen S Riekehr C Kristensen B Schønheyder HC Leibovici L 《Artificial intelligence in medicine》1999,15(2):121-134
Causal probabilistic networks, also called Bayesian networks, allow both qualitative knowledge about the structure of a problem and quantitative knowledge, derived from case databases, expert opinion and literature to be exploited in the construction of decision support systems for diagnosis, treatment and prognosis. This mixing of qualitative and quantitative knowledge will be illustrated, using the selection of antibiotics for a subset of patients with severe infections. The subset consists of patients where bacteria or fungi have been found in the blood. A simple pathophysiological model of infection is used to calculate a prognosis, dependent on the choice of antibiotics. A decision-theoretic approach is used to balance the therapeutic benefit of antibiotic treatment against the cost of antibiotics in the form of direct monetary cost, side effects and ecological cost. A retrospective trial on patients with bacteria or fungi in the blood stemming from the urinary tract indicates that with this approach, it may be possible to suggest balanced choices of antibiotics that not only achieve greater therapeutic benefit, but also reduce the cost of therapy. 相似文献
3.
Mutational analysis of the SOX9 gene in campomelic dysplasia and autosomal sex reversal: lack of genotype/phenotype correlations 总被引:9,自引:1,他引:9
Meyer J; Sudbeck P; Held M; Wagner T; Schmitz ML; Bricarelli FD; Eggermont E; Friedrich U; Haas OA; Kobelt A; Leroy JG; Van Maldergem L; Michel E; Mitulla B; Pfeiffer RA; Schinzel A; Schmidt H; Scherer G 《Human molecular genetics》1997,6(1):91-98
It has previously been shown that, in the heterozygous state, mutations in
the SOX9 gene cause campomelic dysplasia (CD) and the often associated
autosomal XY sex reversal. In 12 CD patients, 10 novel mutations and one
recurrent mutation were characterized in one SOX9 allele each, and in one
case, no mutation was found. Four missense mutations are all located within
the high mobility group (HMG) domain. They either reduce or abolish the
DNA-binding ability of the mutant SOX9 proteins. Among the five nonsense
and three frameshift mutations identified, two leave the C-terminal
transactivation (TA) domain encompassing residues 402-509 of SOX9 partly or
almost completely intact. When tested in cell transfection experiments, the
recurrent nonsense mutation Y440X, found in two patients who survived for
four and more than 9 years, respectively, exhibits some residual
transactivation ability. In contrast, a frameshift mutation extending the
protein by 70 residues at codon 507, found in a patient who died shortly
after birth, showed no transactivation. This is apparently due to
instability of the mutant SOX9 protein as demonstrated by Western blotting.
Amino acid substitutions and nonsense mutations are found in patients with
and without XY sex reversal, indicating that sex reversal in CD is subject
to variable penetrance. Finally, none of 18 female patients with XY gonadal
dysgenesis (Swyer syndrome) showed an altered SOX9 banding pattern in SSCP
assays, providing evidence that SOX9 mutations do not usually result in XY
sex reversal without skeletal malformations.
相似文献
4.
Neurotoxicity associated with neuroleptic-induced oral dyskinesias in rats. Implications for tardive dyskinesia? 总被引:6,自引:0,他引:6
Tardive dyskinesia is a serious motor side effect of long-term treatment with neuroleptics, with an unknown pathophysiologic basis. Brain damage and aging are prominent risk-factors, and together with the persistent character of the disorder, it is likely that long-lasting neuronal changes are involved in the pathogenesis. It has been hypothesized that striatal neurodegeneration caused by excitotoxic mechanisms and oxidative stress may play an important role in the development of the disorder, and the scope of the present work is to review the evidence supporting this hypothesis. The rat model of tardive dyskinesia has been used extensively in the field, and the usefulness of this model will be discussed. Neuroleptics are able to induce oxidative stress in vitro and increase striatal glutamatergic activity in rats, which may lead to toxic effects in the striatum. Drugs that block excitotoxicity inhibit the development of persistent oral dyskinesia in the rat model, and impaired energy metabolism leads to increased frequency of oral dyskinesia. There are also signs of altered striatal histology in rats with high frequency of oral dyskinesia. Furthermore, markers of increased oxidative stress and glutamatergic neurotransmission have been found in the cerebrospinal fluid of patients with tardive dyskinesia. In conclusion, several lines of evidence implicate neurotoxic events in the development of neuroleptic induced tardive dyskinesia. 相似文献
5.
Ebbe Eldrup Simone Theilade Mette Lorenzen Christine H Andreassen Katrine H Poulsen John E Nielsen Ditte Hansen Daniel El Fassi Jais O Berg Per Bagi Anne Jørgensen Martin Blomberg Jensen 《Journal of bone and mineral research》2021,36(2):322-333
Intramuscular injections of paraffin oil can cause foreign body granuloma formation and hypercalcemia. Macrophages with the ability to produce high levels of 1,25(OH)2D3 may induce the mineral disturbance, but no major series of patients have been published to date. Here, medical history, physical evaluation, biochemical, and urinary analysis for calcium homeostasis were obtained from 88 males, who 6 years previously had injected paraffin or synthol oil into skeletal muscle. Moreover, granuloma tissue from three men was cultured for 48 hours ex vivo to determine 1,25(OH)2D3 production supported by qPCR and immunohistochemistry of vitamin D metabolism and immune cell populations after treatment with 14 different drugs. The 88 men were stratified into men with hypercalcemia (34%), whereas normocalcemic men were separated into men with either normal (42%) or suppressed parathyroid hormone (PTH) (24%). All men had high calcium excretion, and nephrolithiasis was found in 48% of hypercalcemic men, 22% of normocalcemic men with normal PTH, and 47% of normocalcemic men with suppressed PTH. Risk factors for developing hypercalcemia were oil volume injected, injection of heated oil, high serum interleukin-2 receptor levels, and high urine calcium. High 1,25(OH)2D3/25OHD ratio, calcium excretion, and low PTH was associated with nephrolithiasis. The vitamin D activating enzyme CYP27B1 was markedly expressed in granuloma tissue, and 1,25(OH)2D3 was released in concentrations corresponding to 40% to 50% of the production by human kidney specimens. Dexamethasone, ketoconazole, and ciclosporin significantly suppressed granulomatous production of 1,25(OH)2D3. In conclusion, this study shows that injection of large oil volumes alters calcium homeostasis and increases the risk of nephrolithiasis. Hypercalciuria is an early sign of disease, and high granulomatous 1,25(OH)2D3 production is part of the cause. Prospective clinical trials are needed to determine if ciclosporin, ketoconazole, or other drugs can be used as prednisolone-sparing treatment. © 2020 American Society for Bone and Mineral Research (ASBMR). 相似文献
6.
7.
Skripitz R Andreassen TT Aspenberg P 《The Journal of bone and joint surgery. British volume》2000,82(1):138-141
Intermittent treatment with parathyroid hormone I(PTH) has an anabolic effect on both intact cancellous and cortical bone. Very little is known about the effect of the administration of PTH on the healing of fractures or the incorporation of orthopaedic implants. We have investigated the spontaneous ingrowth of callus and the formation of bone in a titanium chamber implanted at the medioproximal aspect of the tibial metaphysis of the rat. Four groups of ten male rats weighing approximately 350 g were injected with human PTH (1-34) in a dosage of 0, 15, 60 or 240 microg/kg/day, respectively, for 42 days from the day of implantation of the chamber. During the observation period the chamber became only partly filled with callus and bone and no difference in ingrowth distance into the chamber was found between the groups. The cancellous density was increased by 90%, 132% and 173% in the groups given PTH in a dosage of 15, 60 or 240 microg/kg/day, respectively. There was a linear correlation between bone density and the log PTH doses (r 2= 0.6). Our findings suggest that treatment with PTH may have a potential for enhancement of the incorporation of orthopaedic implants as well as a beneficial effect on the healing of fractures when it is given in low dosages. 相似文献
8.
Optimisation and validation of methods to assess single nucleotide polymorphisms (SNPs) in archival histological material. 总被引:2,自引:0,他引:2
BACKGROUND AND PURPOSE: An increasing amount of evidence indicates that single nucleotide polymorphisms (SNPs) may affect a variety of oncology related phenotypes. Occasionally, it is convenient to base studies addressing genotype-phenotype relationships on historical patient cohorts, from which only archival specimens are available. This study was conducted to validate protocols optimised for assessment of SNPs based on paraffin embedded, formalin fixed tissue samples. PATIENTS AND METHODS: In 137 breast cancer patients, three TGFB1 SNPs were assessed based on archival histological specimens. In 37 of these patients, the SNPs were also assessed using cultured fibroblasts and the assays were validated by direct comparison of the results. From the remaining 100 patients, only archival material was available. In these patients, the existence of a genetic linkage pattern between the assessed TGFB1 SNPs was used to provide an indirect validation of the genotyping results. Furthermore, two different methods for DNA extraction were compared (semi-automatic DNA extraction using the ABI Prism 6100 Nucleic Acid PrepStation versus Proteinase K digestion for 5 days followed by boiling and DNA precipitation). RESULTS: Assessment of SNPs based on archival histological material is encumbered by a number of obstacles and pitfalls. However, these can be widely overcome by careful optimisation of the methods used for sample selection, DNA extraction and PCR. Within 130 samples that fulfil the criteria for analysis a highly reliable SNP assessment was observed. The study demonstrated that different 'down-stream applications' ('single nucleotide primer extension' or 'TaqMan-based' real-time PCR) could be used as genotyping procedure. CONCLUSIONS: Reliable assessment of SNPs in formalin-fixed paraffin-embedded specimens is possible but a number of precautions should be carefully taken. 相似文献
9.
Effect of genetic modification of acute inflammatory responsiveness on tumorigenesis in the mouse 总被引:1,自引:3,他引:1
10.
This study compares the effects of parathyroid hormone (PTH) treatment on new bone formation and normal baseline remodelling in rats. To study new bone formation we used a titanium bone chamber, and to study normal remodelling we used the femur and vertebrae from the same animals. One titanium bone chamber was inserted in the proximal tibia of each of 37 rats. The rats were randomly assigned to daily injections of human PTH (1-34) 60 microg/kg) or vehicle control and killed after 2, 4 or 6 weeks. The total distance of bone growth into the chamber was slightly increased by PTH. Body weight was not affected, and there was only a minor increase in trabecular density of the vertebral and femoral cancellous bone after 6 weeks. The only dramatic effect of PTH was seen in the chambers. In the controls, a marrow cavity formed in the chamber so that the cancellous density decreased from 44% to 24%, and 11% over 2, 4 and 6 weeks. In the PTH-treated animals, a dense network of bone trabeculae was found in the entire bone chamber at all times. The cancellous density increased from 48% to 60%, and 73% at 2, 4 and 6 weeks, respectively. The results suggest that PTH treatment can reduce the development of a resorption cavity. Thus, PTH in this model had a net antiresorptive effect, probably solely because it stimulated osteoblastic activity. Even though osteoclastic activity was present throughout the PTH specimens, it was not sufficient to resorb all newly formed bone. Since PTH seemed to have a greater effect on new bone formation in the chamber than on normal bone remodeling, it might become useful for improving the incorporation of orthopedic implants and stimulating fracture repair. 相似文献