Sporadic Creutzfeldt-Jakob disease in a 18-year-old in the UK.
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Adolescent↗
Biomedical subjects
J Beck
Publications and source records attributed to J Beck.
The leukotriene LTD4 receptor antagonist MK571 specifically modulates MRP associated multidrug resistance.
The multidrug resistant cell lines HL60/AR and GLC4/ADR show high overexpression of the gene encoding the multidrug resistance associated protein MRP compared to their drug sensitive parental counterparts. This and the virtual absence of mdr1/P-glycoprotein gene expression was proven by a complementary DNA polymerase chain reaction (cDNA-PCR) approach. Applying a 72-hour tetrazolium based colorimetric MTT-assay we demonstrate on both MDR sublines a dose-dependent modulation of drug resistances by the leukotriene LTD4 receptor antagonist MK571. A complete reversal of vincristine resistances was achieved at final MK571 concentrations of 30 microM (HL60/AR) or 50 microM (GLC4/ADR) which by itself did not disturb cellular proliferation. The drug resistance of a mdr1/P-gp overexpressing multidrug-resistant HL60 subline, in contrast, was not significantly affected by MK571. Similar effects were seen using the glutathione (GSH) synthesis inhibitor buthionine sulfoximine (BSO). Our results point to a relationship between MRP and a conjugate transporter and identify MK571 as a new tool structure for developing modulators specific for a MRP associated multidrug resistance.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
The specific bisindolylmaleimide PKC-inhibitor GF 109203X efficiently modulates MRP-associated multiple drug resistance.
The newly identified drug transporter MRP is functionally linked to a multiple drug resistance independent from P-glycoprotein. Resistance modifiers for this type of MDR are rare at present. We analyzed the modulating effect of the highly selective bisindolylmaleimide PKC inhibitor GF 109203X on the MRP overexpressing human MDR sublines HL60/AR and GLC4/ADR. Applying a 72 hour MTT-assay we demonstrate a complete reversal of the vincristine resistance of HL60/AR cells. Adriamycin resistance of HL60/AR, or vincristine resistance of GLC4/ADR were partially reversed. Furthermore, rhodamine 123 efflux from HL60/AR was strongly modulated by GF 109203X. Since the PKC inhibitor did not significantly influence MRP gene expression at the mRNA level which was examined by cDNA-PCR, our results suggest either a direct interaction of the compound with MRP or/and an indirect influence on MRP activity via altering the phosphorylation status of the transporter.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of monoamine transporters in neuroblastoma cell lines: correlations to meta-iodobenzylguanidine (MIBG) uptake and tyrosine hydroxylase gene expression.
Radiolabelled meta-iodobenzylguanidine (MIBG) has been widely used in scintigraphy and targeted radiotherapy in patients with neuroblastoma. Recently, it has been demonstrated that MIBG is incorporated into neuroblastoma cells by the noradrenaline transporter. In vitro experiments on SK-N-SH human neuroblastoma cells performed in the present study showed that uptake of MIBG is inhibited by noradrenaline, more so by dopamine and to a lesser extent, by serotonin, indicating that the respective transporters may also contribute to MIBG uptake. However, neither dopamine nor serotonin transporter gene expression was detected. Noradrenaline transporter gene expression was found in 4 of 6 investigated cell lines, which correlated with specific MIBG uptake. Furthermore, an inverse correlation of noradrenaline transporter and tyrosine hydroxylase gene expression, the key regulatory enzyme of catecholamine synthesis, was observed. These data show that MIBG is specifically incorporated only in neuroblastoma cells in which there is noradrenaline transporter gene expression. Furthermore, the catecholamine status in neuroblastoma cells is regulated by a coordinate expression of the key elements of catecholamine synthesis and reuptake systems.
3-Iodobenzylguanidine↗
An expert system based preventive medicine examination adviser.
Periodic preventive medicine examinations generally rely on a standardized approach. In addition, they are often performed by physicians with only limited training in preventive medicine. Evaluation of a corporate-based program led to the prototype development of an artificial intelligence (AI)-based expert system to collect information from employees and make very specific recommendations for primary practitioners. Unique features include the customizing of questions for each subject and the selection of information to be acquired, both based on answers to previous questions. Recommendations are highly person specific and fall into four categories: laboratory testing, primary physician testing, counseling, and referral. The AI approach allows for easy updating of recommendations in order to meet changes in local preventive resources and national recommendations.
Artificial Intelligence↗
Expression of mdr1, mrp, topoisomerase II alpha/beta, and cyclin A in primary or relapsed states of acute lymphoblastic leukaemias.
In a series of 60 ALL samples drawn during different stages of the disease we used a cDNA-PCR approach to analyse the relative mRNA levels of the MDR-associated genes encoding mdr1/P-glycoprotein, mrp, and the topoisomerase II isozymes alpha and beta. Expression analysis of the cyclin A gene was included to examine cellular proliferation activity. The expression of gapdh served as an internal standard. Calculating the mean values we found: (i) a distinctly lower mdr1 gene expression in primary ALL and first relapses compared to bone marrow from healthy donors, (ii) no change in mdr1 and mrp, but a decreased topoisomerase II alpha gene expression in first relapses of ALL compared to the primary leukaemia, and (iii) increased mdr1 and mrp levels combined to decreased topoisomerase II alpha levels in recurrent relapses of ALL showing significant correlations (mdr1/mrp: rs = +0.6833, P < 0.05; mdr1/topoII alpha: rs = -0.6727, P < 0.05). The expression of the topoisomerase II alpha gene was correlated to that of cyclin A, indicating a link of its expression to cellular proliferation. Our findings suggest that a multifactorial MDR including mrp appears particularly in recurrent relapses of ALL, which often do not respond to chemotherapy. Nonetheless, some individual samples showed gene expression levels very different from the mean values calculated for a particular state of the leukaemia, indicating the need of an individual expression analysis of MDR-associated genes.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Effects of muscle-to-electrode distance on the human diaphragm electromyogram.
It has been suggested that esophageal recordings of the diaphragm electromyogram (EMGdi) are influenced by changes in chest wall configuration. Whether the changes are of physiological or artifactual origin is unclear. For example, the distance between the esophageal electrode and the diaphragm is likely to alter with chest wall configuration and may lead to misinterpretations of EMGdi. The aims of this study were 1) to evaluate and quantify the effect of the muscle-to-electrode (ME) distance filter on EMGdi, as obtained with a multiple-array esophageal electrode, 2) to take advantage of the ME distance filter to locate the position of the diaphragm with respect to the electrode, and 3) to evaluate the influence of lung volume and chest wall configuration on EMGdi center frequency (CF) while controlling for the ME distance filter and signal quality. Five subjects performed six static contractions of the diaphragm at each of seven chest wall configurations, as evaluated by the method of K. Konno and J. Mead (J. Appl. Physiol. 22: 407-422, 1967). EMGdi was measured with seven pairs of electrodes mounted on an esophageal catheter. The pair of electrodes whose EMGdi power spectra were the least filtered by the ME distance was assumed to be closest to the diaphragm. The results of the study indicated that 1) EMGdi power spectra were strongly affected by the distance between the diaphragm and the electrodes. CF decreased by approximately 1 Hz/mm displacement away from the electrode pair closest to the diaphragm; and 2) no systematic relationship was found between changes in chest wall configuration and CF, when CF was measured from the electrode pair closest to the diaphragm. We conclude that the EMGdi CF can be reliably measured with a multiple-array esophageal electrode that covers the span of diaphragmatic excursion and by selecting the pair of electrodes that is the closest to the diaphragm.
Diaphragm↗
The role of preoperative localization in primary hyperparathyroidism.
Hyperparathyroidism is being increasingly recognized by the detection of hypercalcemia on routine blood chemistry. Improvement in preoperative localization has been proposed as a way to decrease operative time and decrease morbidity and mortality. The purpose of this study was to retrospectively review the Guthrie Clinic experience of parathyroidectomy with and without preoperative localization. One hundred nineteen patients who presented with primary hyperparathyroidism between 1983 and 1990 were evaluated. There were 27 males and 91 females with an average age of 61. Preoperative localization resulted in a significant decrease in operative time with preoperative localization decreasing operative time from 97 minutes without localization to 70 minutes with localization. Also, complications were less in patients undergoing preoperative localization (5.8% versus 13.9%). Preoperative localization was positively affected by gland size, with larger glands being easier to localized. In conclusion, accurate preoperative localization decreases operative time and decreases complications in this series of patients undergoing exploration for primary hyperparathyroidism. In our institution the thallium technitium scan is most accurate and is the localization procedure of choice.
Adenoma↗
Remission of a lymphoproliferative disorder occurring after second BMT from an unrelated donor in a 5-year-old boy with severe aplastic anemia.
A 5-year-old boy with severe aplastic anemia failed to respond to cyclosporine (CYA), prednisolone and antilymphocyte globulin (ALG). No suitable sibling marrow donor was available, but an HLA-matched unrelated donor was identified. The patient was conditioned with cyclophosphamide (CY), 50 mg/kg/day for 4 days, total nodal irradiation (8 Gy), and ALG 30 mg/kg/day for 3 days. GVHD prophylaxis consisted of daily CYA, methotrexate (MTX) and ALG. The patient failed to achieve sustained engraftment. He was reconditioned with high-dose prednisolone and anti-T lymphocyte monoclonal antibody OKT3. The boy was reinfused with the same donor marrow on day 0 (+49/first BMT). No GVHD prophylaxis was given the second time. He received G-CSF on days 0 to +20 after the second transplant. Full engraftment was achieved on day +16 (+65). However, on day +31 (80) he developed a biopsy-proven B cell lymphoproliferative disorder (BLPD). After the OKT3 administration was stopped and treatment with ganciclovir and high-dose immunoglobulin was initiated, the BLPD resolved and the patient was discharged on day +50 (99). He is currently well with a functioning graft 266 (305) days posttransplant, with no sign of GVHD.
Anemia, Aplastic↗
High mdr1- and mrp-, but low topoisomerase II alpha-gene expression in B-cell chronic lymphocytic leukaemias.
Fifteen samples from 11 patients suffering from chronic lymphocytic leukaemia (CLL; 5 untreated, 6 chemotherapeutically treated) were analysed for their individual gene expression of the multidrug resistance (MDR) associated genes encoding mdr1/P-glycoprotein, mrp, and topoisomerase II alpha/beta-isoenzymes by a complementary DNA polymerase chain reaction (cDNA-PCR) approach. The expression of glyceraldehyde-3-phosphate dehydrogenase (gapdh) served as standard. Thereby, we generally found high mdr1- and mrp-, but low topoisomerase II alpha-mRNA levels. While mdr1 levels of the CLL samples were mostly found to be in the range of values measured in the T-lymphoblastoid, P-glycoprotein MDR cell line CCRF VCR 100, mrp levels were usually found to be 2-4-fold higher compared therewith. This might represent a multifactorial MDR in CLL. In contrast to the low or even absent topoisomerase II alpha gene expression, however, the expression of the topoisomerase II beta gene was generally high in the CLL lymphocytes exceeding the value observed in the cell line CCRF VCR 100 up to 5-fold. mdr1 gene expression correlated significantly with mrp gene expression in samples from patients having received chemotherapy (rs = 0.5833, P < 0.05, n = 10). In two patients the follow-up analysis revealed combined increases in mdr1- and mrp-gene expression levels in the course of the disease.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Expression of gelatinase A, a mediator of extracellular matrix remodeling, by tracheal gland serous cells in culture and in vivo.
Tracheal gland morphogenesis and gland hypertrophy in disease involve the penetration of epithelial cells into the submucosa, a process that requires digestion of the basal lamina and the surrounding extracellular matrix. We observed that bovine tracheal gland cells invaded collagen substrates and were inhibited from doing so in the presence of a metalloproteinase inhibitor GM6001. The gland cells, but not bovine tracheal surface epithelial cells, secreted a 72-kDa metalloproteinase. The purified enzyme could be activated with 4-aminophenylmercuric acetate and converted to an active 65-kDa form that was far more effective in degrading denatured collagen (gelatin) than nondenatured type I and IV collagens and was ineffective in degrading intact interstitial collagen fibers. At 25 degrees C, the initial rate of degradation of acid-solubilized type I collagen was approximately 50 mg of type I collagen cleaved per min per mg of enzyme, whereas acid-solubilized type IV collagen was degraded at approximately 250 mg cleaved per min per mg of enzyme. In contrast, at the same temperature, heat-denatured type I collagen was degraded 1000-fold more rapidly, while heat-denatured type IV collagen was cleaved 50-fold more rapidly. The activity of the enzyme was maximal at pH 7-8 and was completely abolished by the metalloproteinase inhibitors EDTA and 1,10-phenanthroline. In immunoblots, the enzyme was recognized by an antibody directed against human gelatinase A, the 72-kDa gelatinase. The purified enzyme disrupted the distribution pattern of type IV collagen in the gland basal lamina, as well as of interstitial collagen in the underlying stromal tissue, as shown in tissue sections by immunocytochemistry. Using an antibody directed against the purified enzyme, we also showed by immunocytochemistry that the gelatinase was present in tracheal tissue and was specifically located at the periphery of some tracheal gland acini. Northern blots showed higher concentrations of gelatinase A mRNA in glands than in epithelium microdissected from adult cow tracheas. These data indicate that gelatinase A is a specialized product of the tracheal gland epithelial cell, a cell type normally invasive as part of its developmental program; the enzyme may play an important role in normal gland development and disease-associated hypertrophy.
Animals↗
Drug-induced changes in the expression of MDR-associated genes: investigations on cultured cell lines and chemotherapeutically treated leukemias.
The induced expression of multiple drug resistance (MDR)-associated genes as a direct response of tumor cells to antineoplastic drugs could be an important factor influencing the success of cancer chemotherapy. We investigated the effects of such compounds on mdr1/P-glycoprotein (P-gp) gene expression and drug sensitivities in the T-lymphoblastoid human cell line CCRF-CEM and MDR sublines. Thereby, we observed that actinomycin D or adriamycin administered at sublethal concentrations induced increases of mdr1 mRNA levels and resistance within 72 h. Furthermore, on leukemia cell samples collected before and after chemotherapy we checked by a complementary DNA polymerase chain reaction (cDNA-PCR) approach for similar alterations in the relative expression levels of the MDR-associated genes (a) mdr1/P-gp (b) mrp (MDR related protein), and (c) the topoisomerase II isoforms alpha and beta. We found a concomitant increase in mdr1 and mrp gene expression combined with a decreased expression of topoisomerase II alpha in the course of the second relapse of an acute lymphoblastic leukemia (ALL). This points to the emergence of at least three different MDR mechanisms in this type of leukemia unresponsive to chemotherapy. A chronic myeloid leukemia (CML) in blast crisis, however, showed combined increases in mdr1 (about 20-fold) and mrp (about four fold) gene expression after intense but unsuccessful chemotherapy over a 6-month period. Our results indicate the occurrence of induced resistance in vitro and in vivo and suggest a contribution of the newly identified ATP-binding cassette (ABC) transporter MRP in MDR.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Negative symptoms in schizophrenia: considerations for clinical trials. Working group on negative symptoms in schizophrenia.
There is little agreement about the methodology of clinical trials of antipsychotic drugs in patients with negative symptoms. A literature review revealed wide variation in experimental design, rating scales and study duration. This reflects differing views as to the definition and response to treatment of negative symptoms. Some degree of standardization would improve comparability of studies and aid the development of new compounds. Patients included in such studies should have displayed negative symptoms for at least 6 months. Depressive symptoms, positive schizophrenic symptoms and extrapyramidal signs may all influence or be confused with negative symptoms and may respond to treatment; they should be at a low level at baseline and should be measured during the study period. Studies should last at least 8 weeks. Several scales are available for measuring negative symptoms and are reviewed; a global impression score should be used additionally.
Clinical Trials as Topic↗
X;1 translocation in a female Menkes patient: characterization by fluorescence in situ hybridization.
Menkes disease is an X-linked recessive disorder of copper metabolism, characterized by progressive neurological degeneration, abnormal hair and connective tissue manifestations. We present a female Menkes patient, with classical Menkes features, carrying a de novo balanced translocation 46,X,t(X;1)(q13;q12). The breakpoint on the X chromosome was narrowed down to Xq13.3 within a 1 Mb YAC contig containing the Menkes gene, using fluorescence in situ hybridization. The translocated X chromosome was of paternal origin and non-randomly active leading to the expression of the disease. This was additional evidence for paternal origin of de novo chromosome rearrangements, including all the X; autosomal translocations examined so far.
Chromosomes, Artificial, Yeast↗
Interference in the perceived segregation of equal-luminance element-arrangement texture patterns.
Perceived segregation in element-arrangement patterns composed of squares of equal size and luminance, but of two different hues, was investigated in two experiments. Element-arrangement patterns consist of two types of elements, arranged in alternating vertical stripes in the top and bottom regions and in a checkerboard pattern in the center region. Perceived segregation of the striped and checkerboard regions decreased with increasing luminance of the interspaces between the squares, a high-luminance surround, and the increased spacing of the squares. When the luminance of the horizontal interspaces was increased, the decrease in perceived segregation was greater than that when the luminance of the vertical interspaces was increased. Two explanations of the interference of the interspace luminance are discussed. One explanation is in terms of inhibitory interactions among cortical filters tuned to spatial frequency and orientation. A second explanation is in terms of interference with preattentive grouping processes.
Color Perception↗
Organizational experts share their first-class ideas.
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Administrative Personnel↗
Diagnosis of veno-occlusive disease of the liver by color-coded Doppler sonography.
In a girl with bilateral Wilms' tumor veno-occlusive disease occurred during chemotherapy. The diagnosis was established by reversed flow in the portal vein displayed by color and pulsed Doppler sonography. After successful conservative treatment normalization of flow in the portal vein could be shown by both Doppler techniques.
Antineoplastic Combined Chemotherapy Protocols↗