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41.
JR Zierath JN Livingston A Th?rne J Bolinder S Reynisdottir F L?nnqvist P Arner 《Canadian Metallurgical Quarterly》1998,41(11):1343-1354
Increased mobilization of non-esterified fatty acids (NEFA) from visceral as opposed to peripheral fat depots can lead to metabolic disturbances because of the direct portal link between visceral fat and the liver. Compared with peripheral fat, visceral fat shows a decreased response to insulin. The mechanisms behind these site variations were investigated by comparing insulin action on NEFA metabolism with insulin receptor signal transduction through the insulin receptor substrate-1 (IRS-1) pathway in omental (visceral) and subcutaneous human fat obtained during elective surgery. Insulin inhibited lipolysis and stimulated NEFA re-esterification. This was counteracted by wortmannin, an inhibitor of phosphaditylinositol (PI) 3-kinase. The effects of insulin on antilipolysis and NEFA re-esterification were greatly reduced in omental fat cells. Insulin receptor binding capacity, mRNA and protein expression did not differ between the cell types. Insulin was four times more effective in stimulating tyrosine phosphorylation of the insulin receptor in subcutaneous fat cells (p < 0.001). Similarly, insulin was two to three times more effective in stimulating tyrosine phosphorylation of IRS-1 in subcutaneous fat cells (p < 0.01). This finding could be explained by finding that IRS-1 protein expression was reduced by 50 +/- 8% in omental fat cells (p < 0.01). In omental fat cells, maximum insulin-stimulated association of the p85 kDa subunit of PI 3-kinase to phosphotyrosine proteins and phosphotyrosine associated PI 3-kinase activity were both reduced by 50% (p < 0.05 or better). Thus, the ability of insulin to induce antilipolysis and stimulate NEFA re-esterification is reduced in visceral adipocytes. This reduction can be explained by reduced insulin receptor autophosphorylation and signal transduction through an IRS-1 associated PI 3-kinase pathway in visceral adipocytes. 相似文献
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BACKGROUND: Different regions within the left ventricle are preferentially supplied by the left or right sympathetic system. In order to characterize different influences of left vs right sympathetic lateralization on LV function, haemodynamic effects of right and left stellate ganglion stimulations (RSGS and LSGS) as well as a right sympathetic block (RSB) were compared. METHODS: Seven alpha-chloralose anaesthetized open chest dogs were instrumented for measurement of LV pressure (tip manometers) and regional LV wall thickness (WT, sonomicrometry) in the antero-apical wall (AW, innervated by right stellate ganglion) and postero-basal wall (PW, left stellate ganglion). Timing of regional myocadial wall motion was evaluated by the phase of the first Fourier transform of the WT signals, LV asynchrony by the phase difference (phi) between both regions, and LV diastolic function by the time constant of isovolumic relaxation (tau). Measurements were performed before and after RSB (5 ml of lidocaine 1%); in 6 dogs of this group, RSGS and LSGS (4 V, 0.2 ms, 20 Hz) were performed before RSB. In order to investigate a regional inotropic stimulation without systemic effect, 6 additional dogs received intracoronary noradrenaline injections (NIC, 0.25 microgram) into the left circumflex artery perfused myocardium. RESULTS: LSGS and NIC led to an earlier PW-motion within the cardiac cycle (phase reduction by 40.0 +/- 15.0 degree (SEM) and 55.5 +/- 11.2 degrees) and RSGS induced an earlier AW-motion (by 33.7 +/- 15.2 degrees). After RSB, AW-motion was delayed (38.1 +/- 9.2 degrees). The consequence was an asynchronous wall motion pattern after all interventions (change in phi: LSGS-64.7 +/- 18.7 degrees, RSGS 41.1 +/- 15.7 degrees, NIC -74.5 +/- 17.4 degrees, RSB -52.6 +/- 14.6 degrees), and a prolonged relaxation (tau increase: RSGS 9.4 +/- 1.9, NIC 8.3 +/- 1.5, RSB 3.7 +/- 0.8 ms). CONCLUSION: Unilateral increases as well as decreases of sympathetic tone to the heart result in an asynchronous wall motion pattern and an impaired LV relaxation. 相似文献
45.
E Healy C Belgaid M Takata D Harrison NW Zhu DA Burd HS Rigby JN Matthews JL Rees 《Canadian Metallurgical Quarterly》1998,16(17):2213-2218
Loss of genetic material, including loss of loci on chromosome arms 6q, 9p, and 10q, occurs frequently in cutaneous melanoma but infrequently in benign melanocytic nevi or other melanocytic lesions, suggesting that these genetic alterations are important in the development and progression of melanoma. To examine whether allelic loss is of prognostic importance in melanoma, disease-free survival was related to loss of heterozygosity on 6q, 9p and 10q in 83 individuals with sporadic primary cutaneous melanoma. Loss of chromosome arms 6q and 10q were each significantly associated with a poorer clinical outcome (P=0.013 and P=0.001 respectively). In a subgroup of 41 subjects whose primary tumours were allelotyped, the fractional allelic loss (FAL) at 39 autosomal arms also significantly correlated with disease-free survival (P=0.013), with an increase in FAL associated with a poorer outcome; this association remained significant when controlled for tumour thickness (P=0.035). In addition, a greater proportion of cells were immunopositive for Ki67 antigen, p53 and p21WAF1 protein in the primary melanomas than in the benign melanocytic nevi, however, only p53 over-expression was significantly associated with improved survival (P=0.041). 相似文献
46.
v-raf suppresses apoptosis and promotes growth of interleukin-3-dependent myeloid cells 总被引:1,自引:0,他引:1
JL Cleveland J Troppmair G Packham DS Askew P Lloyd M González-Garcia G Nu?ez JN Ihle UR Rapp 《Canadian Metallurgical Quarterly》1994,9(8):2217-2226
Interleukin-3 (IL-3) is required for the proliferation, survival and differentiation of myeloid progenitors. In the absence of IL-3, murine myeloid 32D.3 cells accumulate in the G1 phase of the cell cycle and subsequently undergo programmed cell death, or apoptosis. Here we demonstrate that enforced expression of the v-raf oncogene suppresses apoptosis of myeloid 32D.3 cells following the withdrawal of IL-3. Surprisingly, steady state levels of Bcl-2, an oncogene known to suppress apoptosis, were not dependent upon IL-3 in 32D.3 cells and its levels were not augmented in v-raf clones. This suggests that ability of v-raf to suppress apoptosis in the absence of ligand is either Bcl-2 independent or that v-raf kinase promotes Bcl-2 function. v-raf also promoted growth of these cells in the presence of IL-3. v-raf clones proliferated at an increased rate due to a shortened G1 phase and had decreased requirements for IL-3 for growth. Therefore, transformation of myeloid cells by v-raf involves signaling pathways which promote both cell cycle progression and cell survival. 相似文献
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MD Bachi EE Korshin P Ploypradith JN Cumming S Xie TA Shapiro GH Posner 《Canadian Metallurgical Quarterly》1998,8(8):903-908
A series of 4,8-dimethyl-4-phenylsulfonylmethyl-2,3-dioxabicyclo[3.3.1]+ ++nonanes, carrying a variety of substituents at position-8 (4) were prepared by a short and efficient method from R-(+)-limonene. Key reactions include thiol oxygen cooxidation, and alkylation and acylation of a sterically hindered tertiary alcohol compatible with the endoperoxy functionality. Some of compounds 4, which are structurally related to yingzhaosu A (2), were found to exhibit in vitro antimalarial activity comparable to that of artemisinin (1) and superior to that of arteflene (3). 相似文献
49.
G Velikova RE Banks A Gearing I Hemingway MA Forbes SR Preston NR Hall M Jones J Wyatt K Miller U Ward J Al-Maskatti SM Singh PJ Finan NS Ambrose JN Primrose PJ Selby 《Canadian Metallurgical Quarterly》1998,77(11):1857-1863
The concentrations of the soluble adhesion molecules E-cadherin, E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were investigated in 48 patients with colorectal cancer before treatment, and their relation to clinical, histological and routine laboratory parameters was examined. Data were collected on tumour stage at presentation, presence and sites of metastatic disease, tumour pathology and results of routine laboratory tests. Serum concentrations of ICAM-1 and VCAM-1 were significantly elevated in the patients with colorectal cancer in comparison with a group of healthy subjects (P < 0.00001). Levels of circulating ICAM-1 and VCAM-1 were increased both in patients with local and those with metastatic disease. Although elevated in some patients soluble E-cadherin and E-selectin concentrations were not significantly elevated compared with the control group (P = 0.71 and P = 0.052 respectively). The levels of circulating ICAM-1 were significantly correlated with those of VCAM-1 and E-selectin. A correlation was also found between the serum concentrations of E-selectin and ICAM-1 and alkaline phosphatase, total white cell count and platelet count. VCAM-1 was positively correlated with age and negatively with degree of tumour differentiation and haemoglobin concentration. The biological implications and possible clinical relevance of these findings are discussed. 相似文献
50.
BACKGROUND AND OBJECTIVE: Experience with recombinant human erythropoietin (rHuEPO) in the treatment of the anemia secondary to myelofibrosis with myeloid metaplasia (MMM) is slight up to now. We present our results of the treatment of 6 patients and a review of the literature in search of possible parameters predicting response to this treatment. DESIGN AND METHODS: From January 1994 to June 1996 all transfusion-dependent patients with MMM diagnosed in our hospital were included in this study. We established a minimum period of 4 weeks of treatment and a maximum of 12 if no response was observed. Initial dosages used were 100 U/kg s.c. 3 times weekly, increasing by 50 U/kg every 4 weeks where no response was observed. Response was defined as a reduction > or = 30% of the previous transfusional needs. The review of the literature was made using a MEDLINE search (January 1990-December 1996) on the keywords erythropoietin, myelofibrosis, and agnogenic myeloid metaplasia. A statistical study was made in search of possible parameters to predict response. The parameters studied include age, sex, hemoglobin, serum erythropoietin (sEPO) levels, transfusional dependency, transfusional requirements per month prior to treatment, maximum dosages used and dosage at which response was obtained. RESULTS: Only 2 of our 6 patients responded, both at a dosage of 600 U/kg/week (200 U/kg 3 times weekly s.c.). In addition to our 6 patients we have found only 28 other patients in the literature. For statistical calculation 2 of our patients were not considered as they did not complete the period of study. The overall rate of response was 17/32 (53.1%). In the univariate analysis comparing responders and non-responders we found a tendency to significance with respect to sex (p = 0.07), sEPO (p = 0.07) and transfusional needs in units of packed red blood cells per month (PRBC/m) (p = 0.13). In this way patients with low sEPO, females and those with low transfusional needs (< 3 PRBC/m) respond better. This better response in females could be explained by the fact that their disease situation was more stable (with both lower sEPO levels and transfusional dependency). The best cut-off point in the sEPO to predict response was 123 mU/mL. No important side-effects have been observed except three cases of aggravation of splenomegaly. In two cases this condition improved when the rHuEPO was discontinued. The association of rHuEPO with hydroxyurea or interferon does not seem to affect the response. INTERPRETATION AND CONCLUSIONS: Though the number of patients is low, our data suggest that some MMM patients, in particular females and individuals with low sEPO levels and with low transfusional needs, might benefit from rHuEPO in terms of elevation of hemoglobin levels. Unfortunately, transfusion dependent-patients, i.e. those in whom a beneficial effect of rHuEPO would be most welcome, are unlikely to respond, and more generally, treatment is not cost effective in medically responsive patients. 相似文献