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51.
52.
Ultrastructural confirmation of neuronal protection by melatonin against the neurotoxin 6-hydroxydopamine cell damage 总被引:9,自引:0,他引:9
6-Hydroxydopamine (6-OHDA) is a neurotoxin used in the induction of experimental Parkinson's disease in both animals and cultured neuronal cells. Biochemical and molecular approaches showed previously that low doses of 6-OHDA induced apoptosis in PC12 cells, while high doses of this neurotoxin induced necrosis. Melatonin has been shown to protect against the neuronal programmed cell death induced by 6-OHDA, although it was not able to prevent the massive necrotic cellular death occurring after the addition of high doses of the neurotoxin. In the present work, we demonstrate by ultrastructural analysis that although low doses of 6-OHDA induced apoptosis in PC12 cells, it also damaged the non-apoptotic cells, morphologically corresponding this damage to incipient and reversible necrotic lesions. When the doses of the neurotoxin increase, there are still apoptotic cells, although most of the cells show necrotic irreversible lesions. We also found that melatonin partially prevents the incipient necrotic lesions caused by low doses of 6-OHDA. The fact that melatonin was shown in previous work to prevent apoptosis caused by low doses of 6-OHDA, but not necrosis induced by high doses of the neurotoxin, seemed to indicate that this agent is only able to protect against apoptosis. However, our present results, melatonin preventing also the incipient necrotic neuronal lesions, suggest that this hormone may provide a general protection against cell death, suggesting that higher doses should be tried in order to prevent the necrotic cell death induced by high doses of the neurotoxin. 相似文献
53.
M. D’Amico Clara Di Filippo Ferdinando Esposito Francesco Rossi Amelia Filippelli 《Naunyn-Schmiedeberg's archives of pharmacology》1999,359(6):471-476
We used in vitro autoradiography to identify the endothelin-1 receptor subtype(s) in the nucleus raphe obscurus of rats.
These studies showed dense binding of [125I]PD151242 (for endothelin ETA receptors), while tissues incubated with [125I]BQ3020 (for endothelin ETB receptors) had low binding. In addition, we examined the effects of the endothelin receptor antagonists FR 139317 (endothelin
ETA receptor-selective antagonist), SB 209670 (endothelin ETA/ETB receptor-non-selective antagonist) and BQ-788 (endothelin ETB receptor-selective antagonist) on the blood pressure responses following administration of endothelin-1 into the nucleus
raphe obscurus. The basal mean arterial blood pressure (MABP) of the rats was 110 ± 7 mmHg (n = 5). This was decreased in a dose-dependent manner by endothelin-1 (0.1, 1 and 10 pmol) microinjected into the nucleus
raphe obscurus. This effect occurred within 1–6 s and recovered within 4 ± 1.2 min at a dose of 10 pmol. The doses of 0.1
pmol and 1 pmol ET-1 had responses which lasted 1 ± 0.4 min and 2 ± 0.2 min, respectively. Small decreases in heart rate accompanied
the MAP responses to endothelin-1. For instance, the heart rate decreased by 16 ± 4 beats min–1 after 10 pmol endothelin-1 (control, 366 ± 6 beats min–1, n = 5). Decreases in blood pressure induced by endothelin-1 were greatly reduced by pre-administration to the nucleus raphe
obscurus of FR139317 (5 nmol/rat) or SB209670 (3 nmol/rat; 97 ± 7% and 95 ± 6%, P < 0.01, n = 5, respectively), but were not affected by BQ-788 (50 nmol/rat; 8 ± 3%, P > 0.05, n = 5). The antagonists did not influence heart rate when injected to the nucleus raphe obscurus prior to endothelin-1. FR139317
(0.5 nmol) and SB209670 (0.3 nmol) had no effects on endothelin-induced changes in arterial blood pressure. Therefore, the
autoradiographic study showed that there are binding sites for ET-1 within the nucleus raphe obscurus of rats, which are predominantly
of ETA type. The in vivo study showed that ETA receptors are the predominant mediators of depressor responses induced by endothelin-1 injected into this nucleus.
Received: 6 August 1998 / Accepted: 16 February 1999 相似文献
54.
This paper investigates the effect of wait time for hip fracture surgery in Canada on post-surgery length of stay in hospital and inpatient mortality. After controlling for observed and unobserved patient and hospital characteristics, pre-surgery delay has little effect on either of the two outcome variables. Patients from higher income postal-codes experience only slightly shorter delays, and income has no substantial effect on post-surgery outcomes. For hip fracture patients surgery delay may lead to greater pre-surgery inpatient costs and more patient discomfort, but we find no evidence of a detrimental impact on post-surgery outcomes. 相似文献
55.
Frequency of the ATM IVS10-6T→G variant in Australian multiple-case breast cancer families 下载免费PDF全文
56.
Association of gestational diabetes with abnormal maternal vascular endothelial function 总被引:1,自引:0,他引:1
Gregory A. Knock Research Assistant rew L. McCarthy Consultant Clara Lowy Consultant Lucilla Poston Professor 《BJOG : an international journal of obstetrics and gynaecology》1997,104(2):229-234
Objective To evaluate vascular endothelial function in isolated small arteries from women with gestational diabetes.
Methods Small subcutaneous arteries (mean luminal diameter ∼ 250μm) were dissected from biopsies obtained at caesarean section in 14 normotensive women with gestational diabetes and in 18 normotensive nondiabetic pregnant women. Vascular function was determined after mounting the arteries on a small vessel myograph.
Results Pre-constricted arteries from gestational diabetic pregnant women demonstrated poor relaxation to acetylcholine, an endothelium-dependent vasodilator (pEC50 , mean [SE], 6.98 [0.10] vs normal pregnant, 7.28 [0.08], P < 0.03 ; % maximum relaxation, median [range], 88.2 [42.4–994] vs normal pregnant 94.2 [71.8–100.0], P < 0.01 ). In the presence of indomethacin relaxation to acetylcholine was similar in both groups suggesting a deficiency in dilator prostaglandin synthesis in the arteries from the diabetic women. The nitric oxide synthase inhibitor N -monomethyl-L-arginine further reduced sensitivity of arteries to acetylcholine but to a similar degree in both normal pregnant and gestational diabetic women. Relaxation to sodium nitroprusside, an indicator of sensitivity of the vascular smooth muscle to nitric oxide, was similar in both groups.
Conclusions Maternal vascular endothelial dysfunction may contribute to the increased incidence of cardiovascular disorders in women with gestational diabetes. 相似文献
Methods Small subcutaneous arteries (mean luminal diameter ∼ 250μm) were dissected from biopsies obtained at caesarean section in 14 normotensive women with gestational diabetes and in 18 normotensive nondiabetic pregnant women. Vascular function was determined after mounting the arteries on a small vessel myograph.
Results Pre-constricted arteries from gestational diabetic pregnant women demonstrated poor relaxation to acetylcholine, an endothelium-dependent vasodilator (pEC
Conclusions Maternal vascular endothelial dysfunction may contribute to the increased incidence of cardiovascular disorders in women with gestational diabetes. 相似文献
57.
G. Tormans E. Van Doorslaer P. van Damme R. Clara H. J. Schmitt 《European journal of pediatrics》1998,157(5):395-401
Acellular pertussis vaccines are less reactogenic than whole cell pertussis vaccines, but they are also more expensive. Based
on simulation models, we compared the costs and effects of three alternative pertussis vaccination strategies in German children
to ”no prevention”: (1) vaccination with whole-cell vaccine at 45% coverage (vaccine efficacy 90%), (2) vaccination with acellular
vaccine at 45% coverage (vaccine efficacy 85%), and (3) vaccination with acellular vaccine at 90% coverage. In the two low
coverage scenarios expected annual savings in direct medical costs through prevention of disease were larger for whole-cell
than for acellular vaccination (252 vs 216 million DM, respectively). Direct costs for treating the more important adverse
events induced by whole-cell vaccination (16.9 million DM annually) did not outweigh the higher direct costs of pertussis
infections not prevented with the acellular vaccine and the higher price of the acellular vaccine. However, vaccination with
acellular pertussis vaccine rapidly becomes as cost saving as vaccination with whole-cell vaccine as soon as vaccination coverage
can be raised from 45% to 52.5% with acellular vaccine. Acellular vaccination is also the superior alternative when considering
indirect cost savings resulting from reduction in work-loss due to adverse events.
Conclusion In our simulations, the most cost-effective pertussis prevention strategy was the use of an effective whole-cell vaccine
with a high coverage rate. Introduction of the more expensive acellular pertussis vaccines becomes cost saving if at least
a 7.5% increase in coverage is achieved. If also non-medical indirect costs to parents resulting from vaccine associated side-effects
are accounted for, acellular vaccines may be more cost-effective also in countries with already high whole-cell vaccine coverage.
Received: 22 April 1997 / Accepted in revised form: 21 November 1997 相似文献
58.
Familial gastrointestinal stromal tumor syndrome: phenotypic and molecular features in a kindred. 总被引:5,自引:0,他引:5
Frederick P Li Jonathan A Fletcher Michael C Heinrich Judy E Garber Stephen E Sallan Clara Curiel-Lewandrowski Anette Duensing Matt van de Rijn Lowell E Schnipper George D Demetri 《Journal of clinical oncology》2005,23(12):2735-2743
PURPOSE: Members of a family with hereditary gastrointestinal stromal tumors (GISTs) and a germline KIT oncogene mutation were evaluated for other potential syndrome manifestations. A tumor from the proband was analyzed to compare features with sporadic GISTs. PATIENTS AND METHODS: Members of a kindred in which six relatives in four consecutive generations comprised an autosomal dominant pattern of documented GISTs and cutaneous lesions underwent physical examination, imaging studies, and germline KIT analysis. A recurrent GIST from the proband was studied using microarray, karyotypic, immunohistochemical, and immunoblotting techniques. RESULTS: In addition to evidence of multiple GISTs, lentigines, malignant melanoma, and an angioleiomyoma were identified in relatives. A previously reported gain-of-function missense mutation in KIT exon 11 (T --> C) that results in a V559A substitution within the juxtamembrane domain was identified in three family members. The proband's recurrent gastric GIST had a 44,XY-14,-22 karyotype and immunohistochemical evidence of strong diffuse cytoplasmic KIT expression without expression of actin, desmin, or S-100. Immunoblotting showed strong expression of phosphorylated KIT and downstream signaling intermediates (AKT and MAPK) at levels comparable with those reported in sporadic GISTs. cDNA array profiling demonstrated clustering with sporadic GISTs, and expression of GIST markers comparable to sporadic GISTs. CONCLUSION: These studies provide the first evidence that gene expression and mechanisms of cytogenetic progression and cell signaling are indistinguishable in familial and sporadic GISTs. Current investigations of molecularly targeted therapies in GIST patients provide opportunities to increase the understanding of features of the hereditary syndrome, and risk factors and molecular pathways of the neoplastic phenotypes. 相似文献
59.
60.
Susana B Bravo María E R García-Rendueles Rafael Seoane Vanesa Dosil José Cameselle-Teijeiro Luis López-Lázaro Juan Zalvide Francisco Barreiro Celia M Pombo Clara V Alvarez 《Clinical cancer research》2005,11(21):7664-7673
Undifferentiated (anaplastic) thyroid carcinoma is a highly aggressive human cancer with very poor prognosis. Although there have been a few studies of candidate treatments, the fact that it is an infrequent tumor makes it very difficult to design clinical trials. A strong association has been observed between undifferentiated thyroid carcinoma and TP53 mutations in numerous molecular genetic and expression studies. Plitidepsin (Aplidin, PharmaMar, Madrid, Spain) is a novel anticancer compound obtained from a sea tunicate. This compound has been reported to induce apoptosis independently of TP53 status. We investigated the actions of plitidepsin in human thyroid cancer cells. In initial experiments using primary cultured cells from a differentiated (papillary) carcinoma, we found that 100 nmol/L plitidepsin induced apoptosis, whereas lower doses were cytostatic. Because our aim was to study the effects of plitidepsin at clinically relevant concentrations, subsequent experiments were done with a dosage regimen reflecting plasma concentrations observed in previously reported clinical trials: 100 nmol/L for 4 hours, followed by 10 nmol/L for 20 hours (4(100)/20(10) plitidepsin). This plitidepsin dosage regimen blocked the proliferation of a primary undifferentiated/anaplastic thyroid carcinoma culture obtained in our laboratory and of a commercial cell line (8305C) obtained from an undifferentiated thyroid carcinoma; however, it did not induce apoptosis. The proportion of cells in the G(1) phase of the cell cycle was greatly increased and the proportion in the S/G(2)-M phases greatly reduced, suggesting that plitidepsin blocks G(1)-to-S transition. Levels of the cyclin D1/cyclin-dependent kinase 4/p21 complex proteins were decreased and, in line with this, the levels of unphosphorylated Rb1 increased. The decrease in cell cycle proteins correlated with hypoacetylation of histone H3. Finally, we did experiments to assess how rapidly tumor cells return to their initial pretreatment proliferative behavior after 4(100)/20(10) plitidepsin treatment. Cells from undifferentiated tumors needed more than 3 days to recover logarithmic growth, and after 7 days, cell number was still significantly lower than in control cultures. 4(100)/20(10) plitidepsin inhibited the growth in soft agar. Together, our data show that plitidepsin is able to block in vitro cell cycle progression at concentrations similar to serum concentrations observed in vivo, and that this effect is persistent for several days after plitidepsin removal. Whether plitidepsin will prove to be clinically useful in the treatment of undifferentiated thyroid cancers remains to be established. However, our results raise the possibility that plitidepsin might be effective alone or in combination with radiotherapy and/or other drug treatments. 相似文献