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141.
Ryanodine receptor (RyR) phosphorylation by protein kinase A (PKA) may be important in modulating resting sarcoplasmic reticulum (SR) Ca2+ release, especially in heart failure. However, clear cellular data on PKA-dependent modulation of cardiac RyRs is limited because of difficulty in distinguishing between PKA effects on RyR, phospholamban (PLB), and Ca2+ current. To clarify this, we measured resting Ca2+ sparks in streptolysin-O permeabilized ventricular myocytes from wild-type (WT) and PLB knockout (PLB-KO) mice and transgenic mice expressing only double-mutant PLB (PLB-DM) that lacks the regulatory phosphorylation sites (S16A/T17A). In WT myocytes, cAMP dramatically increased Ca2+ spark frequency (CaSpF) by 2- and 3-fold when [Ca2+] was clamped at 50 and 10 nmol/L (and the SR Ca2+ content also rose by 40% and 50%). However, in PLB-KO and PLB-DM, neither CaSpF nor SR Ca2+ load was changed by the addition of 10 micromol/L cAMP (even with phosphatase inhibition). PKA activation also increased Ca2+ spark amplitude, duration, and width in WT, but not in PLB-KO or PLB-DM. RyR phosphorylation was confirmed by measurements of 32P incorporation on immunoprecipitated RyR. In intact resting myocytes, PKA activation increased CaSpF 2.8-fold in WT, but not in PLB-KO, confirming results in permeabilized myocytes. We conclude that the PKA-dependent increase in myocyte CaSpF and size is entirely attributable to PLB phosphorylation and consequent enhanced SR Ca2+ load. PKA does not seem to have any appreciable effect on resting RyR function in these ventricular myocytes. Moreover, the data provide compelling evidence that elevated intra-SR [Ca2+] increases RyR gating independent of cytosolic [Ca2+] (which was clamped). 相似文献
142.
C. Kattamis Anna Metaxotou-Mavromati Katerina Karamboula Evangelia Nasika H. Lehmann 《British journal of haematology》1973,25(3):375-384
S ummary . Eleven children who are double heterozygotes for β- and δβ-thalassaemia are described. Of their parents one was always heterozygous for β-(A2 ) thalassaemia (increased Hb A2 ), and the other for the high F variant or δβ-thalassaemia (increased Hb F). The clinical syndrome resulting from the combination of β- and δβ-thalassaemia shows some heterogeneity, but in general is of intermediate severity. Red cell abnormalities were considerable, Hb F was very high (mean 70.3 ± 12.6%), Hb A2 was low or normal (mean 2.36 ± 1.52%), and Hb A was absent in five patients. Hb F was nearly homogeneously distributed in the red cells of most patients. These findings are explained as the outcome of a mutation which suppresses δ- and β -chain synthesis which is associated with a genetically determined increased production of γ- chains. 相似文献
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Charmandari E Brook CG Hindmarsh PC 《European journal of endocrinology / European Federation of Endocrine Societies》2004,151(Z3):U77-U82
Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders resulting from deficiency of one of the five enzymes required for synthesis of cortisol in the adrenal cortex. The most common form of the disease is classic 21-hydroxylase deficiency, which is characterized by decreased synthesis of glucocorticoids and often mineralocorticoids, adrenal hyperandrogenism and impaired development and function of the adrenal medulla. The clinical management of classic 21-hydroxylase deficiency is often suboptimal, and patients are at risk of developing in tandem iatrogenic hypercortisolism and/or hyperandogenism. Limitations of current medical therapy include the inability to control hyperandrogenism without employing supraphysiologic doses of glucocorticoid, hyperresponsiveness of the hypertrophied adrenal glands to adrenocorticotropic hormone (ACTH) and difficulty in suppressing ACTH secretion from the anterior pituitary. Puberty imposes increased difficulty in attaining adrenocortical suppression despite optimal substitution therapy and adherence to medical treatment. Alterations in the endocrine milieu at puberty may influence cortisol pharmacokinetics and, consequently, the handling of hydrocortisone used as replacement therapy. Recent studies have demonstrated a significant increase in cortisol clearance at puberty and a shorter half-life of free cortisol in pubertal females compared with males. Furthermore, children with classic CAH have elevated fasting serum insulin concentrations and insulin resistance. The latter may further enhance adrenal and/or ovarian androgen secretion, decrease the therapeutic efficacy of glucocorticoids and contribute to later development of the metabolic syndrome and its complications. 相似文献
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Hand-Foot Syndrome (HFS) is commonly reported in treatment with liposomal doxorubicin (LD) and capecitabine. We present 3 cases of HFS recall with gefitinib after previous LD therapy. The first 2 cases, in patients with head and neck cancer previously treated with paclitaxel and LD, developed on subsequent therapy with gefitinib. One patient had previously developed HFS on LD and the other had not. In both patients HFS resolved after stopping gefitinib. The third case is of a patient with ovarian cancer, also treated with gefitinib after LD, who developed HFS recall which resolved after gefitinib withdrawal. HFS can occur with gefitinib in patients who have been previously exposed to agents known to cause HFS. 相似文献
147.
Mystakidou K Katsouda E Parpa E Kouskouni E Chondros C Tsiatas ML Galanos A Vlahos L 《The American journal of hospice & palliative care》2006,23(1):41-50
In this study, we assessed the safety, tolerability, and effectiveness of two therapeutic regimens relating to the frequency of zoledronic acid (ZOL) infusion. Sixty adult patients with bone metastases were randomly assigned to two study groups. The first group (group A) received 4 mg ZOL every two weeks, and the second group (group B) received 4 mg ZOL every four weeks. Assessment measures included C-telopeptide (CTX) rate, the Greek Brief Pain Inventory (GBPI), the linear analogue scale assessment (LASA) of quality of life, and biochemical markers. Assessments were made at weeks 12, 24, 36, and 48. Clinical endpoints included effective decrease in bone resorption markers, pain relief and improvement of mobility status. The follow-up period was 48 weeks. No statistically significant differences between groups A and B were found in overall profile of biochemical markers, Eastern Cooperative Oncology Group (ECOG) performance status, and GBPI score at the end of the follow-up period. Assessment of bone metastases revealed a slight difference between the two groups, however this difference was not statistically significant. These findings indicate that administering zoledronic acid at four rather that two weeks has no significant impact on overall outcome. 相似文献
148.
Adamopoulos D Venaki E Koukkou E Billa E Kapolla N Nicopoulou S 《Asian journal of andrology》2006,8(4):488-492
目的:报道了一个年轻男运动员大量摄入胡萝卜素后引发性腺机能低下的独特病例。病例报告:一名20岁的患者,在先前一年里坚持自己设计的高胡萝卜素、低动物脂肪的饮食,就诊时症状为肌肉逐渐萎缩、身体活动能力以及性欲减低、勃起功能下降。临床上,他表现出明显的胡萝卜素过量的体征:掌心和脚底都呈黄色。当他的饮食正常化二周后,胡萝卜素 B 值达到了正常范围的上限。方法:在恢复均衡饮食前和恢复均衡饮食3、6和12个月后,分别进行下丘脑、垂体和睾丸功能的重复刺激测试。结果:在均衡饮食数月后,促性腺激素和性腺类固醇由最初测得的非常低的基础值和刺激值逐渐恢复正常,并且胡萝卜素 B 值也有所恢复。诊断9—12个月后,荷尔蒙分泌物和性反应完全恢复。结论:这是第一个与摄入过量胡萝卜素有关的下丘脑式性腺机能低下的病例。 相似文献
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