Pharmacology of KB‐R7943: A Na+–Ca2+ exchange inhibitor

The Na⁺–Ca²⁺ exchange (NCX) system plays a pivotal role in regulating intracellular Ca²⁺ concentration in cardiomyocytes, neuronal cells, kidney and a variety of other cells. It performs a particularly important function in regulating cardiac contractility and electrical activity. One of the leading NCX inhibitors is KB‐R9743 (KBR) that appears to exhibit selectivity for Ca²⁺‐influx‐mode NCX activity (reverse mode of NCX). In this article we reviewed pharmacology of KBR and provide a brief summary of studies with other NCX inhibitors, such as SEA0400 (SEA) and SN‐6 (SN). Potential clinical usefulness of KBR and other NCX inhibitors is still controversial but the reviewed findings may be helpful in designing more selective and clinically useful NCX inhibitors for the treatment of cardiac, neuronal and kidney diseases.     

哺乳妇女单次注射迪波盖司通~长效避孕针后血清和乳液中MPA浓度变化

目的:探讨中国妇女哺乳期使用迪波盖司通后血清和乳液醋酸甲羟孕酮(MPA)浓度变化。方法:10名产后哺乳妇女单次注射迪波盖司通(含MPA150mg),在注射后的第1、2、4、6、8、10和12周采集血样和乳液样本,用放射免疫方法测定MPA。结果:血清MPA浓度于注射后第1周最高,到第2、4周时下降明显,第4周后浓度下降趋势逐渐缓慢。乳液MPA浓度在第1周为最高,第2周比第1周降低了约1/2,之后10周平均浓度变化波动在5.09-8.15ng/ml之间。观察期间乳液/血清MPA浓度比值和曲线下浓度面积比值均为0.55。对象之间和同一对象不同时间点乳液/血清MPA浓度存在明显个体差异。结论:哺乳期使用迪波盖司通,将导致血液和乳液中含有一定量的MPA。     

不同强度运动对女子游泳运动员性激素水平的影响及特点

本研究以放兔分析法观察不同强度运动前后19名女子游泳运动员血清促卵泡激素(FSH)、黄体生成素(LH)、雌二醇(E_2)、孕酮(P)、睾酮(T)及胰岛素(Ins)的变化。受试者在卵泡及黄体两期分别进行短时间高强度间歇运动——6×50m全速力竭性游泳和长时间持续运动——1000m全速力竭性游泳。在运动前5分钟及运动后即刻分别采集静脉血测定各种激素含量。主要结果如下:受试者从事6×50m最大速度间歇游泳后,卵泡期各种激素浓度的变化均显著高于运动前安静状态,黄体期变化不一,FSH、LH降低,E_2、P、T及Ins升高。从事1000m全速游泳后,激素变化表现为卵泡期FSH、LH、E_2、P均升高,T及Ins降低;黄体期E_2、P、T升高,Ins降低,FSH、LH无显著变化,两期相比黄体期运动成绩优于卵泡期。上述结果提示:①受试者月经周期的黄体期机体有氧能力强于卵泡期,运动能力的增强与黄体期E_2、P、T水平升高有关。②FSH、LH与E_2、P分泌变化并非同步一致,说明运动中E_2升高并非受制于促性腺激素,而主要是卵巢分泌量升高所致。③运动中E_2、P、T具有协同效应,可抵抗疲劳,提高人体运动能力。     

The reproducibility of estimates of critical power and anaerobic work capacity in upper-body exercise

The purposes of this study were to apply the linear power versus inverse of time relationship to high-intensity upper-body exercise and to assess the repeatability of the parameters critical power (CP) and anaerobic working capacity (AWC), using limits of agreement (Bland and Altman 1986). Sixteen active male subjects (aged 20–34 years), performed two sets of five constant-power exercises on an adapted cycle ergometer. There were no significant differences between mean estimates of CP [96 (16) W and 95 (17) W] and AWC [7457 (2011) J and 7608 (1684) J] from the first and second sets of bouts. Despite the lack of systematic bias, there was evidence of large random error. Ratio limits of agreement for time to exhaustion during constant-power exercises suggested that a repeat measurement might be expected in 95% of cases to be between 0.64 and 1.59 times the original measurement. The 95% limits of agreement for CP were –15 W to +17 W. The ratio limits of agreement for AWC suggest that in 95% of cases a repeat measurement might be between 0.57 and 1.67 times the original estimate. The results of this study suggest a poor repeatability of constant-power upper-body exercises to exhaustion, which may contribute to a poor repeatability of CP and AWC determined from the linear power versus inverse of time model. Electronic Publication     

Breast cancer risk with postmenopausal hormonal treatment

This review was designed to determine from the best evidence whether there is an association between postmenopausal hormonal treatment and breast cancer risk. Also, if there is an association, does it vary according to duration and cessation of use, type of regimen, type of hormonal product or route of administration; whether there is a differential effect on risk of lobular and ductal cancer; and whether hormone treatment is associated with breast cancers that have better prognostic factors? Data sources for the review included Medline, the Cochrane Database of Systematic Reviews (Cochrane Library, 2005) and reference lists in the identified citations. Eligible citations addressed invasive breast cancer risk among postmenopausal women and involved use of the estrogen products with or without progestin that are used as treatment for menopausal symptoms. Abstracted data were demographic groupings, categories of hormone use, categories of breast cancer, two-by-two tables of exposure and outcome and adjusted odds ratios, relative risks (RRs) or hazard rates. Average estimates of risk were weighted by the inverse variance method, or if heterogeneous, using a random effects model. The average risk of invasive breast cancer with estrogen use was 0.79 [95% confidence interval (95% CI) = 0.61-1.02] in four randomized trials involving 12 643 women. The average breast cancer risk with estrogen-progestin use was 1.24 (95% CI = 1.03-1.50) in four randomized trials involving 19 756 women. The average risks reported in recent epidemiological studies were higher: 1.18 (95% CI = 1.01-1.38) with current use of estrogen alone and 1.70 (95% CI = 1.36-2.17) with current use of estrogen-progestin. The association of breast cancer with current use was stronger than the association with ever use, which includes past use. For past use, the increased breast cancer risk diminished soon after discontinuing hormones and normalized within 5 years. Reasonably adequate data do not show that breast cancer risk varies significantly with different types of estrogen or progestin preparations, lower dosages or different routes of administration, although there is a small difference between sequential and continuous progestin regimens. Epidemiological studies indicate that estrogen-progestin use increases risk of lobular more than ductal breast cancer, but the number of studies and cases of lobular cancer remains limited. Among important prognostic factors, the stage and grade in breast cancers associated with hormone use [corrected] do not differ significantly from those in non-users, but breast cancers in estrogen-progestin users are significantly more likely to be estrogen receptor (ER) positive. In conclusion, valid evidence from randomized controlled trials (RCTs) indicates that breast cancer risk is increased with estrogen-progestin use more than with estrogen alone. Epidemiological evidence involving more than 1.5 million women agrees broadly with the trial findings. Although new studies are unlikely to alter the key findings about overall breast cancer risk, research is needed, however, to determine the role of progestin, evaluate the risk of lobular cancer and delineate effects of hormone use on receptor presence, prognosis and mortality in breast cancer.     

Influence of glucose ingestion by humans during recovery from exercise on substrate utilisation during subsequent exercise in a warm environment

Carbohydrate (CHO) ingestion during short-term recovery from prolonged running has been shown to increase the capacity for subsequent exercise in a warm environment. The aim of this study was to examine the effects of the amount of glucose given during recovery on substrate storage and utilisation during recovery and subsequent exercise in a warm environment. A group of 11 healthy male volunteers took part in two experiments in a controlled warm environment (35°C, 40% relative humidity), 1 week apart. On each occasion the subjects completed two treadmill runs (T1 and T2) at a speed equivalent to 60% of maximal oxygen uptake, for 90 min, until they were fatigued, or until aural temperature (T _aur) reached 39°C. The two runs were separated by a 4 h recovery period (REC), during which subjects consumed 55 g of naturally enriched [U-¹³C]-glucose in the form of a 7.5% carbohydrate-electrolyte solution (CES, mass of solution 667 g) immediately after T1. The subjects then consumed either: the same quantity of CES, or an equivalent volume of an electrolyte placebo, at 60, 120 and 180 min during REC, providing a total of 220 g (C220) or 55 g (C55) of [U-¹³C]-glucose, respectively. Expired gases were collected at 15 min intervals during exercise and 60 min intervals during REC, for determination of total CHO and fat oxidation by indirect respiratory calorimetry, and orally ingested [U-¹³C]-glucose oxidation, estimated from the ¹³C:¹²C ratio of expired CO₂. Substrate metabolism did not differ between conditions during T1. Despite the fact that total CHO (P<0.05) and ingested glucose oxidation (P<0.01) were greater during REC of the C220 condition, glycogen synthesis was estimated to be approximately fivefold greater (P<0.01) than in the C55 condition. During T2 the rate of total CHO oxidation was higher (P<0.01) and total fat oxidation lower (P<0.01) at all times during the C220 compared to the C55 condition. The greater CHO oxidation during C220 appeared to be met from ingested sources, as the rate of [U-¹³C]-glucose oxidation was greater (P<0.01) at all times during T2, compared to C55. Whilst more of the ingested substrate remained unoxidised on completion of T2 during C220, exercise duration was similar in the two experimental conditions, and was limited by thermoregulatory incapacity (T _aur>39°C) rather than substrate availability per se. Electronic Publication     

On the role of additive hormone monotherapy with tamoxifen,medroxyprogesterone acetate and aminoglutethimide,in advanced breast cancer

Summary We analyzed the results of clinical studies on the therapeutic efficacy of hormone monotherapy with tamoxifen, medroxyprogesterone acetate, and aminoglutethimide in metastatic breast cancer, which were published between 1971 and 1986 and involved altogether 7000 patients. The overall response rates in patients treated with these hormonal single agents at various dose levels ranged from 31%–42%. When only estrogen receptor-positive patients were considered, the response rates lay between 41% and 54% in groups which were treated with the antiestrogenic agents tamoxifen or aminoglutethimide. The duration of remission was 12 months for tamoxifen- and aminoglutethimide-treated women, whereas medroxy-progesterone acetate effected remissions lasting from 6–16 months. The overall mean survival from start of therapy in tamoxifen- and aminoglutethimide-treated groups was 20 months, whereas information concerning this therapeutic parameter was available only in a minority of medroxyprogesterone acetate-treated groups. With respect to the response by site of metastatic lesions, all three agents caused a significantly higher degree of remissions in the soft tissue as compared to visceral disease.Abbreviations AG Aminoglutethimide - MPA Medroxyprogesterone acetate - TAM Tamoxifen     

人脐静脉内皮细胞清除补体攻膜复合物的机制

目的：探讨内皮细胞清除补体攻膜复合物（MAC）的途径及其清除动力学，方法：原代培养的人脐静脉内皮细胞以RH414荧光标记质膜双层，0℃组装亚溶剂量的MAC，37℃复苏后，LSCM实时监MAC沉积诱导的质膜囊泡化形成和胞吞，胞吐情况,流式细胞仪定量检测内皮细胞表面MAC抗原的清除情况，结果：MAC沉积后，内皮细胞有的质膜囊泡化形成，囊泡以胞吞和胞吐2种方式离开细胞，并以前者占优，37度条件下，内皮细胞清除表面MAC的半衰期约为5min。结论：内皮细胞可通过胞吞和胞吐2种机制清除细胞表面沉积的MAC，并以胞吞方式为主。     

3D MRI-Based Multicomponent FSI Models for Atherosclerotic Plaques

A three-dimensional (3D) MRI-based computational model with multicomponent plaque structure and fluid-structure interactions (FSI) is introduced to perform mechanical analysis for human atherosclerotic plaques and identify critical flow and stress/strain conditions which may be related to plaque rupture. Three-dimensional geometry of a human carotid plaque was reconstructed from 3D MR images and computational mesh was generated using Visualization Toolkit. Both the artery wall and the plaque components were assumed to be hyperelastic, isotropic, incompressible, and homogeneous. The flow was assumed to be laminar, Newtonian, viscous, and incompressible. The fully coupled fluid and structure models were solved by ADINA, a well-tested finite element package. Results from two-dimensional (2D) and 3D models, based on ex vivo MRI and histological images (HI), with different component sizes and plaque cap thickness, under different pressure and axial stretch conditions, were obtained and compared. Our results indicate that large lipid pools and thin plaque caps are associated with both extreme maximum (stretch) and minimum (compression when negative) stress/strain levels. Large cyclic stress/strain variations in the plaque under pulsating pressure were observed which may lead to artery fatigue and possible plaque rupture. Large-scale patient studies are needed to validate the computational findings for possible plaque vulnerability assessment and rupture predictions.     

Electronic aspects of spinal-cord stimulation in multiple sclerosis

Patients receiving chronic spinal-cord stimulation in the management of multiple sclerosis have been stimulated at a frequency of 33 Hz, with pulses whose duration has been varied between 0·05 ms and 2·0 ms. Measurements on the stimulating pulses show that the energy requirement was at a minimum when the pulse duration was 0·2 ms. The current and energy requirements of different patients using 0·2 ms pulses vary over a large range but measurement of the current requirement of a particular patient can be a useful observation in predicting his response to treatment: low current requirements are often associated with a good response and high currents with a poor response to treatment. The use of 0·2 ms pulses of the amplitude we have used meets the safety requirements established by other workers and our results indicate that this pulse duration is optimal in terms of safety requirements, as well as energy requirements.