一项左旋多巴乙酯对伴有运动波动帕金森病患者疗效的随机对照试验

背景：运动波动是长期接受左旋多巴治疗的帕金森病（PD）患者的一个常见并发症。胃排空减慢及胃肠道左旋多巴溶解性差会延迟给药后疗效的产生。左旋多巴乙酯作为左旋多巴的一种乙酯前体药物具有更好的胃溶性，可迅速进入小肠并快速水解成左旋多巴，缩短了左旋多巴达到最大浓度的时间。目的：确定左旋多巴乙酯对伴有运动波动PD患者的疗效、安全性和耐受性。设计：一项双盲、随机、比较的临床试验。机构：美国和加拿大的44个地区。患者：每日给予左旋多巴后至少需潜伏90min才能达到“开”期（TTON）的327例PD患者。干预：使用左旋多巴乙酯-卡比多巴或左旋多巴-卡比多巴治疗18周。主要观察指标：利用家庭日记测定每日总的TTON相对于基线的改变。结果：左旋多巴乙酯-卡比多巴治疗组平均每日总的TTON减少0．58h，而左旋多巴-卡比多巴治疗组减少了0．79h（P=0．24）。两治疗组在减少治疗无效方面无显著性差异（-6．82％vs-4．69％，P=0．20）。左旋多巴乙酯-卡比多巴（-0．85h）和左旋多巴-卡比多巴治疗组（-0．87h）每日总的“关”期都得到改善且未增加令人棘手的运动障碍。结论：从药物动力学理论上讲，左旋多巴乙酯尽管有优点，但与左旋多巴相比并未能改善TTON、治疗无效和“关”的时间。     

Development of atherosclerosis over a 25 year period: an epidemiological autopsy study in males of 11 towns

We conducted an analysis of the data from two epidemiological autopsy studies of atherosclerosis in men aged 20-59 years in 1963-66 (the first study, 7470 cases) and in 1985-88 (the second study, 9600 cases). The investigations were performed in accordance with a special program of the World Health Organization in 11 town populations: Ashkhabad (Turkmenistan), Bishkek (Kirgizstan), Irkutsk and Yakutsk (Russia), Malmo (Sweden), Prague (Czech Republic), Riga (Latvia), Tallinn and Tartu (Estonia), and Kharkov and Yalta (Ukraine). Native and non-native populations were studied separately in Ashkhabad, Bishkek, and Yakutsk. Atherosclerosis was studied by the visual morphometrical method in the descending thoracic aorta, abdominal aorta and three main coronary arteries. In each vessel the prevalence and extent (percent of intimal surface) of fatty streaks, fibrous plaques, complicated, calcified and also raised lesions (all lesions except fatty streaks) were determined. Coronary stenosis was estimated in arteries as narrowed by more than 50%. Accelerated development of coronary atherosclerosis, especially in the 40-59 year age group, was noted in the second study in the male populations of most towns except Prague and Malmo. In Prague the extent of raised lesions in coronary arteries was practically the same in both studies, in Malmo it decreased in the second study. Aortic atherosclerosis also accelerated the rate of progression in all towns except Prague, where significant differences were not observed between the studies. Accelerated development of atherosclerosis in male populations from towns of Asia was combined with an increase of fatty streaks in all vessels, while in European populations it was not so obvious. In the native populations of Ashkhabad, Bishkek and Yakutsk, atherosclerosis was much less than in non-natives in both studies. In natives of these towns, accelerated development of atherosclerosis begins only from 40 years, in non-natives from 30. For the second study, there was typically an increase of the prevalence and extent of calcified lesions that were combined with an increased prevalence of coronary stenosis in all towns. The average percentage of stenosis in the coronary left anterior descending artery for men of 40-59 years of age was 12% in the first study and 24.9% in the second; for the coronary right artery, 7.4 and 13.8%, respectively. In accordance with findings of more severe atherosclerosis in males in most towns in the second study, there was an increase in the frequency of death from coronary heart disease in the second study in these towns. The data of this study indicate that the development of atherosclerosis in human populations may change very much in the course of the life of one generation.     

Effect of gonadotrophin-releasing hormone agonist treatment on growth hormone secretion in women with polycystic ovarian syndrome

The suppression of the pituitary-gonadal axis by the administration of gonadotrophin-releasing hormone agonists (GnRH-a) is used occasionally as an adjunct therapy with gonadotrophins for ovulation induction in women with polycystic ovarian syndrome (PCOS). A number of recent clinical studies have suggested that women with polycystic ovaries (PCO) may have disturbances of normal growth hormone (GH) kinetics and alterations in the GH/insulin-like growth factor (IGF)-I system. The purpose of this study was to determine the effect of GnRH-a administration on GH-releasing hormone (GHRH)-stimulated GH release in women with PCOS. Eight women with PCO and six control women were studied before and after 2 months of treatment with the long acting GnRH-a triptoreline (3.75 mg monthly injections). GHRH was given as a single i.v. injection and blood samples for GH measurements were obtained at -15, 0, 30, 60, 90 and 120 min. The GH responses were expressed as the area under the curve (AUC) or the differences from the basal value (delta(max)). The GH response to GHRH (mean +/- SEM) was lower in women with PCO (AUC 114.9 +/- 43.1 versus 206.2 +/- 28.7 ng/ml/120 min, P < 0.05 and delta(max) 31.6 +/- 8.2 versus 49.4 +/- 5.8 ng/ml, P < 0.05). After treatment with the GnRH-a, the GH response to GHRH was significantly smaller than before treatment in both groups (PCO AUC 34.6 +/- 9.0 ng/ml/120 min and delta(max) 12.4 +/- 3.1 ng/ml; controls AUC 148.8 +/- 28.4 ng/ml/120 min and delta(max) 31.2 +/- 6.1 ng/ml), but the PCO group had a significantly smaller response. These data demonstrate that women with PCO have a reduced GH response to GHRH compared with normal controls and that GnRH-a administration causes a further GH reduction in both groups. Women with PCO have a greater suppression of GH response to GHRH during treatment with GnRH-a. This suggests that a different level of sensitivity in the somatotrophic axis exists in PCOS.      

Identification of signaling motifs within human Fc gamma RIIa and Fc gamma RIIb isoforms

To assess the functional capacity of the heterogeneous Fc gamma RII (CD32) family and to identify critical regions for functioning, we generated a panel of B-cell transfectants. The Fc gamma R-negative B- cell line IIA1.6 was transfected with wild-type or mutant human Fc gamma RIIa and IIb molecules. Solely Fc gamma RIIa-expressing IIA1.6 cells were capable of phagocytosing opsonized Staphylococcus aureus bacteria, and cross-linking of Fc gamma RIIa triggered a rapid induction of tyrosine phosphorylation after 20 seconds. Analysis of Fc gamma RIIa mutants identified the immunoreceptor tyrosine-based activation motif (ITAM; previously described as ARH-1 motif) within the IIa cytoplasmic tail to be critical for B-cell activation. In contrast, Fc gamma RIIb isoforms triggered tyrosine phosphorylation on cross- linking with much slower kinetics (> 3 minutes) than Fc gamma RIIa. Furthermore, solely Fc gamma RIIb molecules proved capable of downregulating [Ca2+]i and interleukin-2 production on co-cross-linking with sIgG in IIA1.6. The Fc gamma RIIb-mediated functions were absent in Fc gamma RIIb mutants in which the tyrosine or leucine within the YSLL motif in a conserved 13-aa region (now known as immunoreceptor tyrosine-based inhibitor motif [ITIM]) were changed into phenylalanines. In conclusion, these data show the presence of functionally critical motifs within Fc gamma RII cytoplasmic tails. Fc gamma RIIa contains an ITAM involved in B-cell activatory functions, whereas the downregulatory activity of Fc gamma RIIb isoforms is linked to an ITIM.