The GH-releasing effect of ghrelin,a natural GH secretagogue,is only blunted by the infusion of exogenous somatostatin in humans

OBJECTIVE: Ghrelin, a 28-amino-acid peptide purified from the stomach and showing a unique structure with an n-octanoyl ester at the serine 3 residue, is a natural ligand of the GH secretagogue (GHS) receptor (GHS-R). Ghrelin strongly stimulates GH secretion in both animals and humans, showing a synergistic effect with GH-releasing hormone (GHRH) but no interaction with synthetic GHS. However, the activity of ghrelin as well as that of non-natural GHS is not fully specific for GH; ghrelin also induces a stimulatory effect on lactotroph and corticotroph secretion, at least in humans. DESIGN: To further clarify the mechanisms underlying the GH-releasing activity of this natural GHS, we studied the effects of somatostatin (SS, 2.0 microg/kg/h from -30 to +90 min) on the endocrine responses to ghrelin (1.0 microg/kg i.v. at 0 min) in seven normal young male volunteers [age (mean +/- SEM) 28.6 +/- 2.9 years; body mass index (BMI) 22.1 +/- 0.8 kg/m2]. In the same subjects, the effect of SS on the GH response to GHRH (1.0 microm/kg i.v. at 0 min) was also studied. MEASUREMENTS: Blood samples were taken every 15 min from -30 up to +120 min. GH levels were assayed at each time point in all sessions; PRL, ACTH and cortisol levels were assayed after ghrelin administration alone and during SS infusion. RESULTS: The GH response to ghrelin (hAUC0'-->120' 2695.0 +/- 492.6 microg min/l) was higher (P < 0.01) than that after GHRH (757.1 +/- 44.1 microg min/l). SS infusion almost abolished the GH response to GHRH (177.0 +/- 37.7 microg min/l, P < 0.01); the GH response to ghrelin was inhibited by SS (993.8 +/- 248.5 microg min/l, P < 0.01) but GH levels remained higher (P < 0.05) than with GHRH. Ghrelin induced significant increases in PRL, ACTH and cortisol levels and these responses were not modified by SS. CONCLUSIONS: Ghrelin, a natural GHS-R ligand, exerts a strong stimulatory effect on GH secretion in humans and this effect is only blunted by an exogenous somatostatin dose which almost abolishes the GH response to GHRH. The stimulatory effect of ghrelin on lactotroph and corticotroph secretion is refractory to exogenous somatostatin, indicating that these effects occur through pathways independent of somatostatinergic influence.     

丹参酮ⅡA对神经祖细胞系C17．2的保护作用

目的:了解丹参酮ⅡA对神经祖细胞系C17.2的保护作用,探讨其可能的作用机制。方法:本实验于2005年起在广州血液中心器官移植配型中心实验室进行。C17.2祖细胞系由澳大利亚新南威尔士大学解剖教研室David Walsh博士惠赠。将C17.2细胞以1×109L-1的密度接种,用含10%胎牛血清IMDM,37℃、体积分数为0.05CO2、饱和湿度的CO2培养箱培养,接近融合的C17.2细胞用含0.1mmol/LEDTA的胰酶室温消化,按1∶3的比例传代。C17.2细胞以5×107L-1的密度接种于96孔板或25cm2的培养瓶中,用含10%胎牛血清IMDM培养过夜后,加入含4g/L AAPH(水溶性偶氮引发剂2,2'-偶氮二(2-脒基丙烷)二盐酸盐)无血清的IMDM培养基培养建立神经细胞凋亡模型。C17.2细胞以5×103/孔的密度接种于96孔板中,用含10%胎牛血清IMDM培养过夜后,加入含4g/LAAPH无血清的IMDM培养基培养。对照组不加入丹参酮ⅡA,实验组分别加入0.02,0.05,0.1,0.2mg/L丹参酮ⅡA培养8h,噻唑蓝法检测细胞活性:细胞活性的相对值=(实验组吸光度值/对照组吸光度值)×100%,流式细胞仪检测细胞凋亡。结果:①AAPH处理8h后,C17.2细胞被过氧化损害,大多数细胞失去正常的形态,细胞呈圆形,脱落。加入丹参酮ⅡA后,细胞形态基本保持正常,少数细胞呈圆形。②C17.2细胞在IMDM的培养液中,细胞数量是含4g/L AAPH无血清的IMDM培养基条件下的2.5～3倍。浓度为0.02,0.05,0.1mg/L的丹参酮ⅡA对C17.2细胞有保护作用,质量浓度大于0.2mg/L丹参酮ⅡA对C17.2细胞保护作用降低。③AAPH作用前大部分C17.2细胞的线粒体完整,有少量的早期凋亡细胞和凋亡细胞,AAPH作用后凋亡细胞总数、凋亡细胞明显增加。丹参酮ⅡA处理组可以明显减少早期凋亡细胞。结论:在体外丹参酮ⅡA对神经细胞具有抗凋亡的作用,可以保护神经细胞。     

Uveitis in juvenile idiopathic arthritis

OBJECTIVE: To evaluate the frequency of chronic anterior uveitis in patients with juvenile idiopathic arthritis and its association with the presence of antinuclear antibodies. PATIENTS AND METHODS: We retrospectively studied 72 patients with juvenile idiopathic arthritis. All of them were submitted to slit-lamp examination of the anterior chamber at diagnosis. Both antinuclear antibodies and rheumatoid factor were determined. Patients with positive results for antinuclear antibodies were evaluated every three months and those with negative results were assessed every six months. RESULTS: Forty patients were male (55.5%) and 36 were Caucasoid (50%). The mean age at the onset of juvenile idiopathic arthritis was 6.4 years (range = 1 to 14 years) and the mean age at the beginning of the study was 10.4 years (1 to 19 years). According to the type of disease at onset, 32 were pauciarticular (44.4%) (17 boys and 15 girls), 30 were polyarticular (41.6%) (17 boys and 13 girls) and 10 were systemic (14%) (6 boys and 4 girls). We observed chronic anterior uveitis in five patients (6.5%) (mean age = 11.4 years). Among them, four (80%) had pauciarticular juvenile idiopathic arthritis at disease onset (three girls with type I juvenile idiopathic arthritis and positive antinuclear antibodies and one boy with type I juvenile idiopathic arthritis and negative antinuclear antibodies) and one girl with polyarticular juvenile idiopathic arthritis (negative antinuclear antibodies and rheumatoid factor). In this group, the mean age at the onset of juvenile idiopathic arthritis was 5.1 years and the mean age of uveitis onset was 9 years. Antinuclear antibodies were positive in 3/5 patients (60%) with uveitis. Antinuclear antibodies were positive in 12% of the patients without uveitis (n = 67). Among the patients with uveitis, three had only one flare and the other two had four flares with cataract. The frequency of antinuclear antibodies was statistically higher in the patients with uveitis (P< 0.05). CONCLUSION: Although the incidence of uveitis in our study was lower than that reported in the literature, the frequency of uveitis was higher in females, in those with pauciarticular juvenile idiopathic arthritis and in patients with positive antinuclear antibodies.     

PET imaging of fatty acid amide hydrolase in the brain: synthesis and biological evaluation of an 11C-labelled URB597 analogue

IntroductionFatty acid amide hydrolase (FAAH) is part of the endocannabinoid system (ECS) and has been linked to the aetiology of several neurological and neuropsychiatric disorders. So far no useful PET or SPECT tracer for in vivo visualisation of FAAH has been reported. We synthesized and evaluated a carbon-11-labeled URB597 analogue, biphenyl-3-yl [¹¹C]-4-methoxyphenylcarbamate or [¹¹C]-1, as potential FAAH imaging agent.MethodsThe inhibitory activity of 1 was determined in vitro using recombinant FAAH. Radiosynthesis of [¹¹C]-1 was performed by methylation using [¹¹C]-CH₃I, followed by HPLC purification. Biological evaluation was done by biodistribution studies in wild-type and FAAH knock-out mice, and by ex vivo and in vivo metabolite analysis. The influence of URB597 pretreatment on the metabolisation profile was assessed.Results[¹¹C]-1 was obtained in good yields and high radiochemical purity. Biodistribution studies revealed high brain uptake in wild-type and FAAH knock-out mice, but no retention of radioactivity could be demonstrated. Metabolite analysis and URB597 pretreatment confirmed the non-FAAH-mediated metabolisation of [¹¹C]-1. The inhibition mechanism was determined to be reversible. In addition, the inhibition of URB597 appeared slowly reversible.ConclusionsAlthough [¹¹C]-1 inhibits FAAH in vitro and displays high brain uptake, the inhibition mechanism seems to deviate from the proposed carbamylation mechanism. Consequently, it does not covalently bind to FAAH and will not be useful for mapping the enzyme in vivo. However, it represents a potential starting point for the development of in vivo FAAH imaging tools.     

Infected pancreatic fluid collections: percutaneous catheter drainage

Thirty-eight infected pancreatic fluid collections in 23 patients with acute or chronic pancreatitis were drained percutaneously following initial diagnosis with computed tomography and fine-needle aspiration. Fifteen (65.2%) patients were cured completely without surgery. Eight (34.8%) patients required some type of surgery despite successful treatment of the fluid collection, and in two (6.5%) the collection recurred after catheter removal. Complications occurred in three (13%) patients, but only one complication (4%), empyema, was a direct result of catheter drainage. Catheter drainage time averaged 29 days for 16 patients with isolated collections and 96 days and 104 days for patients with collections with pancreatic duct fistulas (nine patients) or gastrointestinal fistulas (14 patients), respectively. This study confirms that infected pancreatic fluid collections can be safely and effectively treated with percutaneous catheter techniques in most patients.     

Sequence comparison of human and yeast telomeres identifies structurally distinct subtelomeric domains

We have sequenced and compared DNA from the ends of three human chromosomes: 4p, 16p and 22q. In all cases the pro-terminal regions are subdivided by degenerate (TTAGGG)n repeats into distal and proximal sub- domains with entirely different patterns of homology to other chromosome ends. The distal regions contain numerous, short (<2 kb) segments of interrupted homology to many other human telomeric regions. The proximal regions show much longer (approximately 10-40 kb) uninterrupted homology to a few chromosome ends. A comparison of all yeast subtelomeric regions indicates that they too are subdivided by degenerate TTAGGG repeats into distal and proximal sub-domains with similarly different patterns of identity to other non-homologous chromosome ends. Sequence comparisons indicate that the distal and proximal sub-domains do not interact with each other and that they interact quite differently with the corresponding regions on other, non- homologous, chromosomes. These findings suggest that the degenerate TTAGGG repeats identify a previously unrecognized, evolutionarily conserved boundary between remarkably different subtelomeric domains.      

Effects of acute hexarelin administration on cardiac performance in patients with coronary artery disease during by-pass surgery

Growth hormone (GH) secretagogues are synthetic molecules with neuroendocrine but also cardiovascular activities mediated by specific GH secretagogue-receptors. The acute administration of hexarelin, a peptidyl GH secretagogue, increases left ventricular ejection fraction in normal subjects and even in patients with severe GH deficiency. We evaluated cardiac performances in patients with coronary artery disease after acute administration of hexarelin (2.0 microg/kg, i.v.) compared to that in patients given with GH-releasing hormone (GHRH; 2.0 microg/kg, i.v.), recombinant human (rh)-GH (10.0 microg/kg, i.v.) or placebo. Cardiac performance was studied in 24 male patients (age [mean +/- S.E.M.]: 59.5 +/- 1.1 years; body mass index: 24.6 +/- 0.9 kg/m(2); left ventricular ejection fraction: 57.2 +/- 1.4%) with coronary artery disease undergoing by-pass surgery during general anesthesia. Left ventricular ejection fraction, left ventricular end diastolic volume, cardiac index and cardiac output were evaluated by intraoperative omniplane transoesophageal echocardiography while wedge pressure, central venous pressure, mean arterial pressure and systemic vascular resistance index were evaluated by systemic and pulmonary arterial catheterization. RhGH, GHRH and placebo did not exert any hemodynamic effect while hexarelin induced a prompt (after +10 min) increase in left ventricular ejection fraction (P < 0.001), cardiac index (P < 0.001) and cardiac output (P < 0.001) lasting up to +90 min without any variation in left ventricular end diastolic volume. Accordingly, hexarelin induced a reduction of wedge pressure (P < 0.01). These changes occurred in the presence of increased mean arterial pressure (P < 0.05) and transient decrease of central venous pressure (P < 0.05 at +30 min only) but no change in systemic vascular resistance index. Heart rate after hexarelin was similar to that after placebo. Hexarelin induced a slight increase in GH levels which was similar to that after GHRH but far lower (P < 0.01) than that after rhGH. Thus, in patients with coronary artery disease undergoing by-pass surgery, the acute administration of hexarelin clearly improves cardiac performance without any relevant variation in systemic vascular resistance. The cardiotropic effect of hexarelin is not shared by GHRH or by rhGH, indicating that it is not mediated by the increase in circulating GH levels but more likely reflects activation of specific cardiovascular GH secretagogue receptors.     

马兜铃酸的倍半萜的酯类化合物VI.绵毛马兜铃中马兜铃酸萜酯I的结构鉴定

从绵毛马兜铃(Aristolocha mannisima Hance)中分得一个马兜铃酸倍半萜的酯类化合物,经红外、紫外、高分辩质谱和多种一维和二维核磁共振谱鉴定,确定了其骨架结构及顺反构型,命名为马兜铃酸萜酯I。