Urinary Excretion of I131-Diodrast Injected Intraventricularly in Communicating Hydrocephalus and Aqueduct Stenosis

Nine cases of expansive infantile hydro-cephalus were investigated by injecting Small amounts of I¹³¹-Diodrast intra-ventricularly. Urinary excretion of the tracer was determined during the first 4-5 hours after injection. The cumulative excretion of Diodrast from the C.S.F. differs in cases with communicating hydrocephalus from those with stenosis of the aqueduct. The investigation is rapid and easily performed and has not produced any side effects.     

Pulmonary hemorrhage complicating radiofrequency ablation, from mild hemoptysis to life-threatening pattern

Purpose  

To assess risk factors and the extent of pulmonary hemorrhage complicating radiofrequency ablation (RFA) of pulmonary neoplasms.     

移植胚鼠神经干细胞对大鼠脊髓损伤后红核神经元损伤的影响

目的研究神经干细胞(NSCs)移植对大鼠脊髓损伤(SCI)后红核神经元的作用。方法5-溴脱氧尿嘧啶核苷(BrdU)法标记处于对数生长期的NSCs,采用电控脊髓损伤打击装置制作大鼠脊髓损伤模型。实验分为3组:NSCs组、SCI组和假手术组(Sham组)。SCI后3 d进行NSCs移植,用免疫组化法观察移植细胞的存活及迁移情况,用辣根过氧化物酶(HRP)逆行示踪技术标记红核神经元,并用四甲基联苯胺(TMB)呈色反应显示红核脊髓束神经元的存活情况,用行为学(BBB)评分法观察大鼠瘫痪肢体的恢复情况。结果在损伤脊髓区域可检测到BrdU标记的阳性NSCs,中脑HRP标记红核神经元数目明显多于SCI组(P<0.01),BBB评分亦明显高于SCI组(P<0.01)。结论体外培养的胚胎大鼠NSCs在移植到脊髓损伤区域后可存活和迁移,对SCI后中脑红核神经元具有保护作用,从而促进了大鼠肢体功能的恢复。     

The major determinant of exendin-4/glucagon-like peptide 1 differential affinity at the rat glucagon-like peptide 1 receptor N-terminal domain is a hydrogen bond from SER-32 of exendin-4

BACKGROUND AND PURPOSE

Exendin-4 (exenatide, Ex4) is a high-affinity peptide agonist at the glucagon-like peptide-1 receptor (GLP-1R), which has been approved as a treatment for type 2 diabetes. Part of the drug/hormone binding site was described in the crystal structures of both GLP-1 and Ex4 bound to the isolated N-terminal domain (NTD) of GLP-1R. However, these structures do not account for the large difference in affinity between GLP-1 and Ex4 at this isolated domain, or for the published role of the C-terminal extension of Ex4. Our aim was to clarify the pharmacology of GLP-1R in the context of these new structural data.

EXPERIMENTAL APPROACH

The affinities of GLP-1, Ex4 and various analogues were measured at human and rat GLP-1R (hGLP-1R and rGLP-1R, respectively) and various receptor variants. Molecular dynamics coupled with in silico mutagenesis were used to model and interpret the data.

KEY RESULTS

The membrane-tethered NTD of hGLP-1R displayed similar affinity for GLP-1 and Ex4 in sharp contrast to previous studies using the soluble isolated domain. The selectivity at rGLP-1R for Ex4(9–39) over Ex4(9–30) was due to Ser-32 in the ligand. While this selectivity was not observed at hGLP-1R, it was regained when Glu-68 of hGLP-1R was mutated to Asp.

CONCLUSIONS AND IMPLICATIONS

GLP-1 and Ex4 bind to the NTD of hGLP-1R with similar affinity. A hydrogen bond between Ser32 of Ex4 and Asp-68 of rGLP-1R, which is not formed with Glu-68 of hGLP-1R, is responsible for the improved affinity of Ex4 at the rat receptor.