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.     

The effects of trauma recall on smoking topography in posttraumatic stress disorder and non-posttraumatic stress disorder trauma survivors

Smoking topography was measured in trauma survivors with and without posttraumatic stress disorder (PTSD) after recalling trauma-related and neutral experiences. Analysis of covariance was performed on puff topography and mood measures using nicotine dependence scores and current major depressive disorder as covariates. Puff volumes were higher in the PTSD group than in the non-PTSD group. The PTSD group exhibited stable puff onset intervals while the non-PTSD group exhibited significantly shorter intervals following trauma recall. These findings support a "ceiling effect" hypothesis in which individuals with PTSD perpetually smoke in such a way as to maximize nicotine delivery, possibly reducing the potentially reinforcing effects of increased smoke delivery in negative affect-inducing situations.     

Hereditary systemic amyloidosis due to Asp76Asn variant β2-microglobulin

We describe a kindred with slowly progressive gastrointestinal symptoms and autonomic neuropathy caused by autosomal dominant, hereditary systemic amyloidosis. The amyloid consists of Asp76Asn variant β(2)-microglobulin. Unlike patients with dialysis-related amyloidosis caused by sustained high plasma concentrations of wild-type β(2)-microglobulin, the affected members of this kindred had normal renal function and normal circulating β(2)-microglobulin values. The Asp76Asn β(2)-microglobulin variant was thermodynamically unstable and remarkably fibrillogenic in vitro under physiological conditions. Previous studies of β(2)-microglobulin aggregation have not shown such amyloidogenicity for single-residue substitutions. Comprehensive biophysical characterization of the β(2)-microglobulin variant, including its 1.40-?, three-dimensional structure, should allow further elucidation of fibrillogenesis and protein misfolding.     

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.