GGA1 acts as a spatial switch altering amyloid precursor protein trafficking and processing

The beta-amyloid (Abeta) precursor protein (APP) is cleaved sequentially by beta-site of APP-cleaving enzyme (BACE) and gamma-secretase to release the Abeta peptides that accumulate in plaques in Alzheimer's disease (AD). GGA1, a member of the Golgi-localized gamma-ear-containing ARF-binding (GGA) protein family, interacts with BACE and influences its subcellular distribution. We now report that overexpression of GGA1 in cells increased the APP C-terminal fragment resulting from beta-cleavage but surprisingly reduced Abeta. GGA1 confined APP to the Golgi, in which fluorescence resonance energy transfer analyses suggest that the proteins come into close proximity. GGA1 blunted only APP but not notch intracellular domain release. These results suggest that GGA1 prevented APP beta-cleavage products from becoming substrates for gamma-secretase. Direct binding of GGA1 to BACE was not required for these effects, but the integrity of the GAT (GGA1 and TOM) domain of GGA1 was. GGA1 may act as a specific spatial switch influencing APP trafficking and processing, so that APP-GGA1 interactions may have pathophysiological relevance in AD.     

Contractile actions of thrombin receptor-derived polypeptides in human umbilical and placental vasculature: evidence for distinct receptor systems.

1. We studied the structure-activity profiles of four thrombin receptor-derived polypeptides (TRPs) (P5, SFLLR; P5-NH2, SFLLR-NH2; P7, SFLLRNP; P7-NH2, SFLLRN) in contractile human placental artery (PA), umbilical artery (UA) and umbilical vein (UV) preparations and in a human platelet aggregation assay. 2. The contractile actions of the TRPs in the two arterial preparations were endothelium-independent, whereas in the UV tissue a contractile response was observed only in an endothelium-denuded preparation; no endothelium-mediated relaxation responses were observed in any of the vascular preparations. 3. In the three vascular preparations, the contractile responses required extracellular calcium and were attenuated by the tyrosine kinase inhibitor, genistein. 4. The relative contractile orders of potencies of the TRPs in the three vascular preparations were distinct from each other (PA: P7-NH2 > P7 > P5-NH2 > P5; UA: P7-NH2 > or = P5-NH2 approximately = P7 > > P5; UV: P5-NH2 > > P7-NH2 = P7 > > P5) and these were in turn distinct from the potency order observed in the platelet aggregation assay (P5-NH2 > or = P7-NH2 > P7 > > P5). 5. Despite the markedly dissimilar TRP potency orders in the placental artery and umbilical vein preparations, the cDNA sequences for the thrombin receptor obtained by polymerase chain reaction cloning of cDNA from the two tissue sources were identical. 6. We conclude that the four tissues studied possess functionally distinct thrombin receptor systems that interact in a distinct way with agonist peptides. In view of the identity of the thrombin receptor cDNA in the two tissues displaying the most dissimilar structure-activity profiles, we suggest that in different tissues, differences in post-translational receptor processing or differences in receptor-effector coupling interactions may result in unique thrombin receptor systems that can display distinct structure-activity profiles.     

Third ventricular primary cerebral neuroblastoma. Electron-microscopic and immunohistochemical study

A case of third ventricular primary cerebral neuroblastoma with secondary hydrocephalus is reported. Light microscopy showed a cell pattern that resembled either ependymoma or oligodendroglioma. The tumor was confirmed to be neuroblastoma by electron microscopy and immunohistochemistry. Immunoperoxidase staining was positive for neuron-specific enolase and negative for glial fibrillary acidic protein.     

Gastroepiploic veins: CT appearance in pancreatic disease.

The frequency with which gastroepiploic vein (GEV) enlargement was seen on CT and its relevance to disease of the portal venous system associated with pancreatic disease were studied. We performed a retrospective study of 50 patients with proved pancreatic disease and another 50 patients without such disease. The CT examinations were done in incremental dynamic fashion after a bolus injection of contrast medium. Scans were evaluated for collateral channel formation, including GEV enlargement, and for involvement of the portal venous system by pancreatic disease. Part of the GEV arcade was visible in 36 patients without pancreatic disease, and on average measured 3.2 mm in diameter (range, 1-5.5 mm). GEV enlargement was visible in 62% of the patients with disease; 16% demonstrated a vessel 6 mm or more in diameter. Thirty-four percent of the patients with disease had portal venous complications: 26% had isolated splenic vein involvement, 2% had isolated portal vein involvement, and 6% had a combination of splenic and portal vein involvement. Of the patients with splenic vein disease, 81% had collateral channel formation, 50% of them demonstrating isolated GEV enlargement. Patients with splenic vein disease due to acute pancreatic disease had a much higher instance of GEV enlargement (83.3%). Collateral vessels are commonly seen on CT scans of patients with splenic vein disease and most often occur via enlarged GEVs. Acute pancreatic disease is frequently associated with GEV enlargement, suggesting that the latter represents an early response to splenic vein disease. In contrast, multiple collateral pathways tend to develop in patients with chronic pancreatic disease.     

Should balloon angioplasty and stents have any role in operative intervention for lower extremity ischemia?

p < 0.01). Cumulative combined primary patency at 1 year by life-table methods was 82 ± 10% in the staged group and 83 ± 9% in the simultaneous group (p= 0.79). Mean follow-up was 13 ± 6 months. There is a role for balloon angioplasty and stent placement in operative revascularization of ischemic limbs in selected patients: patency was similar to that produced with the staged approach while the length of stay was shorter. Intraoperative balloon angioplasty is safe and effective and stents permit a measure of control in assuring an optimal intraoperative postangioplasty result.     

Hemodynamics and survival of patients with portopulmonary hypertension.

It is not known whether patients with pulmonary arterial hypertension associated with portal hypertension (portopulmonary hypertension (PPHTN) have different disease characteristics from those of patients with other forms of pulmonary arterial hypertension. We performed a retrospective cohort study of patients with PPHTN and patients with pulmonary arterial hypertension that was idiopathic, familial, or associated with anorexigen use (IPAH) to determine whether hemodynamics or survival were different between these groups. We included consecutive patients who underwent initial pulmonary artery catheterization and vasodilator testing at our center between January 1997 and May 2001 and who were followed until January 2004. Patients with PPHTN (N = 13) had a higher cardiac index and lower pulmonary vascular resistance than patients with IPAH (N = 33) (P < or = 0.001). Right atrial pressure and pulmonary artery pressure were similar between the groups. Patients with PPHTN had a higher risk of death in multivariate analysis (hazard ratio: [HR] = 2.8, 95% CI 1.04-7.4; P = 0.04). These findings were not affected by adjustment for differences in laboratory values, hemodynamics, or therapy. In conclusion, patients with PPHTN have a higher risk of death than that of patients with IPAH, despite having a higher cardiac index and lower pulmonary vascular resistance. Future studies of the specific mechanisms of and therapy for pulmonary arterial hypertension should focus on the distinctions between the different forms of this disease.