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.     

Effect of peripheral administration of cinnarizine and verapamil on the abstinence syndrome in diazepam-dependent rats

The effects of two calcium channel blockers (verapamil and cinnarizine) were evaluated on diazepam withdrawal symptoms. Rats were made diazepam dependent by chronic treatment with daily injections of the drug, 20 mg/kg IP for 3 weeks. On abrupt termination of the drug, animals showed withdrawal hyperactivity that was assessed by autonomic, behavioural and motor signs. The peak effect was seen 3 days after the withdrawal of diazepam. On IP administration, verapamil and cinnarizine (10, 20 and 40 mg/kg) given on eight occasions at an interval of 12 h reversed the withdrawal-induced increase in spontaneous motor activity. Cinnarizine in higher doses (20 and 40 mg/kg) was found to be effective in suppressing the behavioural signs but verapamil did not show any protective effect against startle response and irritability. These results suggest that modulation of the calcium influx in the CNS might influence withdrawal.This study was presented in XIth International Congress of Pharmacology (IUPHAR) at Amsterdam (July 1–6, 1990)     

Are intravenous corticosteroids required in status asthmaticus?

Seventy-seven patients with status asthmaticus were prospectively studied to compare oral with intravenous methylprednisolone. Patients were given methylprednisolone, either 160 or 320 mg orally or 500 or 1000 mg intravenously, daily in equally divided doses. They were randomly assigned to either group on a daily sequential basis. Spirometry was performed within one hour of the initial dose of steroids. The mean presenting forced expiratory volume in 1 s was 26% of the predicted value. Spirometry was then repeated every six hours for the first 24 hours and then every eight to 12 hours until discharge or 72 hours, whichever occurred first. There were no significant differences in the incidence of respiratory failure, forced expiratory volume in 1 s, days of hospitalization, rate of improvement in pulmonary function, or side effects. No patient who went into respiratory failure did so more than three hours after receiving the initial dose of steroids. We conclude that oral methylprednisolone is safe and effective in the treatment of status asthmaticus.     

Ossifying fibroma of nose in a two year old child

We report a cast of ossifying fibroma of the nose, arising from the bony septum and extending into the nasophaynx in a 2 yrs. old child presenting with features of obstructed nose.     

Lipomas where you least expect them.

Although lipomas are relatively common and found in most anatomical sites, we are not aware of any previous reports of lipomas arising between the two layers of the deep temporal fascia above the zygomatic arch. This is surprising because a fat pad is seen and used during surgery in this area to protect the frontal branch of the facial nerve. This case highlights the importance of understanding the anatomy of this region, because lipomas can potentially arise in any of three fat pads laying near the facial nerve in this area.