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.     

Interaction of active and passive slow eye movement systems

Summary Independent target and background motions have been used to generate conflicting activity within the pursuit and optokinetic systems. Subjects were required to pursue a small target against a structured background which moved independently. Selective enhancement of the response to the target generated high-gain active pursuit which dominated the eye movements. Passive eye movements induced during relative target and background motion are not normally directly quantifiable due to their low gain. By reducing the gain of the active pursuit optokinetically induced eye movements were enhanced and quantified. Three techniques are described for degrading active pursuit: tachistoscopic, eccentric and pseudorandom methods of target presentation. Our results demonstrate the synchronous input of active and passive eye movement drives to the oculomotor system and illustrate their interaction.     

LIMITATIONS OF RADIOTHERAPY IN THE DEFINITIVE TREATMENT OF SQUAMOUS CARCINOMA OF THE TONSILLAR FOSSA

Between 1970 and 1990, 104 patients with squamous cell carcinoma (SCC) of the tonsil were treated. The median age was 58 years and 80% of patients were males. Distribution among clinical stages was: stage I, 19 patients; stage II, 12 patients; stage III, 23 patients; and stage IV, 48 patients. More than 70% of patients had initial radiotherapy as definitive treatment irrespective of stage, reflecting the treatment philosophy over much of this period. The overall survival rate was 26% at 5 years, with survival being significantly affected by T stage, clinical stage and age. Clinical node status did not significantly affect survival rates. Good local control of T₁N₀ cancers was achieved with radiotherapy alone, but patients with more advanced cancers did poorly. We have now moved away from a non-selective policy and use initial surgery combined with postoperative radiotherapy in most patients, reserving radiotherapy alone for mainly early tonsil cancers.     

Selective Embolization of Glomus Jugulare Tumors

Four patients with grade C or D₁ glomus jugulare tumors who underwent preoperative highly selective embolization followed by infratemporal fossa removal of their tumors were compared to three patients undergoing surgery alone with respect to intraoperative blood loss, operative time, cranial nerve palsy, length of hospitalization, and perioperative complications. Embolized patients demonstrated a marked reduction in blood loss (650 vs 1375 cc) compared with the nonembolized group. Operative time was shortened (by 51 minutes). Facial nerve function did not appear related to embolization but was directly related to intraoperative nerve manipulation. Hospital stay, perioperative complications, and lower cranial nerve palsies were not related to embolization.     

CT visualization of medullary sponge kidney

Recognizing the changes of medullary sponge kidney (MSK) on computed tomographic (CT) scans may be of value in both diagnosis and in differentiating this from other disease states. The appearance on CT of MSK has not previously been well described. A case is reported that demonstrates ectatic renal collecting tubules visualized by CT, and techniques are suggested to optimize visualization of these changes.     

Retinal vasculitis

Evidence is now accumulating on both clinical and experimental grounds that the retina is an a priori source of inflammatory activity. Reactive inflammation in the retina may produce many of the clinical signs previously ascribed to uveal inflammation. Autoimmune mechanisms are probably responsible for the majority of cases of retinal vasculitis. Autoimmune retinal vasculitis occurs without other classical signs of inflammatory response in any other parts of the body. When associated systemic manifestations occur they may reflect different underlying immunopathogenic abnormalities. Thus in diseases with predominantly arterial involvement (e.g. systemic lupus erythematosus, polyarteritis nodosa) the retinal arteries bear the brunt of this disease. In Behçet''s disease the systemic involvement is usually venous and ocular involvement produces diffuse capillary and venous inflammation with areas of retinal necrosis and major vascular occlusion. The retinal appearances differ from sarcoidosis in which a granulomatous response produces characteristic periphlebitis. Finally, autoimmune retinal vasculitis produces diffuse capillary and venous damage, without any systemic signs. In the next decade the search will be for the identification of the specific antigens initiating these disparate retinal features. Retinal S antigen is a potent antigen, but rhodopsin, interphotoreceptor binding protein, and transducin all need further experimental investigation. Precise documentation will herald the dawn of new therapeutic measures based on a sound immunological fabric.     

儿童焦虑症治疗的第一步

约有6%～20%的儿童和青少年患有广泛性焦虑、分离性焦虑和社交恐惧症,但是临床医生对于儿童和青少年的精神障碍认识尚不充分.这一问题非常严重,因为如果发病年龄小、病情较重,那么患者成人之后的结局往往很差.此外,如果不能早期诊断,焦虑症、抑郁症和药物滥用的发生率就会增加.在最近的<新英格兰医学杂志>中,发表了由Walkup等人进行的有关儿童-青少年焦虑症的多模型研究(CAMS)的结果,该项研究对上述精神障碍早期治疗的必要性进行了论述.     

The active ingredient in EMDR: is it traditional exposure or dual focus of attention?

Very little is known about the mechanisms that underlie the therapeutic effectiveness of eye movement desensitization and reprocessing (EMDR). This study tested whether the content of participants' responses during EMDR is similar to that thought to be effective for traditional exposure treatments (reliving), or is more consistent with distancing, which would be expected given Shapiro's proposal of dual process of attention. The responses made by 44 participants with post‐traumatic stress disorder (PTSD) were examined during their first EMDR treatment session. An independent rater coded these responses according to whether they were consistent with reliving, distancing or focusing on material other than the primary trauma. The coding system was found to have satisfactory inter‐rater reliability. Greatest improvement on a measure of PTSD symptoms occurred when the participant processed the trauma in a more detached manner. Cross‐lagged panel correlations suggest that processing in a more detached manner was a consequence of the EMDR procedure rather than a measure that covaried with improvement. Copyright © 2006 John Wiley & Sons, Ltd.