Ca2+ and receptor-associated protein are independently required for proper folding and disulfide bond formation of the low density lipoprotein receptor-related protein

The low density lipoprotein receptor-related protein (LRP) is a cysteine-rich, multifunctional receptor that binds and endocytoses a diverse array of ligands. Recent studies have shown that a 39-kDa receptor-associated protein (RAP) facilitates the proper folding and subsequent trafficking of LRP within the early secretory pathway. In the current study, we have examined the potential role of Ca2+ and its relationship to RAP during LRP folding. We found that depletion of Ca2+ following either ionomycin or thapsigargin treatment significantly disrupts the folding process of LRP. The misfolded LRP molecules migrate as high molecular weight aggregates under nonreducing SDS-polyacrylamide gel electrophoresis, suggesting the formation of intermolecular disulfide bonds. This misfolding is reversible because misfolded LRP can be re-folded into functional receptor molecules upon Ca2+ restoration. Using an LRP minireceptor representing the fourth ligand binding domain of LRP, we also observed significant variation in the conformation of monomeric receptor upon Ca2+ depletion. The role of Ca2+ in LRP folding is independent from that of RAP because RAP remains bound to LRP and its minireceptor following Ca2+ depletion. Furthermore, Ca2+ depletion-induced LRP misfolding occurs in RAP-deficient cells. Taken together, these results clearly demonstrate that Ca2+ and RAP independently participate in LRP folding.     

Characterization of a Schwann cell neurite-promoting activity that directs motoneuron axon outgrowth

The aim of the study described here was to correlate coronary artery (CA) stenosis pressure gradients calculated by quantitative coronary arteriography (QCA) to invasively measured transstenotic pressure drops in patients with anginal symptoms and with known or suspected coronary artery disease. Furthermore, the known mathematical models are improved by introducing (1) pressure catheter-corrected minimal stenosis area, (2) modification of flow assumptions, and (3) stenosis exit angle. Included in the study were 45 patients with 61 stenoses. The visually estimated CA lesion severity in these non-complex stenoses was in the equivocal range of 40-70%. All measurements were performed after intracoronary administration of nifedipine and nitroglycerin. Stenosis dimensions were assessed from magnified cinefilms, using hand-held calipers. Highly significant overall correlation was found between measured and calculated pressure gradients with correction for the impact of the intracoronary catheter (P < 0.00001, r = 0.84). In particular, a substantial number of stenoses with haemodynamically-insignificant pressure gradients were identified by hydrodynamic calculations. In conclusion, the great majority of the coronary artery stenoses could be classified reliably by QCA as being haemodynamically insignificant or significant, respectively.     

Repetition priming and experimental context effects

Solving belief problems develops as a skill in normal children during the preschool years. To understand this process of development, it is necessary to provide an analysis of the tasks used to test preschool 'theory of mind' skills. This analysis should allow us to relate the structure of a given task to the underlying cognitive mechanisms that the task engages. In two experiments, we find that 3-year-old children show a pattern of success and failure on belief tasks that is not consistent with 'conceptual deficit' accounts. Young children possess the concept, BELIEF, but have certain characteristic difficulties with correctly calculating the contents of beliefs. In childhood autism, by contrast, the mechanisms that in normal development bestow conceptual competence in this domain are impaired. In the first experiment, parallel task structures are used to show that 3-year-olds are no better at predicting behavior from a partially true belief than they are at predicting behavior from an entirely false belief. We develop specific proposals about task structural factors that either facilitate or hinder success in belief-content calculation. These proposals are supported in a second experiment. We compare two false-belief tasks, one of which has helpful structural factors, the other of which has hampering factors, with a third task which exemplifies a hampering task structure but without any theory of mind content. We compare 3- and 4-year-olds' patterns of performance with that of autistic children. Each of the three groups shows a distinct performance profile across the three tasks, as predicted for each case by our model. Innate attentional mechanisms provide the conceptual foundations for 'theory of mind' but must be supplemented by a robust executive process that allows false beliefs to achieve 'conceptual pop-out.' Our approach has general implications for the study of conceptual development.     

Interposition grafting for reoperation on the common femoral artery

PURPOSE: This report details our experience with common femoral artery resection and Dacron interposition grafting in the management of vascular reoperations involving the common femoral artery. DESIGN: Retrospective review. SETTING: University teaching hospital. SUBJECTS: Consecutive reoperative patients who had common femoral artery interposition grafting for arteriosclerotic occlusive disease from 1986 to 1997. INTERVENTIONS: Common femoral artery resection and interposition grafting. MAIN OUTCOME MEASURES: Operative morbidity and mortality rates and long-term patency, limb salvage, patient survival, freedom-from-graft-infection, and freedom-from-reoperation rates. RESULTS: Ninety-nine common femoral arteries (16 bilateral) were resected and replaced with Dacron interposition grafts in 83 patients (50 male, 33 female; mean age, 65 years) who had had 237 previous ipsilateral common femoral artery operations (mean, 2.4 operations; range, 1-9 operations). Simultaneous infrainguinal bypass grafts were performed in 52 operations (53%), and 60 operations (61%) were performed in patients who had had previous ipsilateral proximal bypass grafts. Operative mortality was 2%, with a 14% rate of perioperative wound complications. Mean follow-up time was 22 months. One- and 3-year assisted primary patency rates for the interposition grafts were 90% and 77%, respectively. Both 1- and 3-year life-table-determined limb salvage rates were 95%. One- and 3-year life-table-determined freedom-from-reoperation rates were 74% and 43%, respectively. One- and 3-year life-table-determined freedom-from-infection rates were 99% and 92%, respectively. One- and 3-year life-table-determined survival rates were 82% and 73%, respectively. CONCLUSIONS: Common femoral artery resection and Dacron interposition grafting are safe, and they obviate many difficulties associated with reoperative common femoral artery surgery with satisfactory long-term results.     

Widespread unilateral increased rib uptake on bone scan

Some neuropathological changes characteristic of aging and Alzheimer's disease (AD) in humans are present also in senescent non-human primates. The human apoE4 allele is associated with an increased risk of developing late-onset familial and sporadic AD. We found that rhesus monkeys and three subspecies of squirrel monkeys are homozygous for apoE phenotype with arginine at positions 112 and 158 as in human apoE4. However, in both species threonine replaces arginine at position 61 of human apoE. It was previously shown that arginine 61 was critical in determining apoE4 lipoprotein distribution in humans.     

Overestimate of vaccine coverage? New evidence from a survey in Pau da Lima]

To evaluate vaccination coverage in children 0 to 5 years of age, a cross-sectional study based on a household survey was carried out in 1992 in the Pau de Lima Health District, Salvador, Bahia, Brazil, using a cluster sampling technique. The district was subdivided into 30 small areas that were homogeneous with respect to socioeconomic characteristics. Information on the vaccination status of 385 children was obtained through verification of a vaccination card or campaign voucher, or, in the absence of these items, through verbal confirmation from the mother or other responsible person. Based on all the sources of information, the study found vaccination coverage rates in the entire age range of 69% for polio vaccine; 56% for DTP; 74% for measles vaccine; and 87% for BCG. These results suggest that rates obtained from routine records of the health services and vaccination campaigns may be overestimates. The authors discuss the implications of the low coverage rates found in the entire age group and especially among children under 1 year old.