A role for presenilin 1 in regulating the delivery of amyloid precursor protein to the cell surface

Presenilin 1 (PS1) and presenilin 2 play a critical role in the gamma-secretase processing of amyloid precursor protein (APP) and Notch1. Here, we investigate maturation and intracellular trafficking of APP and other membrane proteins in cells expressing an experimental PS1 deletion mutant (deltaM1,2). Stable expression of deltaM1,2 impairs gamma-secretase processing of Notch1 and delays Abeta secretion. Kinetic studies show enhanced O-glycosylation and sialylation of holo-APP and marked accumulation of APP COOH-terminal fragments (CTFs). Surface biotinylation, live staining, and trafficking studies show increased surface accumulation of holo-APP and CTFs in deltaM1,2 cells resulting from enhanced surface delivery of newly synthesized APP. Expression of a loss-of-function PS1 mutant (D385A) or incubation of cells with gamma-secretase inhibitors also increases surface levels of holo-APP and CTFs. In contrast to APP, glycosylation and surface accumulation of another type I membrane protein, nicastrin, are markedly reduced in deltaM1,2 cells. Finally, expression of deltaM1,2 results in the increased assembly and surface expression of nicotinic acetylcholine receptors, illustrating that PS1's influence on protein trafficking extends beyond APP and other type I membrane protein substrates of gamma-secretase. Collectively, our findings provide evidence that PS1 regulates the glycosylation and intracellular trafficking of APP and select membrane proteins.     

Detecting exaggeration and malingering with the trail making test

The purpose of this study was to examine whether unusual performance on the Trail Making Test could be indicative of deliberate exaggeration. Participants were 571 patients seen as part of a hospital trauma service who had acute traumatic brain injuries, and 228 patients involved in head injury litigation. As expected, the hospital patients with more severe traumatic brain injuries performed more poorly than the patients with less severe brain injuries on Trails A and Trails B. Cutoff score tables were developed for the patients with acute traumatic brain injuries for the total sample and by injury severity groups. Scores falling at or below the 5th percentile were considered suspicious for possible exaggeration. The performances of the head injury litigants who exaggerated on at least one well-validated symptom validity test were compared to these cutoffs. Very high positive predictive values for individuals with very mild head injuries on Trails A and B were identified (i.e., both 100%); lower positive predictive values were obtained for individuals with more severe head injuries (55.6-60%). The negative predictive values were only moderate (range=66.4-78.2%), and the sensitivity was very low (range = 7.1-18.5%) for all groups. Scores that fall in the range of possible biased responding should be considered "red flags" for the clinician because they likely do not make biological or psychometric sense. However, the sensitivity of the test for deliberate exaggeration is very low, so clinicians who rely on this test in isolation to identify deliberately poor performance will fail to identify the vast majority of cases.     

Adapting to psychiatric disability and needs for home- and community-based care

The objective of the study was to describe adaptation strategies and use of formal and informal support by individuals with psychiatric disabilities, to delineate remaining needs, and to determine how home- and community-based services might address those needs. Using in-depth interviews and structured questionnaires, we examined functional status, adaptation, and needs for home- and community-based care among 33 severely mentally ill members of a large health maintenance organization. Despite success in community living, participants had significant functional deficits (physical and emotional), relied heavily on only one or two key informal caregivers, and often needed significant support from mental health professionals. Limited numbers of caregivers and social isolation placed participants at risk of negative outcomes if informal support resources were to be lost. Home- and community-based care interventions that attempt to increase informal support networks and provide instrumental help (cooking, cleaning, transport) on short notice during flare-ups could augment existing (but limited) informal caregiving, help severely mentally ill individuals remain independent, and reduce the likelihood that loss of an informal caregiver would result in unwanted outcomes.     

Motivational versus social cognitive interventions for promoting fruit and vegetable intake and physical activity in African American Adolescents

Strategic self-presentation (motivational intervention [MI]) is a theoretical approach that is distinct from social cognitive theory (SCT). Specifically, strategic self-presentation involves increasing motivation by creating cognitive dissonance and inducing shifts in self-concept by generating positive coping strategies during a videotaped session. Fifty-three healthy African American adolescents were randomized to a SCT + MI, SCT-only, or an education-only group for increasing fruit and vegetable (F&V) intake and physical activity. The SCT + MI and SCT-only groups received a 12-week SCT program. Students in the SCT+ MI group also participated in a strategic self-presentation videotape session. Participantscompleted3-dayfoodrecords, completedmeasures of self-concept and self-efficacy, and wore an activity monitor for 4 days atpre-and posttreatment. Both the SCT+MI (2.6 ± 1.4vs. 5.7 ± 2.2, p<. 05) andthe SCT-only (2.5 ± 1.2 vs. 4.8 ± 2.4, p <. 05) groups showed greater increases in F&V intake from pre-to posttreatment as compared with the education-only group (2.3 ± 1.0, vs. 3.3 ± 2.1, p > .05). There were no significant time or group effects for any of the physical activity measures. Correlation analyses revealed that only the SCT + MI group showed that dietary self-concept (r = .58,r = .67,p<.05) and dietary self-efficacy (r = .65, r = .85, p < .05) were significantly correlated with posttreatment F&V intake and change in F&V intake, respectively. These findings suggest that the change in F&V intake in the SCT + MI group resulted from strategic self-presentation, which induced positive shifts in self-concept and self-efficacy. This project was supported by a National Kidney Foundation Virginia State Affiliate Grant to Dawn K. Wilson and by GCRC Grant M01RR00065 at Virginia Commonwealth University.     

The relationship between disease control strategies and health system development: the case of TB

This paper focuses on the lack of dialogue and policy consonance between those taking the lead in health systems change and those developing specific disease control strategies. In the first part, the origins and characteristics of this situation are explained using, as an example, TB control. Attention is then paid to the development of disease control friendly health systems. Four aspects of policy development are analysed paying particular attention to TB control: analysis of policy context, mechanisms for collaboration between policy actors; agreement on decision-making processes; development of common aims and objectives. Although the focus is on TB control, the principles illustrated carry some relevance for other disease control programmes.     

Can nurse practitioners and physicians beat parochialism into plowshares?

Nurse practitioners have evolved into a large and flexible workforce. Far too often, nurse practitioner and physician professional organizations do not work together but rather expend considerable effort jousting in policy arenas. Turf battles interfere with joint advocacy for needed health system change and delay development of interdisciplinary teams that could help patients. A combined, consistent effort is urgently needed for studying, training, and deploying a collaborative, integrated workforce aimed at improving the health care system of tomorrow. The country can ill afford doctors and nurses who ignore one another's capabilities and fail to maximize each other's contributions cost-effectively.     

Management of hip dislocation with postural management

BACKGROUND: Hip dislocation in children with cerebral palsy has a well-documented history and morbidity. OBJECTIVE: This paper presents a retrospective study of children with bilateral cerebral palsy who had various postural management and its effect on hip deformity. The most widely accepted theoretical model of hip subluxation/dislocation is that an imbalance in muscle length and strength around the hip leads to acetabular dysplasia and consequent hip subluxation. Maintenance of muscle length and strength and loadbearing is therefore a logical prevention. Research on normal infants' postures has provided biomechanical data to form the theoretical basis of 24 h postural management equipment. METHODS: The notes and X-rays of 59 children with bilateral cerebral palsy from East and West Sussex and Oxfordshire were examined and measured to determine whether a relationship existed between postural management and the level of hip subluxation/dislocation. X-rays were measured using Reimers' hip migration percentage. Postural management support was divided into three groups for analysis. Category 1: use of a 24-h postural management approach using Chailey Adjustable Postural Support (CAPS) systems in lying, sitting and standing; category 2: two items of CAPS (either lying/sitting or sitting/standing supports); category 3: use of the CAPS seat only and/or any other postural supports. Hip status was recorded for analysis as both hips safe (under 33% migrated), or one/both hips subluxed. RESULTS: Children using 'All CAPS' before hip subluxation maintained significantly more hip integrity than other groups (chi2 P < 0.05). CONCLUSIONS: Postural management interventions have an important role in the prevention of hip dysplasia.