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.     

The management of epilepsy in pregnancy

While most women with epilepsy can expect a normal pregnancy outcome, epilepsy remains a significant contributor to both maternal and perinatal morbidity. Pre-pregnancy planning must address reliable contraception and optimisation of antiepileptic drug (AED) regimens to minimise teratogenic risk while maintaining seizure control. The most recent data from the AED registries regarding malformations is presented in this review, as is the limited data on the newer AEDs and studies linking neurocognitive outcomes to AED exposure. During pregnancy, important considerations include; therapeutic drug monitoring, surveillance for obstetric complications and vigilance for seizures during the intrapartum and postpartum period.     

Connecting humor,health, and masculinities at prostate cancer support groups

Objective: Many commentaries about men's health practices and masculinities indicate that men do not typically engage with self‐health or acknowledge illness, let alone openly discuss their health concerns with other men. Prostate cancer support groups (PCSGs) appear to run contrary to such ideals, yet the factors that influence men's attendance and engagement at group meetings are poorly understood. As part of a larger PCSG study, we noticed that humor was central to many group interactions and this prompted us to examine the connections between humor, health, and masculinities. Methods: A qualitative ethnographic design was used to direct fieldwork and conduct participant observations at the meetings of 16 PCSGs in British Columbia, Canada. Individual semi‐structured interviews were completed with 54 men who attended PCSGs to better understand their perceptions about the use of humor at group meetings. Results: Four themes, disarming stoicism, marking the boundaries, rekindling and reformulating men's sexuality, and when humor goes south were drawn from the analyses. Overall, humor was used to promote inclusiveness, mark the boundaries for providing and receiving mutual help, and develop masculine group norms around men's sexuality. Although there were many benefits to humor there were also some instances when well‐intended banter caused discomfort for attendees. Conclusions: The importance of group leadership was central to preserving the benefits of humor, and the specificities of how humor is used at PCSGs may provide direction for clinical practice and the design of future community‐based men's health promotion programs. Copyright © 2009 John Wiley & Sons, Ltd.     

Feasibility of using interpolated contours of targets and organs at risk in intensity‐modulated radiation therapy treatment planning for advanced‐stage nasopharyngeal carcinoma

To assess the dosimetric effect of using interpolated contours in planning intensity‐modulated radiation therapy (IMRT) for advanced T‐stage nasopharyngeal carcinoma. The present study focused on T3–T4 tumours where the proximity of targets to neurological organs poses a stringent test on the feasibility of such an approach. Contours of targets and organs were delineated on CT images of 2.5‐mm interval and a reference IMRT plan was generated. An investigative (INV) IMRT plan was then generated with the same planning protocol, but based on interpolated contours that replaced deleted contours on alternate slices. The reference and INV plans were compared. Regarding target coverage, all targets in the INV plans met the acceptance criteria except for the PTV in one case. Regarding organs, the mean dose to 1% volume of the brainstem and spinal cord in the INV plans were kept below their dose limits. No significant differences in the mean doses to others organs were found. Satisfactory target coverage and protection of critical organs to a degree similar to full‐scale contouring could be achieved with use of interpolated contours. The saving in manpower time for contouring is expected to significantly improve the throughput of the IMRT planning process.     

Same-day transfer of patients to the cardiac telemetry unit after surgery: the Rapid after Bypass Back into Telemetry (RABBIT) program

Early data from this project suggest that the RABBIT program fulfilled the process improvement goals of decreasing costs of cardiac surgery and maintaining high quality. Decreased cost was achieved by decreasing time to extubation and decreasing length of stay in the ICU and the total length of stay in the hospital. The cost savings were achieved without compromising the quality of care, which was assessed by measuring rates of readmission to the ICU and to the hospital and by surveying patients about their level of satisfaction. The success of the RABBIT program can be attributed to several factors. First, members of the cardiac surgery quality improvement team worked well together to solve problems and overcome obstacles, particularly after the pilot program. Second, naming the program helped to motivate staff, physicians, and patients. Outcome data was shared with the staff quarterly, and successes were celebrated. Finally, the use of a facilitator early in the process to establish the process with the surgeons and the staff was invaluable. Opportunities for continued improvement include resolving operational difficulties related to availability of beds and staffing, continuing work with physicians in changing practice patterns, increasing efficiency in scheduling operating rooms, and adjusting the preoperative education provided to patients and their families about the length of stay to expect. Quarterly outcome analysis continues, with reports to the cardiac surgery quality improvement team. The team continues to explore creative solutions to the aforementioned issues, as the goal of having 25% of patients who undergo cardiac surgery be transferred to the CTU on the day of surgery has remained elusive.     

DNA testing for fragile X syndrome in schools for learning difficulties

Fragile X syndrome is the most common inherited cause of mental retardation. Early diagnosis is important not only for appropriate management of individuals but also to identify carriers who are unaware of their high risk of having an affected child. The disorder is associated with a cytogenetically visible fragile site (FRAXA) at Xq27.3, caused by amplification of a (CGG)n repeat sequence within the gene at this locus designated FMR1. Clinical and molecular studies have been undertaken to screen for fragile X syndrome in 154 children with moderate and severe learning difficulties of previously unknown origin. Southern blot analysis of peripheral blood showed the characteristic abnormally large (CGG)n repeat sequence associated with fragile X syndrome in four of the 154 children. The findings were confirmed by cytogenetic observation of the fragile site and by further molecular studies. The families of the affected children were offered genetic counselling and DNA tests to determine their carrier status. These findings show that there are still unrecognised cases of fragile X syndrome. Given the difficulty of making a clinical diagnosis and the implications for families when the diagnosis is missed, screening in high risk populations may be justified. The issues involved in screening all children in special schools for fragile X syndrome are discussed.     

Laparoscopic intracorporeal ultrasound versus fluoroscopic intraoperative cholangiography

BACKGROUND: The purpose of this study was to compare the results of laparoscopic intracorporeal ultrasound (LICU) to those of fluoroscopic intraoperative cholangiography (FIOC) during laparoscopic cholecystectomy (LC) after the initial learning curve for LICU. METHODS: Data were prospectively collected on patients undergoing LC. A consecutive series of 394 LICU patients was compared to a consecutive series of 400 FIOC patients when each imaging procedure was preferentially performed. Patients during the transition period, including the first 100 LICU patients, were excluded. RESULTS: Demographics and preoperative diagnoses were similar in the two groups. Excluding those who were converted to open cholecystectomy and those in whom an imaging exam was not attempted, FIOC was successful in 361 of 374 (97%) patients and LICU was successful in 377 of 380 (99%) patients (p < 0.03). The mean times (+/-SEM) to complete FIOC and LICU were 16.0 (+/-0.5) min and 5.1 (+/-0.1) min (p < 0.0001), respectively, Choledocholithiasis was detected in 25 patients (7%) undergoing FIOC and in 39 patients (10%) undergoing LICU (p = 0.1). During LICU the common bile duct was visualized in continuity from the cystic duct to ampulla in 90% of cases. The common bile duct could not be completely visualized in continuity at the middle or distal portion of the common bile duct in 5% and 6% of LICU cases, respectively. One LICU patient (0.3%) with an incompletely visualized duct had a suspected stone confirmed by postoperative endoscopic retrograde cholangiopancreaticography (ERCP). One patient with negative FIOC (0.3%) had a retained stone treated by postoperative ERCP. CONCLUSION: LICU is safe and accurate, and it permits a more rapid evaluation of bile duct stones than FIOC during laparoscopic cholecystectomy. The false-negative rate of both imaging techniques is less than 1%.     

Low-dose inhaled nitric oxide for neonates with pulmonary hypertension

Objective : Inhaled nitric oxide (iNO) has been shown to cause selective pulmonary vasodilatation and improve ventilation-perfusion matching and may be an important therapeutic option for the treatment of persistent pulmonary hypertension of the newborn (PPHN). We report our experience on the use of iNO in neonates with severe PPHN.
Methodology : Inhaled NO was administered to 10 infants with PPHN and persistent hypoxaemia (meconium aspiration syndrome, n = 9; pneumonia, n = 1) after failure of conventional therapy to improve oxygenation. With the exception of one infant, iNO was commenced at 10 ppm.
Results : After 30 min exposure to iNO, the arterial oxygen tension (PaO₂) rose from a median of 49 mmHg (6.5 kPa) [range 12-82 mmHg (1.6-10.9 kPa)] to 75 mmHg (10 kPa) [range 17-450 mmHg (2.3-60 kPa)] ( P = 0.005), while the median oxygenation index fell (pre-iNO of 37 vs post-iNO 20) ( P = 0.005) and median systemic arterial pressure rose (pre-iNO 46.5 mmHg (6.2 kPa) [range 32-63 mmHg (4.3 to 8.4 kPa vs post-iNO 54.5 mmHg (7.3 kPa) [range 36-74 kPa]) P = 0.005). All infants subsequently continued to receive iNO with the duration of exposure to iNO ranging from 12 to 168 h (median duration 100 h). Three infants died despite showing an initial beneficial response to iNO. The mean duration of intubation for survivors was 11.9 ± 2.6 days. Methaemoglobinaemia and toxic levels of nitrogen dioxide were not seen during iNO administration. Of the seven survivors, 12 month follow up in two infants and 4 month follow up in four infants showed age-appropriate neurodevelopmental skills, with one infant having very mild hearing loss.
Conclusions : Inhaled NO reduces the oxygenation index by improving the PaO₂ and decreasing ventilation pressures, and appears to be clinically useful in severely hypoxaemic infants with PPHN refractory to conventional treatment.     

Inhaled nitric oxide during emergency neonatal transportation

ABSTRACT Inhaled nitric oxide is currently being investigated as a selective pulmonary vasodilator for neonates with persistent pulmonary hypertension. The use of continuous inhaled nitric oxide during emergency transportation of three critically ill neonates with meconium aspiration and pulmonary hypertension is described. The successful application of this technique may allow safer transportation of neonates who require high level intensive care including ongoing nitric oxide, high frequency ventilation and/or extracorporeal life support. Regionally based nitric oxide-equipped retrieval teams may relieve the pressure on smaller neonatal intensive care units to provide inhaled nitric oxide therapy and allow centralization of nitric oxide resources, thus facilitating development of expertise and the completion of meaningful research programs with substantial recruitment.