No abstract

Calnexin is an endoplasmic reticulum (ER) lectin that mediates protein folding on the rough ER. Calnexin also interacts with ER calcium pumps that localize to the mitochondria-associated membrane (MAM). Depending on ER homeostasis, varying amounts of calnexin target to the plasma membrane. However, no regulated sorting mechanism is so far known for calnexin. Our results now describe how the interaction of calnexin with the cytosolic sorting protein PACS-2 distributes calnexin between the rough ER, the MAM, and the plasma membrane. Under control conditions, more than 80% of calnexin localizes to the ER, with the majority on the MAM. PACS-2 knockdown disrupts the calnexin distribution within the ER and increases its levels on the cell surface. Phosphorylation by protein kinase CK2 of two calnexin cytosolic serines (Ser554/564) reduces calnexin binding to PACS-2. Consistent with this, a Ser554/564 ➞ Asp phosphomimic mutation partially reproduces PACS-2 knockdown by increasing the calnexin signal on the cell surface and reducing it on the MAM. PACS-2 knockdown does not reduce retention of other ER markers. Therefore, our results suggest that the phosphorylation state of the calnexin cytosolic domain and its interaction with PACS-2 sort this chaperone between domains of the ER and the plasma membrane. INTRODUCTIONA principal function of the ER is chaperone-mediated oxidative folding of newly synthesized proteins, thought to occur close to the translocon on the rER with the help of chaperones (Chen and Helenius, 2000). Recent research has started to view the ER as a multifunctional organelle that comprises distinct domains devoted to specific tasks. Examples are oxidative protein folding that occurs on the rough ER (rER) or lipid synthesis that is associated with the mitochondria-associated membrane (MAM; Vance, 1990;Borgese et al., 2006;Levine and Loewen, 2006). It is also emerging that many ER proteins, including chaperones, localize to multiple ER membrane domains, where they perform distinct functions. Examples are the chaperones calnexin (CNX), calreticulin and ERp44, which interact with the MAM-enriched IP 3 R and SERCA2b, respectively (John et al., 1998;Roderick et al., 2000;Higo et al., 2005).Coat-and receptor-based retention and retrieval mechanisms ensure that ER folding chaperones and oxidoreductases localize to the ER (Teasdale and Jackson, 1996;Duden, 2003;Michelsen et al., 2005). However, in addition to multiple domains of the ER, many ER chaperones such as BiP/ GRP78, PDI , and CNX have also been found on the plasma membrane, suggesting that their intracellular retention and trafficking along the secretory pathway varies (Wiest et al., 1995;Mezghrani et al., 2000;Arap et al., 2004;Misra et al., 2006). For instance, high levels of CNX characterize the plasma membrane of immature thymocytes. Conversely, ER stress can reduce surface CNX (Wiest et al., 1995;Okazaki et al., 2000). Changing the amount of CNX on the plasma membrane could affect cell surface properties and might have implications on phagocytosi...

BACKGROUND AND OBJECTIVES: The Management of Myelomeningocele Study (MOMS), a randomized trial of prenatal versus postnatal repair for myelomeningocele, found that prenatal surgery resulted in reduced hindbrain herniation and need for shunt diversion at 12 months of age and better motor function at 30 months. In this study, we compared adaptive behavior and other outcomes at school age (5.9-10.3 years) between prenatal versus postnatal surgery groups. METHODS: Follow-up cohort study of 161 children enrolled in MOMS. Assessments included neuropsychological and physical evaluations. Children were evaluated at a MOMS center or at a home visit by trained blinded examiners. RESULTS: The Vineland composite score was not different between surgery groups (89.0 6 9.6 in the prenatal group versus 87.5 6 12.0 in the postnatal group; P = .35). Children in the prenatal group walked without orthotics or assistive devices more often (29% vs 11%; P = .06), had higher mean percentage scores on the Functional Rehabilitation Evaluation of Sensori-Neurologic Outcomes (92 6 9 vs 85 6 18; P , .001), lower rates of hindbrain herniation (60% vs 87%; P , .001), had fewer shunts placed for hydrocephalus (49% vs 85%; P , .001) and, among those with shunts, fewer shunt revisions (47% vs 70%; P = .02) than those in the postnatal group. Parents of children repaired prenatally reported higher mean quality of life z scores (0.15 6 0.67 vs 0.11 6 0.73; P = .008) and lower mean family impact scores (32.5 6 7.8 vs 37.0 6 8.9; P = .002). CONCLUSIONS: There was no significant difference between surgery groups in overall adaptive behavior. Long-term benefits of prenatal surgery included improved mobility and independent functioning and fewer surgeries for shunt placement and revision, with no strong evidence of improved cognitive functioning. WHAT'S KNOWN ON THIS SUBJECT: Prenatal surgery was found to reduce hydrocephalus and hindbrain herniation in infants with myelomeningocele as well as improve motor function at 30 months of age. WHAT THIS STUDY ADDS: Among school-aged children with myelomeningocele whose mothers were randomly assigned to surgery before birth versus standard postnatal repair, there were no significant differences in adaptive behavior, but motor function and quality of life were better.

Survivors of GBS meningitis continue to have substantial long-term morbidity, highlighting the need for ongoing developmental follow-up and prevention strategies such as maternal immunization.

RATIONALE and OBJECTIVE Delirium assessments in critically ill infants and young children pose unique challenges due to evolution of cognitive and language skills. The objectives of this study were to determine the validity and reliability of a fundamentally objective and developmentally appropriate delirium assessment tool for critically ill infants and preschool-aged children, and to determine delirium prevalence. DESIGN and SETTING Prospective, observational cohort validation study of the PreSchool Confusion Assessment Method for the ICU (psCAM-ICU) in a tertiary medical center pediatric ICU. PATIENTS Participants aged 6 months to 5 years and admitted to the pediatric ICU regardless of admission diagnosis were enrolled. INTERVENTIONS, MEASUREMENTS and MAIN RESULTS An interdisciplinary team created the psCAM-ICU for pediatric delirium monitoring. To assess validity, patients were independently assessed for delirium daily by the research team using the psCAM-ICU and by a child psychiatrist using the Diagnostic and Statistical Manual of Mental Disorders criteria. Reliability was assessed using blinded, concurrent psCAM-ICU evaluations by research staff. A total of 530-paired delirium assessments were completed among 300 patients, with a median age of 20 months (IQR 11, 37) and 43% requiring mechanical ventilation. The psCAM-ICU demonstrated a specificity of 91% (95%CI 90, 93), sensitivity of 75% (72, 78), negative predictive value of 86% (84, 88), positive predictive value of 84% (81, 87), and a reliability kappa statistic of 0.79 (0.76, 0.83). Delirium prevalence was 44% using the psCAM-ICU and 47% by the reference-rater. The rates of delirium were 53% vs. 56% in patients < 2 years of age and 33% vs. 35% in patients ≥ 2 - 5 years of age using the psCAM-ICU and reference-rater respectively. The short-form psCAM-ICU maintained a high specificity (87%) and sensitivity (78%) in post-hoc analysis. CONCLUSIONS The psCAM-ICU is a highly valid and reliable delirium instrument for critically ill infants and preschool-aged children, in whom delirium is extremely prevalent.

The high incidence of Poly Implant Prothèse shell rupture is most likely a result of inadequate quality control, with contributory factors being shell thickness variation and manufacturing defects on both inner and outer surfaces of the shell. No evidence of shell degradation with implantation time was determined.

Based on the available evidence, nasoseptal flap (NSF) elevation with or without use in reconstruction likely leads to impairment in objective olfactory function. Endoscopic sellar and parasellar surgery without the elevation of an NSF may lead to a transient reduction in olfactory function. In the absence of a high a priori risk of cerebrospinal fluid (CSF) leak, it is an option to avoid routine NSF elevation in sellar and parasellar procedures, with preservation of at least 1 vascular pedicle during the approach. Monopolar electrocautery for mucosal incisions may increase the risk of olfactory impairment. If an NSF is used, donor site defect reconstruction may be considered.

pTCBIs are a viable alternative to percutaneous devices in a carefully selected group of patients. These devices have demonstrated good audiological outcomes, low morbidity, and high patient satisfaction.