Hirschsprung Disease in an Infant with L1 syndrome: Report of a New Case and a novel L1CAM variant.

L1syndrome is an X-linked disorder manifesting with congenital hydrocephalus, adducted thumbs and spasticity. There are rare cases of L1 syndrome and coincident Hirschsprung disease, with mutations in the L1CAM gene thought to underlie both. We present a novel pathogenic L1CAM variant in someone with L1 syndrome and Hirschsprung disease.

Children's Learning and Goal-Setting at a Diabetes Camp.

Objective. This study provides information about children's learning and goal attainment related to change in their self-management skills during a diabetes camp. Design and methods. One hundred and thirty-one children completed an evaluation for the first year (year 1), and 68 children completed an evaluation for the second year (year 2). All of the children had type 1 diabetes. During both years, parents provided information about goals for their child before camp started. Children's learning about diabetes self-management, as well as their satisfaction with camp, was assessed at the end of the camp session. In the evaluation for year 2, a goal-setting intervention was also developed, and its effectiveness was assessed through both physicians' and children's reports. Results. Children learned new information during camp about recognizing and managing the signs of hypo- and hyperglycemia and about counting carbohydrates and rotating insulin pump sites. Children were better able to recall their self-management goals in year 2. In terms of benefiting from camp, boys reported learning more than girls about diabetes management, whereas girls were more likely than boys to report that greater opportunities to express feelings were of value. Conclusions. Goal-setting was successful in improving children's recall of their self-management goals. Children benefited from the supportive and educational camp atmosphere. Future research should assess the benefits of camp across multiple camp settings and determine whether educational benefits have long-term effects on children's goal-setting and knowledge and whether these benefits lead to psychosocial improvements.

Differential responses of pancreatic ß-cells to ROS and RNS.

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) direct the activation of distinct signaling pathways that determine cell fate. In this study, the pathways activated and the mechanisms by which ROS and RNS control the viability of pancreatic ß-cells were examined. Although both nitric oxide and hydrogen peroxide (H2O2) induce DNA damage, reduce cell viability, and activate AMPK, the mechanisms of AMPK activation and cell death induction differ between each reactive species. Nitric oxide activates the unfolded protein and heat shock responses and MAPK kinase signaling, whereas H2O2 stimulates p53 stabilization and poly(ADP-ribose) polymerase (PARP) activation but fails to induce the unfolded protein or heat shock responses or MAPK activation. The control of cell fate decisions is selective for the form of stress. H2O2-mediated reduction in ß-cell viability is controlled by PARP, whereas cell death in response to nitric oxide is PARP independent but associated with the nuclear localization of GAPDH. These findings show that both ROS and RNS activate AMPK, induce DNA damage, and reduce cell viability; however, the pathways controlling the responses of ß-cells are selective for the type of reactive species.

Cytokine-mediated ß-cell damage in PARP-1-deficient islets.

Poly(ADP)-ribose polymerase (PARP) is an abundant nuclear protein that is activated by DNA damage; once active, it modifies nuclear proteins through attachment of poly(ADP)-ribose units derived from ß-nicotinamide adenine dinucleotide (NAD(+)). In mice, the deletion of PARP-1 attenuates tissue injury in a number of animal models of human disease, including streptozotocin-induced diabetes. Also, inflammatory cell signaling and inflammatory gene expression are attenuated in macrophages isolated from endotoxin-treated PARP-1-deficient mice. In this study, the effects of PARP-1 deletion on cytokine-mediated ß-cell damage and macrophage activation were evaluated. There are no defects in inflammatory mediator signaling or inflammatory gene expression in macrophages and islets isolated from PARP-1-deficient mice. While PARP-1 deficiency protects islets against cytokine-induced islet cell death as measured by biochemical assays of membrane polarization, the genetic absence of PARP-1 does not effect cytokine-induced inhibition of insulin secretion or cytokine-induced DNA damage in islets. While PARP-1 deficiency appears to provide protection from cell death, it fails to provide protection against the inhibitory actions of cytokines on insulin secretion or the damaging actions on islet DNA integrity.

Association of nursing workload and unplanned extubations in a pediatric intensive care unit.

OBJECTIVE: To estimate nursing workload from the patient acuity level (PAL) assigned to patients in a pediatric intensive care unit (PICU) and to determine its influence on unplanned extubations. DESIGN: Prospective cohort study. SETTING: The 19-bed PICU of an urban, university-affiliated, tertiary children's hospital. PATIENTS: All patients admitted to the PICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The study encompassed 2,193 nursing shifts and 1,919 admissions to the PICU over 24 months. The shift census averaged 12.0 patients (range 5-18) and was staffed by 9.4 nurses (range 4-16) for an average patient/nurse ratio of 1.3 +/- 0.2. Patients were assigned a PAL of 1-7 based on a classification system derived from time studies of 12 general nursing tasks. The total PALs per shift divided by the number of nursing staff yielded an average assignment of 5.8 +/- 0.7 PALs. Forty unplanned extubations (0.76 unplanned extubations/100 ventilator days) were observed during the study period. Logistic regression revealed positive associations between unplanned extubations and patient/nurse ratio (p = .03) and the shift PAL/nurse ratio (p = .01). The likelihood of an unplanned extubation when nurses covered >6.3 PALs was 3.8 times higher than during those shifts when they covered <5.3 PALs. CONCLUSIONS: The likelihood of an unplanned extubation increased with higher patient/nurse and patient acuity/nurse ratios. Successful interventions to reduce the frequency of this medical error may need to address both nurse demand methodology and workload.

Children with diabetes: perceptions of supports for self-management at school.

Diabetes affects many children. Researchers know little about children's perceptions of what type of support they need at school, which was a focus of this study. Group interviews and surveys examined children's perceptions of support in caring for their diabetes (type I diabetes) from school nurses, teachers, and friends. Results indicated the children felt supported at school, but improved flexibility by teachers and nurses (e.g., let me keep my meter with me always) and individualized care plans may improve their ability to manage their diabetes at school. Participating in after-school activities may be difficult for middle school youth. Children reported they needed additional help and support to cope with hypoglycemic episodes.

Poly(ADP-ribose) polymerase-1 regulates activation of activator protein-1 in murine fibroblasts.

Poly(ADP-ribose) polymerase (PARP)-1 is activated in response to DNA injury in the nucleus of eukaryotic cells and has been implicated in cell dysfunction in inflammation. We investigated the role of PARP-1 on the AP-1 pathway, which is involved in the signal transduction of the inflammatory process. In murine wild-type fibroblasts, oxidative challenge by peroxynitrite and hydrogen peroxide or immunological challenge by IL-1 and 20% FCS induced phosphorylation of the mitogen-activated protein kinase kinase-4, activation of c-Jun N-terminal kinase (JNK), and DNA binding of AP-1. In comparative experiments, peroxynitrite induced DNA binding of heat shock factor-1. Pretreatment of wild-type cells with 5-iodo-6-amino-1,2-benzopyrone, a PARP-1 inhibitor, inhibited JNK activation and DNA binding of AP-1. In parallel experiments in PARP-1-deficient fibroblasts, DNA binding of AP-1 was completely abolished. Activation of JNK was significantly elevated at basal condition, but it exhibited a lesser increase after oxidative or immunological challenge than in wild-type fibroblasts. Nuclear content of phosphorylated mitogen-activated protein kinase kinase-4 was observed in PARP-1-deficient cells after peroxynitrite challenge only. Western blotting analysis for AP-1 subunits indicated that c-Fos was similarly expressed in wild-type and PARP-1-deficient cells. Phosphorylated c-Jun was expressed after oxidative or immunological challenge, but not in basal condition, in wild-type cells; however, it was significantly elevated at basal condition and further enhanced after oxidative or immunological challenge in PARP-1-deficient cells. No DNA binding of heat shock factor-1 was observed in PARP-1-deficient cells. These data demonstrate that PARP-1 plays a pivotal role in the modulation of transcription.