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Members of the Burkholderia cepacia complex are virulent, multi-drug resistant pathogens that survive and replicate intracellularly in patients with cystic fibrosis (CF). We have discovered that B. cenocepacia cannot be cleared from CF macrophages due to defective autophagy, causing continued systemic inflammation and infection. Defective autophagy in CF is mediated through constitutive reactive oxygen species (ROS) activation of transglutaminase-2 (TG2), which causes the sequestration (accumulation) of essential autophagy initiating proteins. Cysteamine is a TG2 inhibitor and proteostasis regulator with the potential to restore autophagy. Therefore, we sought to examine the impact of cysteamine on CF macrophage autophagy and bacterial killing. Human peripheral blood monocyte-derived macrophages (MDMs) and alveolar macrophages were isolated from CF and non-CF donors. Macrophages were infected with clinical isolates of relevant CF pathogens. Cysteamine caused direct bacterial growth killing of live B. cenocepacia, B. multivorans, P. aeruginosa and MRSA in the absence of cells. Additionally, B. cenocepacia, B. multivorans, and P. aeruginosa invasion were significantly decreased in CF MDMs treated with cysteamine. Finally, cysteamine decreased TG2, p62, and beclin-1 accumulation in CF, leading to increased Burkholderia uptake into autophagosomes, increased macrophage CFTR expression, and decreased ROS and IL-1β production. Cysteamine has direct anti-bacterial growth killing and improves human CF macrophage autophagy resulting in increased macrophage-mediated bacterial clearance, decreased inflammation, and reduced constitutive ROS production. Thus, cysteamine may be an effective adjunct to antibiotic regimens in CF.

Fifteen children with spinal muscular atrophy type 1 received gene-replacement therapy with a single dose of adeno-associated virus containing SMN. In marked contrast to well-characterized historical cohorts, all the patients survived at least 20 months and most reached motor milestones.

Purpose - Previous studies have found general differences between non-lean and lean production systems, but none of them have identified the major factors in supporting operations such as maintenance which are important in shifting the production from a non-lean to a lean system. The purpose of this paper is to determine the major factors and parameters of maintenance operations that are most effective in enhancing production to a lean system.Design methodology approach - A questionnaire is constructed and a direct mail survey is conducted in the greater Cincinnati tri-state region. The data collected are analyzed with SAS software using contingency tables with Fisher's exact test and a logistic regression analysis method.Findings - The results show strong correlations between a lean production system and some of the major maintenance variables and parameters such as annual costs of maintenance personnel, parts materials, and training.Originality value - The results of this study can be used as a guideline for engineers, experts and managers in order to monitor the maintenance operation during the transition process from a non-lean to a lean production system.

To describe 13 neurologically normal infants with chronic respiratory symptoms who had swallowing dysfunction with silent chronic aspiration without gastroesophageal reflux (GER) as the cause of their respiratory symptoms. Infants with neurologic disorders and infants with GER are known to have chronic respiratory symptoms. Isolated swallowing dysfunction and aspiration without GER in neurologically normal infants have not been widely reported. Retrospective chart review. A tertiary pulmonary-care center at a children's hospital. One hundred twelve otherwise healthy infants referred for respiratory symptoms who underwent esophageal pH studies and videofluoroscopic swallow studies (VSSs). The records of infants referred between January 1997 and December 1999 to the Department of Pediatric Pulmonology who underwent 24-h esophageal pH monitoring and VSS as part of an evaluation for recurrent stridor and/or wheezing were reviewed. Significant GER was diagnosed if the percentage of time with esophageal pH < 4 was > 6%. Infants included in the study presented with recurrent respiratory symptoms, were born at term, were neurologically normal, had normal results of esophageal pH studies, but had abnormal results of VSSs (n = 13). All 13 infants presented with a variety of recurrent respiratory symptoms including wheezing and intermittent stridor. Ten of 13 infants had spitting and/or choking episodes with feeding. The mean (± SD) age at the onset of symptoms was 2.0 ± 1.6 months, and the mean age at VSS was 5.9 ± 3.4 months. All 13 infants had normal results of 24-h esophageal pH studies but had abnormal results for VSSs. All infants had evidence of swallowing dysfunction and direct silent aspiration of liquids with thin consistency. Six infants also were aspirating liquids with thick and/or semi-thick consistencies. None of the infants had evidence of structural anomalies on esophagograms. Nine infants were treated with thickened food, and in four infants oral feedings were stopped. Three of these infants required nasojejunal feeding, and one infant required gastrostomy tube feeding. VSSs were repeated every 3 months. In all infants, swallowing dysfunction resolved within 3 to 9 months. All infants tolerated the resumption of oral feeding. Videofluoroscopic documentation of the resolution of aspiration was followed by the resolution of respiratory symptoms in all infants. There is a subgroup of otherwise healthy infants, presenting with wheeze and/or stridor, who have isolated swallowing dysfunction and silent aspiration as the cause of their respiratory symptoms.

While both patients and physicians identify communication of bad news as an area of great challenge, the factors underlying this often complex task remain largely unknown. Emotional intelligence (EI) has been positively correlated with good general communication skills and successful leadership, but there is no literature relating EI to the delivery of bad news. Our objectives were to determine: 1) performance of first-year pediatric residents in the delivery of bad news in a standardized patient (SP) setting; and 2) the role of EI in these assessments. Our hypothesis was that pediatric trainees with higher EI would demonstrate more advanced skills in this communication task. Forty first- year residents participated. Skill in bad news delivery was assessed via SP encounters using a previously published assessment tool (GRIEV_ING Death Notification Protocol). Residents completed the Emotional and Social Competency Inventory (ESCI) as a measure of EI. Residents scored poorly on bad news delivery skills but scored well on EI. Intraclass correlation coefficients indicated moderate to substantial inter-rater reliability among raters using the delivering bad news assessment tool. However, no correlation was found between bad news delivery performance and EI. We concluded that first-year pediatric residents have inadequate skills in the delivery of bad news. In addition, our data suggest that higher EI alone is not sufficient to effectively deliver death news and more robust skill training is necessary for residents to gain competence and acquire mastery in this important communication domain.

Multiissue negotiations present opportunities for tradeoffs that create gains for one or more parties without causing any party to be worse off. The literature suggests that parties are often unable to identify and capitalize on such trades. We present a Negotiation Support System, called NEGOTIATION ASSISTANT, that enables negotiators to analyze their own preferences and provides a structured negotiation process to help parties move toward optimal trades. The underlying model is based on a multiattribute representation of preferences and communications over a computer network where offers and counteroffers are evaluated according to one's own preferences. The parties can send and receive both formal offers and informal messages. If and when agreement is reached, the computer evaluates the agreement and suggests improvements based on the criteria of Pareto-superiority. In this paper, we motivate the system, present its analytical foundations, discuss its design and development, and provide an experimental assessment of its \"value-in-use.\" Our results strongly suggest that parties using the system in structured negotiation settings would achieve better outcomes than parties negotiating face to face or over an e-mail messaging facility, other things being equal. For example, only 4 of the 34 dyads (11.1%) negotiating a simulated sales transaction face to face or over e-mail reached an \"integrative\" settlement, as compared with 29 of the 68 dyads (42.6%) using NEGOTIATION ASSISTANT. Systems such as NEGOTIATION ASSISTANT have the potential to be used in emerging \"electronic markets.\"