A Complete Pathway Model for Lipid A Biosynthesis in Escherichia coli.

Lipid A is a highly conserved component of lipopolysaccharide (LPS), itself a major component of the outer membrane of Gram-negative bacteria. Lipid A is essential to cells and elicits a strong immune response from humans and other animals. We developed a quantitative model of the nine enzyme-catalyzed steps of Escherichia coli lipid A biosynthesis, drawing parameters from the experimental literature. This model accounts for biosynthesis regulation, which occurs through regulated degradation of the LpxC and WaaA (also called KdtA) enzymes. The LpxC degradation signal appears to arise from the lipid A disaccharide concentration, which we deduced from prior results, model results, and new LpxK overexpression results. The model agrees reasonably well with many experimental findings, including the lipid A production rate, the behaviors of mutants with defective LpxA enzymes, correlations between LpxC half-lives and cell generation times, and the effects of LpxK overexpression on LpxC concentrations. Its predictions also differ from some experimental results, which suggest modifications to the current understanding of the lipid A pathway, such as the possibility that LpxD can replace LpxA and that there may be metabolic channeling between LpxH and LpxB. The model shows that WaaA regulation may serve to regulate the lipid A production rate when the 3-deoxy-D-manno-oct-2-ulosonic acid (KDO) concentration is low and/or to control the number of KDO residues that get attached to lipid A. Computation of flux control coefficients showed that LpxC is the rate-limiting enzyme if pathway regulation is ignored, but that LpxK is the rate-limiting enzyme if pathway regulation is present, as it is in real cells. Control also shifts to other enzymes if the pathway substrate concentrations are not in excess. Based on these results, we suggest that LpxK may be a much better drug target than LpxC, which has been pursued most often

Symptom Persistence in Seriously Emotionally Disordered Children: Findings of a Two-Year Follow-up after Residential Treatment

Residential treatment is arguably the most costly and intensive part of the children’s mental health system. Yet, research suggests that a subset of the emotionally disordered children and youth admitted to intensive tertiary care treatment facilities fail to demonstrate symptom reductions upon discharge, with many continuing to deteriorate in their adjustment during the follow-up period. This study reports on the factors that characterize the children and youth that, while showing marginal benefit from residential treatment, continue to show community conduct problems at a two-year follow-up period. The results are discussed in the context of how knowledge of these factors can help inform future treatment and research directions

Impulsivity and Attention Deficit-Hyperactivity Disorder: Subtype Classification Using the UPPS Impulsive Behavior Scale

This study examined the classification accuracy of the UPPS Impulsive Behavior Scale (UPPS) in discriminating several attention deficit/hyperactivity disorder (ADHD) subtypes, including predominantly inattentive type (ADHD/I), combined type (ADHD/C), and combined type with behavioral problems (ADHD/ODD), between each other and a non-ADHD control group using logistic regression analyses. The sample consisted of 88 children ranging in age from 9.0 years to 12.8 years, with a mean of 10.9 years. Children were predominantly male (74%) and Caucasian (86%) and in grades 3–7. Results indicated that the UPPS performed well in classifying ADHD subtypes relative to traditional diagnostic measures. In addition, analyses indicated that differences in symptoms between subtypes can be explained by specific pathways to impulsivity. Implications for the assessment of ADHD and conceptual issues are discussed

Detailed assessment of hypothalamic damage in craniopharyngioma patients with obesity

Background/objectives: Hypothalamic obesity (HO) occurs in 50% of patients with the pituitary tumor craniopharyngioma (CP). Attempts have been made to predict the risk of HO based on hypothalamic (HT) damage on magnetic resonance imaging (MRI), but none have included volumetry. We performed qualitative and quantitative volumetric analyses of HT damage. The results were explored in relation to feeding related peptides and body fat. Subjects/methods: A cross-sectional study of childhood onset CPs involving 3 Tesla MRI, was performed at median 22 years after first operation; 41 CPs, median age 35 (range: 17–56), of whom 23 had HT damage, were compared to 32 controls. After exclusions, 35 patients and 31 controls remained in the MRI study. Main outcome measures were the relation of metabolic parameters to HT volume and qualitative analyses of HT damage. Results: Metabolic parameters scored persistently very high in vascular risk particularly among HT damaged patients. Patients had smaller HT volumes compared to controls 769 (35–1168) mm3 vs. 879 (775–1086) mm3; P < 0.001. HT volume correlated negatively with fat mass and leptin among CP patients (rs = −0.67; P <.001; rs = −0.53; P = 0.001), and explained 39% of the variation in fat mass. For every 100 mm3 increase in HT volume fat mass decreased by 2.7 kg (95% CI: 1.5–3.9; P < 0.001). Qualitative assessments revealed HT damage in three out of six patients with normal volumetry, but HT damage according to operation records. Conclusions: A decrease in HT volume was associated with an increase in fat mass and leptin. We present a method with a high inter-rater reliability (0.94) that can be applied by nonradiologists for the assessment of HT damage. The method may be valuable in the risk assessment of diseases involving the HT