Hyperadiponectinemia During Infliximab Induction Therapy in Pediatric Crohn Disease

Objectives: The inflammatory process in Crohn disease (CD) involves the visceral fat, characterized by adipocyte hyperplasia and altered adipose tissue and serum concentrations of tumor necrosis factor (TNF), leptin, adiponectin and resistin. We investigated the effect of anti-TNF therapy with infliximab (IFX) on serum adipokine levels in pediatric CD. Methods: Serum concentrations of resistin (ng/mL), leptin (ng/mL), and total adiponectin (mu g/mL) were assessed by enzyme-linked immunosorbent assays (ELISA) in 18 pediatric CD patients (mean age 15.0 +/- 1.5 years) before first, second, and fourth IFX infusion (weeks 0, 2, and 14) and compared with baseline values from sex- and BMI-matched healthy controls (HC, mean age 13.4 +/- 1.6 years). Results: At baseline, CD patients (mean age 15.0 +/- 1.5 years, 10 of 18 boys) compared with HC (13.4 +/- 1.6 years, 7 of 15 boys) had higher resistin levels (median 14.7 ng/mL, range 5.1-50.5 vs 7.3 ng/mL, 0.5-14.5);P = 0.0002). At weeks 2 and 14, resistin decreased to 6.9 ng/mL (2.9-16.8) (P < 0.0001) and 9.2 ng/mL (4.1-20.6;P = 0.0011), respectively. Leptin and adiponectin were comparable between patients and HC at baseline. Leptin increased in girls from 9.5 ng/mL (4.0-30.1) to 16.0 ng/mL (7.9-35.2;P = 0.0156) and 17.2 ng/mL (10.8-26.8;P = 0.1953) at weeks 0, 2, and 14 respectively;with a trend in boys from 2 (0.6-12.9) to 2.8 (1.7-8.6;P = 0.0840) and 3.3 (1.34.6;P = 0.1309). Adiponectin peaked initially from 7.8 mu g/mL (4.6-11.9) at week 0 to 9.2 mu g/mL (4.1-20.7;P = 0.0005) at week 2 and thereafter fell to 6.5 mu g/mL (3.0-12.7;P = 0.0182) at week 14. Conclusions: TNF blockade is associated with changes in circulating adipokines. The marked early increase of the potent anti-inflammatory adiponectin may contribute to the rapid response to IFX in CD

Consensus Recommendations for the Use of Automated Insulin Delivery (AID) Technologies in Clinical Practice

International audienceThe significant and growing global prevalence of diabetes continues to challenge people with diabetes (PwD), healthcare providers and payers. While maintaining near-normal glucose levels has been shown to prevent or delay the progression of the long-term complications of diabetes, a significant proportion of PwD are not attaining their glycemic goals. During the past six years, we have seen tremendous advances in automated insulin delivery (AID) technologies. Numerous randomized controlled trials and real-world studies have shown that the use of AID systems is safe and effective in helping PwD achieve their long-term glycemic goals while reducing hypoglycemia risk. Thus, AID systems have recently become an integral part of diabetes management. However, recommendations for using AID systems in clinical settings have been lacking. Such guided recommendations are critical for AID success and acceptance. All clinicians working with PwD need to become familiar with the available systems in order to eliminate disparities in diabetes quality of care. This report provides much-needed guidance for clinicians who are interested in utilizing AIDs and presents a comprehensive listing of the evidence payers should consider when determining eligibility criteria for AID insurance coverage

Hemizygous variants in protein phosphatase 1 regulatory subunit 3F (<i>PPP1R3F</i>) are associated with a neurodevelopmental disorder characterized by developmental delay, intellectual disability, and autistic features

Abstract PPP1R3F (R3F) is a member of the glycogen targeting subunits (GTSs), which belong to the large group of regulatory subunits of protein phosphatase 1 (PP1), a major eukaryotic serine/threonine protein phosphatase that regulates diverse cellular processes. Here, we describe the identification of hemizygous variants in PPP1R3F associated with a novel X-linked recessive neurodevelopmental disorder in 13 unrelated individuals. This disorder is characterized by developmental delay, mild intellectual disability, neurobehavioral issues such as autism spectrum disorder, seizures, and other neurological findings including tone, gait, and cerebellar abnormalities. PPP1R3F variants segregated with disease in affected hemizygous males that inherited the variants from their heterozygous carrier mothers. We show that R3F is predominantly expressed in brain astrocytes and localizes to the endoplasmic reticulum in cells. Glycogen content in PPP1R3F knockout astrocytoma cells appears to be more sensitive to fluxes in extracellular glucose levels than in wild-type cells, suggesting that R3F functions in maintaining steady brain glycogen levels under changing glucose conditions. We performed functional studies on nine of the identified variants and observed defects in PP1 binding, protein stability, subcellular localization, and regulation of glycogen metabolism in most of them. Collectively, the genetic and molecular data indicate that deleterious variants in PPP1R3F are associated with a new X-linked disorder of glycogen metabolism, highlighting the critical role of GTSs in neurological development. This research expands our understanding of neurodevelopmental disorders and the role of PP1 in brain development and proper function.</jats:p

M13 Bacteriophage Display Framework That Allows Sortase-Mediated Modification of Surface-Accessible Phage Proteins

We exploit bacterial sortases to attach a variety of moieties to the capsid proteins of M13 bacteriophage. We show that pIII, pIX, and pVIII can be functionalized with entities ranging from small molecules (e.g., fluorophores, biotin) to correctly folded proteins (e.g., GFP, antibodies, streptavidin) in a site-specific manner, and with yields that surpass those of any reported using phage display technology. A case in point is modification of pVIII. While a phage vector limits the size of the insert into pVIII to a few amino acids, a phagemid system limits the number of copies actually displayed at the surface of M13. Using sortase-based reactions, a 100-fold increase in the efficiency of display of GFP onto pVIII is achieved. Taking advantage of orthogonal sortases, we can simultaneously target two distinct capsid proteins in the same phage particle and maintain excellent specificity of labeling. As demonstrated in this work, this is a simple and effective method for creating a variety of structures, thus expanding the use of M13 for materials science applications and as a biological tool.United States. Army Research Office. (Institute for Collaborative Biotechnologies Grant W911NF-09-0001