Citations

ABSTRACTUlcerative colitis (UC) and Crohn disease (CD), collectively referred to as inflammatory bowel disease (IBD), are chronic inflammatory disorders that can affect the gastrointestinal tract of children and adults. Like other autoimmune processes, the cause(s) of these disorders remain unknown but likely involves some interplay between genetic vulnerability and environmental factors. Children, in particular with UC or CD, can present to their primary care providers with similar symptoms, including abdominal pain, diarrhea, weight loss, and bloody stool. Although UC and CD are more predominant in adults, epidemiologic studies have demonstrated that a significant percentage of these patients were diagnosed during childhood. The chronic nature of the inflammatory process observed in these children and the waxing and waning nature of their clinical symptoms can be especially disruptive to their physical, social, and academic development. As such, physicians caring for children must consider these diseases when evaluating patients with compatible symptoms. Recent research efforts have made available a variety of more specific and effective pharmacologic agents and improved endoscopic and radiologic assessment tools to assist clinicians in the diagnosis and interval assessment of their patients with IBD; however, as the level of complexity of these interventions has increased, so too has the need for practitioners to become familiar with a wider array of treatments and the risks and benefits of particular diagnostic testing. Nonetheless, in most cases, and especially when frequent visits to subspecialty referral centers are not geographically feasible, primary care providers can be active participants in the management of their pediatric patients with IBD. The goal of this article is to educate and assist pediatricians and adult gastroenterology physicians caring for children with IBD, and in doing so, help to develop more collaborative care plans between primary care and subspecialty providers.

Aims: Percutaneous coronary intervention (PCI) is frequently accompanied by myocardial injury. The present study was performed to determine whether remote ischemic preconditioning (IP) induces cardioprotection during PCI. Methods: We enrolled 95 patients requiring nonemergency PCI for stable disease or unstable angina into this prospective clinical trial. Patients were randomized to either remote IP (induced by three 3‐min cycles of blood pressure cuff inflations to 200 mm Hg around the upper arm, followed by 3‐min of reperfusion n = 47) or sham control ( n = 48) immediately preceding PCI. The primary outcome measure was the frequency of post‐PCI myonecrosis, defined as a peak postprocedural cTnT T ≥0.03 ng/dL. Secondary outcome measures were the change in plasma high‐sensitivity C‐reactive protein (hsCRP) levels following PCI and in endothelial progenitor cells (EPC) counts following IP. Results: There was no difference in the primary endpoint of the frequency of PCI related myonecrosis which occurred in 22 (47%) and 19 (40%) patients in the remote IP and control groups, respectively, P = 0.42. There was significant increase in hsCRP post‐PCI in both groups ( P < 0.001), but there was no difference between the groups (median %change in hsCRP 46% vs. 54%, P = 0.73). There was no significant change in circulating early (CD34 −/CD133+/KDR+), intermediate (CD34+/CD133+/KDR+), or late (CD34+/CD133−/KDR+) EPC in the two groups immediately following IP. The composite rate of death, myocardial infarction, and target lesion revascularization at 1 year was 14.1% versus 13.7% ( P = 0.90). Conclusions: Our study indicates that remote IP immediately before PCI does not induce cardioprotection in low to moderate risk patients. © 2012 Wiley Periodicals, Inc.

Wiskott–Aldrich syndrome protein (WASPs) control actin dynamics in cellular processes, including cell motility, receptor-mediated endocytosis, bacterial invasion, and vesicular trafficking. We demonstrated that WASH, a recently identified WASP family protein, colocalizes on endosomal subdomains with the cargo-selective complex (CSC) of the retromer, where it regulates retrograde sorting from endosomes in an actin-dependent manner. However, the mechanism of WASH recruitment to these retromer-enriched endosomal subdomains is unclear. Here we show that a component of the WASH regulatory complex (SHRC), FAM21, which contains 21 copies of a novel L-F-[D/E]3-10-L-F motif, directly interacts with the retromer CSC protein VPS35. Endosomal localization of FAM21 is VPS35 dependent and relies on multivalency of FAM21 repeat elements. Using a combination of pull-down assays and isothermal calorimetry, we demonstrate that individual repeats can bind CSC, and binding affinity varies among different FAM21 repeats. A high-affinity repeat can be converted into a low-affinity one by mutation of a hydrophobic residue within the motif. These in vitro data mirror the localization of FAM21 to retromer-coated vesicles in cells. We propose that multivalency enables FAM21 to sense the density of retromer on membranes, allowing coordination of SHRC recruitment, and consequent actin polymerization, with retromer sorting domain organization/maturation.

High-density electroencephalography (EEG) was used to evaluate cortical activity patterns during the auditory processing of speech presented at various levels of degradation in a sentence verification task. 25 healthy participants listened to true-false sentences produced with one of 3 channel levels (1, 6, 16), ranging from unintelligible, moderately intelligible, and highly intelligible. Behavioral data were collected via button press (reaction time and accuracy) for each sentence. The analysis of cortical activation patterns includes 1) the identification of independent components that account for variations of activity associated with degradation levels and 2) the examination of associated event-related potentials. Statistical analyses will be performed on individuals' cortical activity, in tandem with behavioral data. Preliminary results reveal differences in the timing and magnitude of frontal and temporal lobe activation that coincide with task difficulty. Results of the present investigation will inform hypotheses about regions of interest for further investigation and will bear on models of connected speech perception, including the neurobiological underpinnings of individual differences and manifestations in a listener's understanding of degraded speech.

More than two decades have passed since genetically modified HIV was used for gene delivery. Through continuous improvements these early marker gene-carrying HIVs have evolved into safer and more effective lentiviral vectors. Lentiviral vectors offer several attractive properties as gene-delivery vehicles, including: (i) sustained gene delivery through stable vector integration into host genome; (ii) the capability of infecting both dividing and non-dividing cells; (iii) broad tissue tropisms, including important gene- and cell-therapy-target cell types; (iv) no expression of viral proteins after vector transduction; (v) the ability to deliver complex genetic elements, such as polycistronic or intron-containing sequences; (vi) potentially safer integration site profile; and (vii) a relatively easy system for vector manipulation and production. Accordingly, lentivector technologies now have widespread use in basic biology and translational studies for stable transgene overexpression, persistent gene silencing, immunization, in vivo imaging, generating transgenic animals, induction of pluripotent cells, stem cell modification and lineage tracking, or site-directed gene editing. Moreover, in the present high-throughput ‘-omics’ era, the commercial availability of premade lentiviral vectors, which are engineered to express or silence genome-wide genes, accelerates the rapid expansion of this vector technology. In the present review, we assess the advances in lentiviral vector technology, including basic lentivirology, vector designs for improved efficiency and biosafety, protocols for vector production and infection, targeted gene delivery, advanced lentiviral applications and issues associated with the vector system.

Direct FFA storage in adipose tissue is a recently appreciated pathway for postabsorptive lipid storage. We evaluated the effect of body fat distribution on direct FFA storage in women with different obesity phenotypes. Twenty-eight women [10 upper body overweight/obese (UBO; WHR >0.85, BMI >28 kg/m2), 11 lower body overweight/obese (LBO; WHR <0.80, BMI >28 kg/m2), and 7 lean (BMI <25 kg/m2)] received an intravenous bolus dose of [9,10-3H]palmitate- and [1-14C]triolein-labeled VLDL tracer followed by upper body subcutaneous (UBSQ) and lower body subcutaneous (LBSQ) fat biopsies. Regional fat mass was assessed by combining DEXA and CT scanning. We report greater fractional storage of FFA in UBSQ fat in UBO women compared with lean women ( P < 0.01). The LBO women had greater storage per 106fat cells in LBSQ adipocytes compared with UBSQ adipocytes ( P = 0.04), whereas the other groups had comparable storage in UBSQ and LBSQ adipocytes. Fractional FFA storage was significantly associated with fractional VLDL-TG storage in both UBSQ ( P < 0.01) and LBSQ ( P = 0.03) adipose tissue. In conclusion, UBO women store a greater proportion of FFA in the UBSQ depot compared with lean women. In addition, LBO women store FFA more efficiently in LBSQ fat cells compared with UBSQ fat cells, which may play a role in development of their LBO phenotype. Finally, direct FFA storage and VLDL-TG fatty acid storage are correlated, indicating they may share a common rate-limiting pathway for fatty acid storage in adipose tissue.

AbstractLearning Objectives:After completing this course, the reader will be able to:Identify the components of the “postembolization syndrome”: elevated liver function tests, right upper quadrant pain, nausea and vomiting, and fever.Distinguish the postembolization syndrome from rare complications of embolization that would merit an extended hospitalization.CME This article is available for continuing medical education credit at CME.TheOncologist.comBackground.There is scant evidence to guide the management of patients after hepatic artery embolization (HAE). We examined length of stay (LOS), laboratory patterns, medication usage, morbidity, and mortality of patients hospitalized after HAE for metastatic neuroendocrine tumors.Methods.Data were abstracted retrospectively from electronic medical records on LOS, liver function tests (LFTs), i.v. antibiotics, analgesia, peak temperature, bacteremia, hepatic abscess formation, carcinoid crisis, and metastatic burden on cross-sectional imaging.Results.In 2005–2009, 72 patients underwent 174 HAEs for carcinoid and islet cell tumors. The median LOS was 4 days (range, 1–8 days). There was no correlation between peak LFTs and tumor burden. Declines in LFTs were not uniform before hospital discharge; 25%, 37%, 30%, 53%, and 67% of patients were discharged before their respective aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and total and direct bilirubin levels began to decline, with no readmissions for acute hepatic failure. The median i.v. analgesia dose was 60 mg oral morphine equivalents (range, 3–1,961 mg). Pre-HAE i.v. antibiotics were administered in 99% of cases; post-HAE fever occurred in 37% of patients, with no documented bacteremia. One patient developed a hepatic abscess after HAE. There were two carcinoid crises. The single in-hospital death was associated with air in the portal veins.Conclusions.The duration and intensity of in-hospital care following HAE should be managed on an individual basis. A downward trend in LFTs is not required before discharge. Modest use of i.v. analgesia suggests that many patients could exclusively receive oral analgesics. Given the rarity of serious complications, hospital stays could be shortened, thereby reducing costs and nosocomial risks.