Clinical Effects of a Topically Applied Toll-like Receptor 9 Agonist in Active Moderate-to-Severe Ulcerative Colitis.

Background And Aims: Toll-like receptors [TLRs] are potential drug targets for immunomodulation. We determined the safety and efficacy of the TLR-9 agonist DNA-based immunomodulatory sequence 0150 [DIMS0150] in ulcerative colitis [UC] patients refractory to standard therapy.

Methods: In this randomized, double-blind, placebo-controlled trial, 131 patients with moderate-to-severe active UC were randomized to receive two single doses of the oligonucleotide DIMS0150 [30 mg] or placebo administered topically during lower GI endoscopy at baseline and Week 4.

Measuring the Pharmacokinetic Properties of Drugs with a Novel Surgical Rat Model.

Unlabelled: Purpose/aim of the study: The pharmacokinetic (PK) parameters in animal models can help optimize novel candidate drugs prior to human trials. However, due to the complexity of pharmacokinetic experiments, their use is limited in academia. We present a novel surgical rat model for investigation of pharmacokinetic parameters and its use in an anti-obesity drug development program.

Novel circulating placental markers prokineticin-1, soluble fms-like tyrosine kinase-1, soluble endoglin and placental growth factor and association with late miscarriage.

Study Question: Are novel circulating placental markers prokineticin-1 (PK-1), soluble fms-like tyrosine kinase-1 (sFlt-1), soluble endoglin (sEng) and placental growth factor (PlGF) associated with late miscarriage in asymptomatic first trimester pregnant women?

Summary Answer: Increased serum sFlt-1 or PlGF, but not sEng or PK-1, were significantly associated with reduced miscarriage risk after adjustment for age, BMI, gestational age, smoking and blood pressure.

What Is Known Already: Abnormal placental development is observed in two-thirds of miscarriages. Identifying women at high risk of late miscarriage could help diagnose potentially treatable causes of miscarriage such as infection, thrombosis or immunological disease.

Impact of metabolic acidemia at birth on neonatal outcomes in infants born before 34 weeks' gestation.

Purpose: To examine prematurity-associated neonatal outcomes in early preterm infants with metabolic acidemia compared to those without such acidemia.

Methods: We performed a retrospective cohort analysis to assess the impact of metabolic acidemia on prematurity-associated complications in a large cohort of singleton live-born infants with complete umbilical cord gas analyses delivered between 24 0/7 and 33 6/7 weeks. Metabolic acidemia was defined as an umbilical artery pH less than 7.

Randomised clinical study: inulin short-chain fatty acid esters for targeted delivery of short-chain fatty acids to the human colon.

Background: Short-chain fatty acids (SCFA) produced through fermentation of nondigestible carbohydrates by the gut microbiota are associated with positive metabolic effects. However, well-controlled trials are limited in humans.

Aims: To develop a methodology to deliver SCFA directly to the colon, and to optimise colonic propionate delivery in humans, to determine its role in appetite regulation and food intake.

Investigating the KNDy Hypothesis in Humans by Coadministration of Kisspeptin, Neurokinin B, and Naltrexone in Men.

Context: A subpopulation of hypothalamic neurons colocalize three neuropeptides, namely kisspeptin, neurokinin B (NKB), and dynorphin, collectively termed KNDy neurons. Animal studies suggest they interact to affect pulsatile GnRH release (KNDy hypothesis); kisspeptin stimulates, NKB modulates, and dynorphin (an opioid) inhibits.

Objective: To investigate the KNDy hypothesis in humans, we assessed for the first time the effects of the coadministration of kisspeptin-54, NKB, and an opioid receptor antagonist, naltrexone, on LH pulsatility (surrogate marker for GnRH pulsatility) and gonadotropin release.

At-risk adolescents as experts in a new requirements elicitation procedure for the development of a smart phone psychoeducational trauma-informed care application.

Background/purpose: Adolescents from urban, socioeconomically disadvantaged communities of color encounter high rates of adverse childhood experiences. To address the resulting multidimensional problems, we developed an innovative approach, Experiential Participatory and Interactive Knowledge Elicitation (EPIKE), using remote experiential needs elicitation methods to generate design and content requirements for a mobile health (mHealth) psychoeducational intervention.

Methods: At a community-based organization in a northeastern city, the research team developed EPIKE by incorporating elicitation of input on the graphics and conducting remotely recorded experiential meetings and iterative reviews of the design to produce an mHealth smartphone story application (app) prototype for the participants to critique.

Critical Role of the Disintegrin Metalloprotease ADAM-like Decysin-1 [ADAMDEC1] for Intestinal Immunity and Inflammation.

Background And Aims: ADAM [A Disintegrin And Metalloproteinase] is a family of peptidase proteins which have diverse roles in tissue homeostasis and immunity. Here, we study ADAM-like DECysin-1 [ADAMDEC1] a unique member of the ADAM family. ADAMDEC1 expression is restricted to the macrophage/dendritic cell populations of the gastrointestinal tract and secondary lymphoid tissue.

Insights into the role of neuronal glucokinase.

Glucokinase is a key component of the neuronal glucose-sensing mechanism and is expressed in brain regions that control a range of homeostatic processes. In this review, we detail recently identified roles for neuronal glucokinase in glucose homeostasis and counterregulatory responses to hypoglycemia and in regulating appetite. We describe clinical implications from these advances in our knowledge, especially for developing novel treatments for diabetes and obesity.

A Clinic Model: Post-Intensive Care Syndrome and Post-Intensive Care Syndrome-Family.

The number of patients surviving critical illness in the United States has increased with advancements in medicine. Post-intensive care syndrome and post-intensive care syndrome-family are terms developed by the Society of Critical Care Medicine in order to address the cognitive, psychological, and physical sequelae emerging in patients and their families after discharge from the intensive care unit. In the United Kingdom and Europe, intensive care unit follow-up clinics have been used to address the complications of post-intensive care syndrome for some time.

What we have learned about intrapartum fetal monitoring trials in the MFMU Network.

The vast majority of pregnant women are subjected to electronic fetal heart monitoring during labor. There is limited evidence to support its benefit compared with intermittent auscultation. In addition, there is significant variability in interpretation and its false-positive rate is high.

Allosteric Optical Control of a Class B G-Protein-Coupled Receptor.

Allosteric regulation promises to open up new therapeutic avenues by increasing drug specificity at G-protein-coupled receptors (GPCRs). However, drug discovery efforts are at present hampered by an inability to precisely control the allosteric site. Herein, we describe the design, synthesis, and testing of PhotoETP, a light-activated positive allosteric modulator of the glucagon-like peptide-1 receptor (GLP-1R), a class B GPCR involved in the maintenance of glucose homeostasis in humans.

Kisspeptin Expression in the Human Infundibular Nucleus in Relation to Sex, Gender Identity, and Sexual Orientation.

Context: Since the discovery of its central role in reproduction, our functional neuroanatomical knowledge of the hypothalamic kisspeptin system is predominantly based on animal studies. Although sex differences in kisspeptin expression have been shown in humans in adulthood, the developmental origin of this sex difference is unknown.

Objectives: Our objectives were to determine the following: 1) when during development the sex difference in kisspeptin expression in the infundibular nucleus would emerge and 2) whether this sex difference is related to sexual orientation or transsexuality.

Proglucagon Promoter Cre-Mediated AMPK Deletion in Mice Increases Circulating GLP-1 Levels and Oral Glucose Tolerance.

Background: Enteroendocrine L-cells synthesise and release the gut hormone glucagon-like peptide-1 (GLP-1) in response to food transit. Deletion of the tumour suppressor kinase LKB1 from proglucagon-expressing cells leads to the generation of intestinal polyps but no change in circulating GLP-1 levels. Here, we explore the role of the downstream kinase AMP-activated protein kinase (AMPK) in these cells.

Identification of Risk Factors for Cervical Spine Injury from Pediatric Trauma Registry.

Background: Cervical spine injuries are rare in children. Our goal is to establish guidelines for cervical spine clearance that are practical for our pediatric population, and, in the process, to reduce the risk of radiation exposure from unnecessary advanced imaging.

Methods: We retrospectively reviewed the records from the registries of two pediatric trauma centers from the past 11 years (January 2002 to June 2013).

L-arginine promotes gut hormone release and reduces food intake in rodents.

Aims: To investigate the anorectic effect of L-arginine (L-Arg) in rodents.

Methods: We investigated the effects of L-Arg on food intake, and the role of the anorectic gut hormones glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), the G-protein-coupled receptor family C group 6 member A (GPRC6A) and the vagus nerve in mediating these effects in rodents.

Results: Oral gavage of L-Arg reduced food intake in rodents, and chronically reduced cumulative food intake in diet-induced obese mice.

Association of Cervical Effacement With the Rate of Cervical Change in Labor Among Nulliparous Women.

Objective: To assess the association of cervical effacement with the rate of intrapartum cervical change among nulliparous women.

Methods: We conducted a secondary analysis of a prospective trial of intrapartum fetal pulse oximetry. For women who had vaginal deliveries, interval-censored regression was used to estimate the time to dilate at 1-cm intervals.

Investigating the Glucagon Receptor and Glucagon-Like Peptide 1 Receptor Activity of Oxyntomodulin-Like Analogues in Male Wistar Rats.

Aims: To investigate the effect of Glu-3 OXM-like analogues on food intake and bodyweight in male rats.

Background: Oxyntomodulin (OXM) is a natural agonist at both the glucagon receptor (GCGr) and the glucagon-like peptide 1 receptor (GLP-1r), and peripheral administration reduces food intake and increases energy expenditure in rodents and humans. Substituting the native glutamine (Gln) at amino acid position 3 of OXM for glutamate (Glu) has previously been shown to diminish GCGr activity without affecting GLP-1r activity.

Proglucagon-Derived Peptides Do Not Significantly Affect Acute Exocrine Pancreas in Rats.

Objectives: Reports have suggested a link between treatment with glucagon-like peptide 1 (GLP-1) analogs and an increased risk of pancreatitis. Oxyntomodulin, a dual agonist of both GLP-1 and glucagon receptors, is currently being investigated as a potential antiobesity therapy, but little is known about its pancreatic safety. The aim of the study was to investigate the acute effect of oxyntomodulin and other proglucagon-derived peptides on the rat exocrine pancreas.

Gastrointestinal hormones and their role in obesity.

Purpose Of Review: Pandemic obesity is the most pressing health issue of this century. The most successful treatment so far is bariatric surgery, but for various reasons, surgery cannot be applied to all patients who require treatment. Gastrointestinal hormones are likely to play a key role in the success of bariatric surgery.

Optical Control of Insulin Secretion Using an Incretin Switch.

Incretin mimetics are set to become a mainstay of type 2 diabetes treatment. By acting on the pancreas and brain, they potentiate insulin secretion and induce weight loss to preserve normoglycemia. Despite this, incretin therapy has been associated with off-target effects, including nausea and gastrointestinal disturbance.

Subcutaneous infusion of kisspeptin-54 stimulates gonadotrophin release in women and the response correlates with basal oestradiol levels.

Background And Objective: Kisspeptin stimulates hypothalamic GnRH secretion resulting in gonadotrophin release and has potential as a future therapeutic. Chronic subcutaneous infusion of kisspeptin via a pump (similar to an insulin pump) may provide an alternative route of administration in the future. We investigated for the first time in humans, the gonadotrophin response to subcutaneous (SC) infusions of kisspeptin-54 in healthy women.

Implications for practice: Resurgence and differential reinforcement of alternative responding.

During the maintenance stages of differential reinforcement of alternative responding (DRA), failure to reinforce alternative responses could result in a resurgence of problem behavior. However, translational work done with arbitrary human responses suggests that teaching individuals to emit multiple alternative responses in sequential order may facilitate the resurgence of appropriate, rather than problem, behavior. This paper discusses the practical implications of serial DRA training on problem and appropriate behavior resurgence, as presented in the preceding article, "Serial Alternative Response Training As Intervention for Target Response Resurgence.