Difelikefalin, a peripherally restricted KOR (kappa opioid receptor) agonist, produces diuresis through a central KOR pathway.

Difelikefalin is a peripherally restricted kappa opioid receptor (KOR) agonist that was recently approved by the FDA to treat pruritis in dialysis patients. Here, we investigated the cardiovascular and renal responses to difelikefalin, and using the KOR antagonist norbinaltorphimine (norBNI), examined whether any difelikefalin-induced changes in the renal excretion of water and/or electrolytes were mediated through a central or peripheral KOR pathway. The effects of norBNI pretreatment on nalfurafine, a KOR agonist that crosses the blood-brain barrier, were also examined.

Nalfurafine, a G-Protein-Biased KOR (Kappa Opioid Receptor) Agonist, Enhances the Diuretic Response and Limits Electrolyte Losses to Standard-of-Care Diuretics.

Nalfurafine is a G-protein-biased KOR (kappa opioid receptor) agonist that produces analgesia and lacks central nervous system adverse effects. Here, we examined the cardiovascular and renal responses to intravenous and oral nalfurafine alone and in combination with furosemide, hydrochlorothiazide, or amiloride. We hypothesized that nalfurafine, given its distinct mechanism of vasopressin inhibition, would increase urine output to these diuretics and limit electrolyte loss.

Cardiovascular and renal effects of novel nonpeptide nociceptin opioid peptide receptor agonists.

Background And Purpose: Partial agonists of the nociceptin opioid peptide (NOP) receptor have potential therapeutic use as antihypertensive and water diuretics (aquaretics). To date, peptide NOP receptor ligands have failed to progress in clinical trials due to poor pharmacokinetics and adverse effects. Nonpeptide, small-molecule NOP receptor ligands may be more suitable as therapeutic agents.

Interactive effects of (±)-trans-U50488 and its stereoisomers with cannabinoids.

The adverse effects of mu opioid agonists have spurred a renewed interest in using kappa opioid receptor (KOR) agonists as analgesics. KOR agonists also have potential for development as diuretics for the treatment of edema and hypertension. Here, we evaluated the discriminative stimulus, antinociceptive, and diuretic effects of the kappa agonist (±)-trans-U-50488 and its stereoisomers (-)-(1S,2S)-U-50488 or (+)-(1R,2R)-U-50488) alone and in combination with the cannabinoid agonist (-)-CP 55,940.

Mouse model systems of autism spectrum disorder: Replicability and informatics signature.

Phenotyping mouse model systems of human disease has proven to be a difficult task, with frequent poor inter- and intra-laboratory replicability, particularly in behavioral domains such as social and cognitive function. However, establishing robust animal model systems with strong construct validity is of fundamental importance as they are central tools for understanding disease pathophysiology and developing therapeutics. To complete our studies of mouse model systems relevant to autism spectrum disorder (ASD), we present a replication of the main findings from our two published studies of five genetic mouse model systems of ASD.

Downregulation of Brain Gα12 Attenuates Angiotensin II-Dependent Hypertension.

Background: Angiotensin II (Ang II) activates central Angiotensin II type 1 receptors to increase blood pressure via multiple pathways. However, whether central Gα proteins contribute to Ang II-induced hypertension remains unknown. We hypothesized that Angiotensin II type 1 receptors couple with Gα12 and/or Gαq to produce sympatho-excitation and increase blood pressure and downregulation of these Gα-subunit proteins will attenuate Ang II-dependent hypertension.

Comprehensive analysis of two Shank3 and the Cacna1c mouse models of autism spectrum disorder.

To expand, analyze and extend published behavioral phenotypes relevant to autism spectrum disorder (ASD), we present a study of three ASD genetic mouse models: Feng's Shank3 model, hereafter Shank3/F, Jiang's Shank3 model, hereafter Shank3/J and the Cacna1c deletion model. The Shank3 models mimick gene mutations associated with Phelan-McDermid Syndrome and the Cacna1c model recapitulates the deletion underlying Timothy syndrome. This study utilizes both standard and novel behavioral tests with the same methodology used in our previously published companion report on the Cntnap2 null and 16p11.

Cognitive Training at a Young Age Attenuates Deficits in the zQ175 Mouse Model of HD.

Huntington's Disease (HD) is a progressive neurodegenerative disorder that causes motor, cognitive, and psychiatric symptoms. In these experiments, we tested if operant training at an early age affected adult cognitive deficits in the zQ175 KI Het (zQ175) mouse model of HD. In Experiment 1 we trained zQ175 mice in a fixed-ratio/progressive ratio (FR/PR) task to assay learning and motivational deficits.

Changes in inflammation and QoL after a single dose of infliximab during ongoing IBD treatment.

Background And Objectives: Infliximab is used increasingly as maintenance therapy for inflammatory bowel disease (IBD); however, the effects of a single maintenance dose of infliximab are unclear with respect to the quality of life and hormones related to growth and puberty. The aim of the present study was to determine the time course of inflammatory, hormonal, and quality-of-life changes following a single dose of infliximab in the context of ongoing therapy, as related to presence of IBD symptoms at time of administration.

Methods: Children and adolescents with IBD receiving ongoing therapy with infliximab for clinical indications were recruited.

Real world use of an Internet intervention for pediatric encopresis.

Background: The Internet is a significant source of medical information and is now being shown to be an important conduit for delivering various health-related interventions.

Objective: This paper aimed to examine the utility and impact of an Internet intervention for childhood encopresis as part of standard medical care in a "real world" setting.

Methods: Patients diagnosed with encopresis were given a Web-based information prescription to use an Internet intervention for pediatric encopresis.

Does "stubbornness" have a role in pediatric constipation?

The objective of this study was to determine if children with constipation are more stubborn, both in general and specifically regarding toileting behaviors, than children without constipation. A secondary objective was to determine if constipated children who are more stubborn are less likely to respond to routine therapeutic interventions than less stubborn constipated children. One hundred one children aged 2 to 6 years, who were first-time presenters (never received treatment) to their primary care physician (PCP) with constipation, were compared with 84 nonconstipated control children of similar age range.

Using the internet to provide information prescriptions.

Introduction: An information prescription is the provision of specific information to a patient on how to help manage a health problem. The Internet is being used increasingly as a source for information prescriptions, with clinicians directing patients to specific Web sites. As with any health care intervention, patients' lack of compliance is a barrier to the effectiveness of Web-based information prescriptions (WebIPs).

Treatment of childhood constipation by primary care physicians: efficacy and predictors of outcome.

Objective: Childhood constipation accounts for 3% of visits to general pediatric clinics and as many as 30% of visits to pediatric gastroenterologists. The majority of children who experience constipation and whose caregivers seek medical care are seen by primary care physicians such as pediatricians or family physicians. Little is known about how primary care physicians treat childhood constipation or the success of their treatments.

Recurrent vomiting and persistent gastroesophageal reflux caused by unrecognized constipation.

Over a 2-year period, 34 children were referred to the division of pediatric gastroenterology at the University of Virginia with chronic upper gastrointestinal symptoms whose symptoms rapidly and completely resolved when their unrecognized constipation was treated. The average age at presentation was 8.24 (SD 0.

Discordant erythrocyte sedimentation rate and C-reactive protein in children with inflammatory bowel disease taking azathioprine or 6-mercaptopurine.

Background: Inflammatory bowel disease (IBD) is characterized by periods of relapse and remission. Treatment is aimed at reducing symptoms during relapse and prolonging the duration of remissions. 6-Mercaptopurine (6-MP) and its prodrug azathioprine (AZA) are commonly used to prolong clinical remissions.

An Internet intervention as adjunctive therapy for pediatric encopresis.

This study evaluated the benefits of enhanced toilet training delivered through the Internet for children with encopresis. Twenty-four children with encopresis were randomly assigned to the Internet intervention group (Web) or no Internet intervention group (No-Web). All participants continued to receive routine care from their primary care physician.

Assessment of behavioral mechanisms maintaining encopresis: Virginia Encopresis-Constipation Apperception Test.

Objective: To develop and test a scale for parent and child, evaluating theoretical and clinical parameters relevant to children with encopresis. Encopretic children were hypothesized to have more bowel-specific, but not more generic, psychological problems, as compared with nonsymptomatic control children. In addition, mothers were also believed to be more discerning than children.

Precipitants of constipation during early childhood.

Background: Childhood constipation is a common problem, accounting for 3% of visits to pediatric clinics and 30% of visits to pediatric gastroenterologists. Estimates of the prevalence of childhood constipation vary from 0.3% to 28% with younger children being affected most often.

Psychological differences between children with and without chronic encopresis.

Objective: To validate a theoretical model of encopresis in terms of psychological factors that differentiates children with and without chronic encopresis and to identify scales that demonstrate these differences.

Methods: Eighty-six children with encopresis were compared to 62 nonsymptomatic children on five psychometric instruments. Differences in the mean scores and the percentages of children falling beyond preselected clinical thresholds were compared across the patient-control groups.

Treatment of childhood encopresis: a randomized trial comparing three treatment protocols.

Objectives: To compare short- and long-term effectiveness of three additive treatment protocols in children experiencing chronic encopresis.

Methods: Children, 6 to 15 years of age, who experienced at least weekly fecal soiling for 6 months or longer were eligible for the study. Children were randomly assigned to a group that received intensive medical therapy (IMT), a group that received intensive medical therapy plus a behavior management program called enhanced toilet training (ETT), or a group that received intensive medical therapy with enhanced toilet training and external anal sphincter electromyographic biofeedback (BF).

Review of the treatment literature for encopresis, functional constipation, and stool-toileting refusal.

This review summarizes the literature on randomized, controlled, published studies involving medical, behavioral, psychological, and biofeedback treatments for encopresis/functional constipation and stool-toileting refusal in preschool-age and school-age children. Nine such studies were located in the literature involving school-age children. No randomized, controlled treatment studies involving preschool-age children have been published.

Manifestations and linkage analysis in X-linked autoimmunity-immunodeficiency syndrome.

The clinical findings of a kindred with an X-linked disorder are characterized by autoimmune polyendocrinopathy, enteropathy with villous atrophy, chronic dermatitis, and variable immunodeficiency. Linkage analysis was performed on 20 members of the affected kindred to determine the location of the responsible locus. Informative recombinations limited the region to an approximate 20 cM interval bordered by DXS1055 and DXS1196/DXS1050.

Differences in toileting habits between children with chronic encopresis, asymptomatic siblings, and asymptomatic nonsiblings.

No studies have compared toileting-specific behaviors of encopretic children with those of asymptomatic children and have controlled for environmental factors such as parental attitudes, parenting styles, and bathroom facilities. This study prospectively examined the toileting habits of 86 chronically encopretic children compared with those of 27 asymptomatic siblings and 35 asymptomatic nonsiblings. Although encopretic children experienced significantly more soiling than did controls, the total number of daily bowel movements passed in the toilet (+/-SD) was comparable in the three groups (.