Endometrial hyperplasia with loss of APC in a novel population of Lyz2-expressing mouse endometrial epithelial cells.

Loss of heterozygosity and promoter hypermethylation of APC is frequently observed in human endometrial cancer, which is the most common gynecological cancer in the USA, but its carcinogenic driver status in the endometrial epithelium has not been confirmed. We have identified a novel population of progenitor endometrial epithelial cells (EECs) in mice that express lysozyme M (LysM) and give rise to approximately 15% of all EECs in adult mice. LysM is a glycoside hydrolase that is encoded by Lyz2 and functions to protect cells from bacteria as part of the innate immune system. Its expression has been shown in a subset of hematopoietic stem cells and in specialized lung and small intestinal epithelial cells. Conditional deletion of Apc in LysM + EECs results in significantly more epithelial cells compared to wild-type mice. At 5 months of age, the ApccKO mice have enlarged uterine horns with pathology that is consistent with endometrial hyperplasia with cystic endometrial glands, non-villous luminal papillae and nuclear atypia. Nuclear accumulation of ß-catenin and ERα, both of which are known to induce endometrial hyperplasia, was observed in the EECs of the ApccKO mice. These results confirm that loss of APC in EECs can result in a phenotype similar to endometrial hyperplasia.

Evaluating changes in salivary oxytocin and cortisol following positive reinforcement training in two adult male western lowland gorillas (Gorilla gorilla gorilla).

Positive reinforcement training (PRT) is associated with increases in species-typical behavior and decreases in stereotypic and abnormal behavior in participating animals. Physiological changes following PRT, for example, increases in oxytocin (OXT) and/or decreases in cortisol (CORT), may facilitate these behavioral changes. This study evaluated salivary OXT and salivary CORT concentrations in two adult male western lowland gorillas (Gorilla gorilla gorilla) following PRT with their primary animal care staff. Following PRT, no change in OXT was observed. CORT decreased in one subject following PRT. Changes in endogenous OXT are related to affiliative interactions and interact with strongly bonded conspecifics. PRT may not activate the oxytocinergic system because PRT is not a species-specific affiliative interaction and/or animal care staff are not viewed as conspecifics. Regardless, PRT may still be viewed as a positive interaction resulting in stress reduction via a decrease in CORT. Relationships are unique, thus these results only apply to these two gorillas and one animal caregiver. Larger population-level studies are needed to understand overall trends in human-animal interactions, and ultimately human-animal relationships. Further evaluation of physiological changes following human-animal interactions should be informative for understanding the human-animal relationship in zoos.

Improving Satisfaction with Pediatric Pain Management by Inviting the Conversation.

BACKGROUND: Patient satisfaction with pain management is associated with improved patient adherence to medical management and efficient service utilization. Pediatric pain control is challenging, given the inability to elicit reliable histories, particularly in younger patients. Several studies have suggested that communication surrounding pain management can improve satisfaction, although there are limited data describing structured interventions with measurable outcomes. A quality improvement project was conducted to determine if reliably asking families about pain management was associated with improved patient satisfaction with pain management. METHODS: In an academic pediatric hospital, nurse manager rounds were used to invite a conversation about pain management. The question, "Pain management is very important to us. Has your child's pain been well controlled?" was added to the established standard questions asked during nurse manager rounds. Effectiveness was measured using the preexisting Press Ganey survey question, "How well was your child's pain controlled?" Responses were compared between those patients who were and were not exposed to the rounding question. RESULTS: Data for 1,032 patients were used to establish baseline satisfaction with pain management scores. In the intervention period, 328 patients received nurse manager rounds and 121 did not. The median of the weighted mean patient survey satisfaction scores were baseline, 91.5%; receiving intervention, 94.2%; and not receiving intervention, 90.0%. Patients who received the intervention reported higher satisfaction with pain management than those who did not (p <0.0001). CONCLUSION: Hospitals seeking to improve satisfaction with pain management should encourage health care providers to reliably discuss pain control with pediatric patients.

Pain care for patients with epidermolysis bullosa: best care practice guidelines.

BACKGROUND: Inherited epidermolysis bullosa (EB) comprises a group of rare disorders that have multi-system effects and patients present with a number of both acute and chronic pain care needs. Effects on quality of life are substantial. Pain and itching are burdensome daily problems. Experience with, and knowledge of, the best pain and itch care for these patients is minimal. Evidence-based best care practice guidelines are needed to establish a base of knowledge and practice for practitioners of many disciplines to improve the quality of life for both adult and pediatric patients with EB. METHODS: The process was begun at the request of Dystrophic Epidermolysis Bullosa Research Association International (DEBRA International), an organization dedicated to improvement of care, research and dissemination of knowledge for EB patients worldwide. An international panel of experts in pain and palliative care who have extensive experience caring for patients with EB was assembled. Literature was reviewed and systematically evaluated. For areas of care without direct evidence, clinically relevant literature was assessed, and rounds of consensus building were conducted. The process involved a face-to-face consensus meeting that involved a family representative and methodologist, as well as the panel of clinical experts. During development, EB family input was obtained and the document was reviewed by a wide variety of experts representing several disciplines related to the care of patients with EB. RESULTS: The first evidence-based care guidelines for the care of pain in EB were produced. The guidelines are clinically relevant for care of patients of all subtypes and ages, and apply to practitioners of all disciplines involved in the care of patients with EB. When the evidence suggests that the diagnosis or treatment of painful conditions differs between adults and children, it will be so noted. CONCLUSIONS: Evidence-based care guidelines are a means of standardizing optimal care for EB patients, whose disease is often times horrific in its effects on quality of life, and whose care is resource-intensive and difficult. The guideline development process also highlighted areas for research in order to improve further the evidence base for future care.

Home Milrinone in Pediatric Hospice Care of Children with Heart Failure.

CONTEXT: The symptom profile of children dying from cardiac disease, especially heart failure, differs from those with cancer and other non-cardiac conditions. Treatment with vasoactive infusions at home may be a superior therapy for symptom control for these patients, rather than traditional pain and anxiety management with morphine and benzodiazepines. OBJECTIVES: We report our experience using outpatient milrinone in children receiving hospice care for end-stage heart failure. METHODS: Retrospective review of a contemporary cohort of all patients at Lucile Packard Children's Hospital, Stanford who were discharged on intravenous milrinone and hospice care between 2008 and 2021. Clinical data, including cardiac diagnosis, milrinone dose and route of administration, total milrinone days, symptoms reported, rehospitalization rates, concurrent therapies and complications were analyzed. RESULTS: Among 8 patients, median duration of home milrinone infusion was 191 (33, 572) days with the longest support duration 1,054 days. All (100%) patients were also receiving diuretics at the time of death. Five (63%) were receiving no other pain control medications until the active phase of dying. From milrinone initiation to last outpatient assessment, a reduction in the number of patients reporting respiratory discomfort, abdominal pain, weight loss/lack of appetite, and fatigue was observed. Six (75%) died at home. CONCLUSION: We used milrinone with oral diuretics effectively for symptom control in children with heart failure on palliative care. Our experience was that this combination can be used safely in the outpatient setting for long-term use without the addition of opiates, benzodiazepines, or supplemental oxygen in most cases.

A1 adenosine receptor upregulation accompanies decreasing myocardial adenosine levels in mice with left ventricular dysfunction.

BACKGROUND: It is well known that adenosine levels are increased during ischemia and protect the heart during ischemia/reperfusion. However, less is known about the role of adenosine-adenosine receptor (AR) pathways in hearts with left ventricular dilation and dysfunction. Therefore, we assessed adenosine levels and selective AR expression in transgenic mice with left ventricular systolic dysfunction secondary to overexpression of tumor necrosis factor-alpha (TNF 1.6). METHODS AND RESULTS: Cardiac adenosine levels were reduced by 70% at 3 and 6 weeks of age in TNF 1.6 mice. This change was accompanied by a 4-fold increase in the levels of A1-AR and a 50% reduction in the levels of A2A-AR. That the increase in A1-AR density was of physiological significance was shown by the fact that chronotropic responsiveness to the A1-AR selective agonist 2-chloro-N6-cyclopentanyladenosine was enhanced in the TNF 1.6 mice. Similar changes in adenosine levels were found in 2 other models of heart failure, mice overexpressing calsequestrin and mice after chronic pressure overload, suggesting that the changes in adenosine-AR signaling were secondary to myocardial dysfunction rather than to TNF overexpression. CONCLUSIONS: Cardiac dysfunction secondary to the overexpression of TNF is associated with marked alterations in myocardial levels of adenosine and ARs. Modulation of the myocardial adenosine system and its signaling pathways may be a novel therapeutic target in patients with heart failure.

Regulated overexpression of the A1-adenosine receptor in mice results in adverse but reversible changes in cardiac morphology and function.

BACKGROUND: Both the A1- and A3-adenosine receptors (ARs) have been implicated in mediating the cardioprotective effects of adenosine. Paradoxically, overexpression of both A1-AR and A3-AR is associated with changes in the cardiac phenotype. To evaluate the temporal relationship between AR signaling and cardiac remodeling, we studied the effects of controlled overexpression of the A1-AR using a cardiac-specific and tetracycline-transactivating factor-regulated promoter. METHODS AND RESULTS: Constitutive A1-AR overexpression caused the development of cardiac dilatation and death within 6 to 12 weeks. These mice developed diminished ventricular function and decreased heart rate. In contrast, when A1-AR expression was delayed until 3 weeks of age, mice remained phenotypically normal at 6 weeks, and >90% of the mice survived at 30 weeks. However, late induction of A1-AR still caused mild cardiomyopathy at older ages (20 weeks) and accelerated cardiac hypertrophy and the development of dilatation after pressure overload. These changes were accompanied by gene expression changes associated with cardiomyopathy and fibrosis and by decreased Akt phosphorylation. Discontinuation of A1-AR induction mitigated cardiac dysfunction and significantly improved survival rate. CONCLUSIONS: These data suggest that robust constitutive myocardial A1-AR overexpression induces a dilated cardiomyopathy, whereas delaying A1-AR expression until adulthood ameliorated but did not eliminate the development of cardiac pathology. Thus, the inducible A1-AR transgenic mouse model provides novel insights into the role of adenosine signaling in heart failure and illustrates the potentially deleterious consequences of selective versus nonselective activation of adenosine-signaling pathways in the heart.

Psychiatric medications for the treatment of pruritus.

OBJECTIVES: To review the use of psychiatric medications in the treatment of pruritus. METHODS: A literature review was conducted using the key words pruritus, psychiatric, and treatment. RESULTS: Three categories of pruritus are described: dermatologic, systemic, and psychogenic. Peripheral and central nervous system mechanisms of pruritus are reviewed. Conventional dermatologic treatments for pruritus are contrasted with some of the common psychopharmacologic treatment modalities that include anxiolytic, antidepressant, and antipsychotic agents. A treatment algorithm is offered to help guide the treatment of patients with pruritus. CONCLUSIONS: Psychiatric medications have been used successfully in the treatment of pruritus that is associated with both psychocutaneous and systemic disorders, which are resistant to conventional treatment.

Training Pediatric Fellows in Palliative Care: A Pilot Comparison of Simulation Training and Didactic Education.

BACKGROUND: Pediatric fellows receive little palliative care (PC) education and have few opportunities to practice communication skills. OBJECTIVE: In this pilot study, we assessed (1) the relative effectiveness of simulation-based versus didactic education, (2) communication skill retention, and (3) effect on PC consultation rates. DESIGN: Thirty-five pediatric fellows in cardiology, critical care, hematology/oncology, and neonatology at two institutions enrolled: 17 in the intervention (simulation-based) group (single institution) and 18 in the control (didactic education) group (second institution). Intervention group participants participated in a two-day program over three months (three simulations and videotaped PC panel). Control group participants received written education designed to be similar in content and time. MEASUREMENTS: (1) Self-assessment questionnaires were completed at baseline, post-intervention and three months; mean between-group differences for each outcome measure were assessed. (2) External reviewers rated simulation-group encounters on nine communication domains. Within-group changes over time were assessed. (3) The simulation-based site's PC consultations were compared in the six months pre- and post-intervention. RESULTS: Compared to the control group, participants in the intervention group improved in self-efficacy (p = 0.003) and perceived adequacy of medical education (p < 0.001), but not knowledge (p = 0.20). Reviewers noted nonsustained improvement in four domains: relationship building (p = 0.01), opening discussion (p = 0.03), gathering information (p = 0.01), and communicating accurate information (p = 0.04). PC consultation rate increased 64%, an improvement when normalized to average daily census (p = 0.04). CONCLUSIONS: This simulation-based curriculum is an effective method for improving PC comfort, education, and consults. More frequent practice is likely needed to lead to sustained improvements in communication competence.

Comparison of near-infrared and laser-induced breakdown spectroscopy for determination of magnesium stearate in pharmaceutical powders and solid dosage forms.

Near-infrared (NIR) spectroscopy has become well established in both the pharmaceutical arena and other areas as a useful technique for rapid quantitative analysis of solid materials. Though laser-induced breakdown spectroscopy (LIBS) has not been widely applied in the pharmaceutical industry, the technique has been used for rapid quantitative analysis of solids in many other applications. One analysis amenable to each technique is the determination of magnesium stearate in solids during the lubrication blending unit operation of pharmaceutical processing. A comparative study of the utility of these two techniques for this application will be presented. Necessary sample preparations and the extent and type of matrix effects will be discussed. Additionally, it will be shown that NIR provides better accuracy and precision than LIBS with the experimental parameters used; however, LIBS showed superior selectivity as it was demonstrated to be more robust to sample matrix perturbations. Examples of blending applications will also be presented.

Improved pain management in pediatric postoperative liver transplant patients using parental education and non-pharmacologic interventions.

A pain management intervention, consisting of pretransplant parental education and support, pre- and postoperative behavioral pediatrics consultation, postoperative physical and occupational therapy consultation, and implementation of non-pharmacologic pain management strategies, was introduced to all pediatrics patients receiving liver transplants at Lucile Packard Children's Hospital beginning August 2001. Children receiving transplants pre-intervention (May, 2000 to February, 2001) and post-intervention (August, 2001 to March, 2002) were compared using pain scores, parent perception of pain ratings, length of stay, ventilator days, total cost, and opioid use. A total of 27 children were evaluated (13 historical control, 14 intervention). The two populations did not differ on age at transplant (mean age 53.8 vs. 63.6 months), sex (46.1% vs. 50% male), ethnicity (53.8% vs. 57.1% white, non-Hispanic) weight at transplant (17.5 vs. 24.7 kg), percent with biliary atresia as the primary reason for transplant (42.9% vs. 69.2%), percent with status 1 transplant listing score (38.5% vs. 50.0%), or public insurance status (30.8 vs. 57.2% with Medicaid). No differences were found in mean pediatric intensive care unit (PICU) postoperative length of stay (6.7 vs. 5.3 days), total postoperative length of stay (17.5 vs. 17.5 days), total inpatient length of stay (27.0 vs. 24.4 days), time to extubation (30 vs. 24.3 h), total cost (dollar 147,983 vs. dollar 157,882) or opioid use through postoperative day (POD) 6 (0.24 vs. 0.25 mg/kg/day morphine equivalent). A decrease in mean pain score between POD 0 and 6 (2.82 vs. 2.12; p = 0.047), a decrease in mean parental pain perception score (3.1 vs. 2.1; p = 0.001), and an increase in number of pain assessments per 12 h shift (3.43 vs. 6.79; p < 0.005) were seen. A comprehensive non-pharmacologic postoperative pain management program in children receiving a liver transplant was associated with decreased pain scores, improved parent perception of pain, and an increased number of pain assessments per 12 h shift. No increases in lengths of stay (PICU, postoperative, total), time to extubation, or total cost were found.