Retromer Stabilization Improves Cognitive Function and Synaptic Plasticity in a Mouse Model of Down Syndrome.

BACKGROUND: Retromer complex proteins are decreased in postmortem brain tissues from Down syndrome subjects and inversely correlate with the Alzheimer's disease-like neuropathology. However, whether targeting in vivo the retromer system affects cognitive deficits and synaptic function in Down syndrome remains unknown. OBJECTIVE: The aim of the current study was to examine the effects of pharmacological retromer stabilization on cognitive and synaptic functions in a mouse model of Down syndrome. METHODS: Ts65dn mice were administered the pharmacological chaperone, TPT-172, or vehicle from 4 to 9 months of age and then assessed for changes in cognitive function. To assess the effects of TPT-172 on synaptic plasticity, hippocampal slices from Ts65dn mice were incubated in TPT-172 and used for field potential recordings. RESULTS: Chronic TPT-172 treatment improved performance in cognitive function tests, its incubation with hippocampal slices ameliorated synaptic function response. CONCLUSION: Pharmacological stabilization of the retromer complex improves synaptic plasticity and memory in a mouse model of Down syndrome. These results support the therapeutic potential of pharmacological retromer stabilization for individual with Down syndrome.

A new multiplex qPCR assay to detect and differentiate big cat species in the illegal wildlife trade.

All species of big cats, including tigers, cheetahs, leopards, lions, snow leopards, and jaguars, are protected under the Convention on the International Trade in Endangered Species (CITES). This is due in large part to population declines resulting from anthropogenic factors, especially poaching and the unregulated and illegal trade in pelts, bones, teeth and other products that are derived from these iconic species. To enhance and scale up monitoring for big cat products in this trade, we created a rapid multiplex qPCR test that can identify and differentiate DNA from tiger (Panthera tigris), cheetah (Acinonyx jubatus), leopard (Panthera pardus), lion (Panthera leo), snow leopard (Panthera uncia), and jaguar (Panthera onca) in wildlife products using melt curve analysis to identify each species by its unique melt peak temperature. Our results showed high PCR efficiency (> 90%), sensitivity (detection limit of 5 copies of DNA per PCR reaction) and specificity (no cross amplification between each of the 6 big cat species). When paired with a rapid (< 1 h) DNA extraction protocol that amplifies DNA from bone, teeth, and preserved skin, total test time is less than three hours. This test can be used as a screening method to improve our understanding of the scale and scope of the illegal trade in big cats and aid in the enforcement of international regulations that govern the trade in wildlife and wildlife products, both ultimately benefiting the conservation of these species worldwide.

Improving Small-Volume Antibiotic Administration for Surgical Prophylaxis: A Quality Improvement Project.

No clear policy on administration methods for small-volume intravenous antibiotic bags (≤ 100 mL) for surgical prophylaxis lead to wide variation in anesthesia provider practice at a large academic medical center. Administration via secondary tubing is the recommended practice to minimize significant medication losses from dead volumes. An observation of current practice and measurements of dead volumes was followed by an educational intervention on best practices for administration of small-volume antibiotics. Three postintervention cycles were conducted to evaluate change in practice and reductions in dead volumes over a 6-week period. Mean dead volume losses were evaluated using one-way ANOVA. Statistically significant (P = .0012) decreases in dead volume losses were observed postintervention, from 8.48 mL (SD 6.80) to 0.93 mL (SD 1.46). The most common pre- and postintervention tubing sets used were primary tubing (pre) and secondary tubing (post). Mean dead volume losses for these respective tubing sets were 13.45 mL (SD 4.74) and 0.79 mL (SD 1.40) (P < .0001). Preintervention administration methods resulted in incomplete antibiotic administration. Overall, there was a significant reduction in dead volumes of antibiotic by changing practice to secondary tubing. With strong provider acceptance and sustained reduction in medication wastage, this intervention has shown to be a beneficial new practice moving forward.

Development of a structured musculoskeletal and rheumatic disease continuing education program for nurse practitioners.

ABSTRACT: The workforce shortage of musculoskeletal and rheumatic disease (MSK-RMD) trained providers has led to the need for additional education for nurse practitioners (NPs) in MSK-RMD. An educational certificate was developed and implemented collaboratively between an academic medical center and a college of nursing. The NP-focused MSK-RMD education program enhanced the assessment and treatment of a variety of common RSK-RMD conditions. Interviews and online surveys were conducted with participants to evaluate the program experience. Participant interviews and survey findings demonstrate overall NP satisfaction with the program. Expanding the program to create an accessible virtual continuing education course may improve accessibility of MSK-RMD education for NPs in primary care and multidisciplinary environments.

Dysfunction of the retromer complex system contributes to amyloid and tau pathology in a stem cell model of Down syndrome.

Introduction: Retromer complex proteins are decreased in Down syndrome (DS) brains and correlate inversely with brain amyloidosis. However, whether retromer dysfunction contributes to the amyloid beta (Aß) and tau neuropathology of DS remains unknown. Methods: Human trisomic induced Pluripotent Stem Cells (iPSCs) and isogenic controls were differentiated into forebrain neurons, and changes in retromer proteins, tau phosphorylated epitopes, and Aß levels were assessed in euploid and trisomic neurons using western blot and enzyme-linked immunosorbent assay (ELISA). Genetic overexpression and pharmacological retromer stabilization were used to determine the functional role of the retromer complex system in modulating amyloid and tau pathology. Results: Trisomic neurons developed age-dependent retromer core protein deficiency associated with accumulation of Aß peptides and phosphorylated tau isoforms. Enhancing retromer function through overexpression or pharmacological retromer stabilization reduced amyloid and tau pathology in trisomic neurons. However, the effect was greater using a pharmacological approach, suggesting that targeting the complex stability may be more effective in addressing this neuropathology in DS. Discussion: Our results demonstrate that the retromer complex is directly involved in the development of the neuropathologic phenotype in DS, and that pharmacological stabilization of the complex should be considered as a novel therapeutic tool in people with DS.

Association of Retromer Deficiency and Tau Pathology in Down Syndrome.

Retromer deficiency is reported in Down syndrome and correlates with amyloidosis, however, its association with tau neuropathology remains unclear. Down syndrome and control brain tissues were evaluated for phosphorylated tau, tau modulators, and cathepsin-D activity. Several kinases and phosphatase PP2A were unchanged, but tau phosphorylation was elevated, and cathepsin-D activity decreased in aged patients with Down syndrome. Retromer proteins positively associated with soluble tau, whereas pathogenic tau negatively correlated with retromer proteins and cathepsin-D activity. Retromer deficiency and consequent reduction of cathepsin-D activity may contribute to pathogenic tau accumulation, thus, retromer represents a viable therapeutic target against tau pathology in Down syndrome. ANN NEUROL 2022;91:561-567.

School Nurse Poverty Education: Why It Is Important to Your Practice.

School nurses are seeing increased numbers of children who are living in poverty. The Missouri Community Action Program Poverty Simulation was presented to school nurses to increase their awareness of what it might be like to live in poverty and the related healthcare barriers. Participants shared their reactions and knowledge gained in the simulation in a postparticipation survey with the simulation facilitators. Some participants shared practice changes that they made as a result of their participation in the simulation, which included use of additional referral resources, being less judgmental, and increased empathy.

Gestational high fat diet protects 3xTg offspring from memory impairments, synaptic dysfunction, and brain pathology.

Maternal history for sporadic Alzheimer's disease (AD) predisposes the offspring to the disease later in life. However, the mechanisms behind this phenomenon are still unknown. Lifestyle and nutrition can directly modulate susceptibility to AD. Herein we investigated whether gestational high fat diet influences the offspring susceptibility to AD later in life. Triple transgenic dams were administered high fat diet or regular chow throughout 3 weeks gestation. Offspring were fed regular chow throughout their life and tested for spatial learning and memory, brain amyloidosis, tau pathology, and synaptic function. Gestational high fat diet attenuated memory decline, synaptic dysfunction, amyloid-ß and tau neuropathology in the offspring by transcriptional regulation of BACE-1, CDK5, and tau gene expression via the upregulation of FOXP2 repressor. Gestational high fat diet protects offspring against the development of the AD phenotype. In utero dietary intervention could be implemented as preventative strategy against AD.

Development and feasibility of a community pharmacy-driven 24-hour ambulatory blood pressure monitoring service.

BACKGROUND: Although 24-hour ambulatory blood pressure monitoring (ABPM) is recommended by practice guidelines, access to ABPM is poor in the United States. Other countries have increased ABPM access by making it available in community pharmacies. It is not known if a similar approach is feasible in the United States. OBJECTIVE: The objective of this study was to develop and evaluate the feasibility of a community pharmacy-driven ABPM service in the United States. SETTING: Two independent community pharmacies. PRACTICE DESCRIPTION: The ABPM service was developed through a collaboration between an academic partner and the clinical service leads of each pharmacy. Eligible patients were those referred by their provider or self-referred for white coat, masked, or sustained hypertension (HTN), symptoms of hypotension, or requiring confirmation of an initial diagnosis of HTN. The service was appointment-based, and the pharmacist sent the ABPM results and interpretation to the referring provider via facsimile. PRACTICE INNOVATION: This is the first description of a community pharmacy-driven ABPM service in the United States. EVALUATION: Descriptive statistics were used to summarize the data for the baseline demographics, ABPM findings, and a 9-question patient satisfaction survey. RESULTS: A total of 52 patients with a mean (SD) age of 56.6 (16.1) years, 50% women, 75% white, and 71.2% with a prior diagnosis of HTN were enrolled. Forty-six patients (88.5%) had successful ABPM readings with the most common blood pressure phenotypes being nocturnal HTN (91.3%), nondipper (52.1%), sustained HTN (41.3%), normotensive (23.9%), and white coat HTN (19.6%). Overall, 88% of the patients strongly agreed or agreed that they were very satisfied with their experience using the ABPM service. CONCLUSION: A community pharmacy-driven ABPM service is feasible in the United States and may be one approach to improve access to ABPM.

Dysregulation of the Retromer Complex System in Down Syndrome.

OBJECTIVE: Most of the patients with Down syndrome (DS) develop Alzheimer's disease (AD) neuropathology by age 40. Although this increased susceptibility to AD in DS is thought to be primarily due to triplication of the amyloid precursor protein located on chromosome 21, the precise molecular mechanisms are not well understood. Recent evidence has implicated defective protein sorting and trafficking secondary to deficiencies in retromer complex proteins in AD pathogenesis. Thus, the objective of the present study is to assess the retromer complex system in DS. METHODS: Human postmortem brain tissue and fibroblasts from subjects with DS and healthy controls were examined for the various retromer protein components using Western blot analysis and reverse transcription quantitative polymerase chain reaction (RT-qPCR). RESULTS: Retromer recognition core proteins were significantly decreased in DS fibroblasts, and in both the hippocampi and cortices of young (age 15-40 years old) and aged (40-65 years old) subjects with DS compared with controls. Correlation analyses showed a significant inverse relationship between recognition core proteins and levels of soluble forms of Aß 1-40 and 1-42 in both hippocampus (n = 33, Spearman = -0.59 to -0.38, p ≤ 0.03 for VPS35, VPS26, VPS29, and VPS26B) and cortex tissue (n = 57, Spearman = -0.46 to -0.27, p ≤ 0.04 for VPS35, VPS26, and VPS29) of the same patients. INTERPRETATION: We conclude that dysregulation of the retromer complex system is an early event in the development of the AD-like pathology and cognitive decline in DS, and for this reason the system could represent a novel potential therapeutic target for DS. ANN NEUROL 2020 ANN NEUROL 2020;88:137-147.

Autophagy Dysfunction in Alzheimer's Disease: Mechanistic Insights and New Therapeutic Opportunities.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory loss due to aberrant accumulation of misfolded proteins inside and outside neurons and glial cells, leading to a loss of cellular protein homeostasis. Today, no therapy is available to block or slow down AD progression, and the mechanisms of the disease are not fully understood. Autophagy is an intracellular degradation pathway crucial to maintaining cellular homeostasis by clearing damaged organelles, pathogens, and unwanted protein aggregates. In recent years, autophagy dysfunction has gained considerable attention in AD and other neurodegenerative diseases because it has been linked to the accumulation of misfolded proteins that ultimately causes neuronal death in many of these disorders. Interestingly, autophagy-activating compounds have also shown some promising results in both clinical trials and preclinical studies. This review aims at summarizing the current knowledge on autophagy dysfunction in the context of AD pathophysiology, providing recent mechanistic insights on AD-mediated autophagic flux disruption and highlighting potential and novel therapeutic opportunities that target this system for AD therapy.

Development of a nurse-led ultrasound-guided peripheral intravenous program.

Establishing reliable peripheral intravenous access is one of the most common procedures performed daily by nurses across clinical settings in the hospital. The insertion of peripheral intravenous access devices is usually guided by palpation, direct visualization, landmark technique, or by trial and error. The invasive nature of the procedure accompanied by the associated risks requires successful cannulation on the initial attempt. In an effort to decrease the number of peripheral venous access attempts in patients with difficult venous access, a course was developed to educate a cohort of registered nurses on the basic principles and use of ultrasound. After successful completion of the course, each registered nurse was required to perform a minimum of 10 proctored successful ultrasound venous peripheral intravenous catheter insertions. The first attempt success rate for the proctored ultrasound venous peripheral intravenous catheter attempts was 83%, which was higher than that reported in the literature (20%-50%). Overall, the program effectively demonstrated a decrease in the number of attempts required to insert a peripheral venous catheter in patients with difficult venous access.

Pharmacological Properties of Chromobacterium violaceum Violacein at the Human Serotonin 2C Receptor.

The monoamine neurotransmitter serotonin (5-HT) plays a role in many physiological responses by interacting with various receptor subtypes. The 5-HT2C receptor subtype is a 7-transmembrane, G protein-coupled receptor (GPCR) that is involved in neuronal excitability, spatial learning, mood, and appetite. The microorganism Chromobacterium violaceum produces a purple pigment, violacein, which can be extracted and purified. Violacein has antibiotic, antileishmanial, antifungal and antitumoral properties in various cancer cell lines. Violacein is derived from the amino acid tryptophan as is 5-HT and therefore, the two have similar chemical structures. However, no one has reported the activity of violacein at 5-HT receptors. Therefore the Fentress lab decided to investigate whether or not violacein had an effect on 5-HT2C receptor trafficking. Human Embryonic Kidney (HEK) 293 cells expressing fluorescently-tagged 5-HT2C receptor were treated with 5-HT, violacein, water or vehicle and then cells were fixed and visualized with fluorescent microscopy. Violacein treatment did not cause receptor internalization. Recent studies suggest that the 5-HT2C receptor can activate the JAK/STAT pathway. To see if violacein can modulate this pathway, HEK 293 cells expressing 5-HT2C receptor were treated with either 5-HT, violacein, or pretreated with violacein followed by incubation with 5-HT. Phosphorylation states of JAK2 and STAT3 were examined by immunoblotting. Results determined that 5-HT2C receptor activation had no effect on JAK2 phosphorylation and that violacein blocked STAT3 phosphorylation. Primary radioligand binding determined that violacein has a low affinity for 5-HT2C receptor but has a higher affinity for adrenergic receptors. Future studies will examine G protein-coupling by measuring phosphoinositide hydrolysis and cAMP assay to investigate adrenergic pathways.

Noninvasive Immunometabolic Cardiac Inflammation Imaging Using Hyperpolarized Magnetic Resonance.

RATIONALE: Current cardiovascular clinical imaging techniques offer only limited assessment of innate immune cell-driven inflammation, which is a potential therapeutic target in myocardial infarction (MI) and other diseases. Hyperpolarized magnetic resonance (MR) is an emerging imaging technology that generates contrast agents with 10- to 20 000-fold improvements in MR signal, enabling cardiac metabolite mapping. OBJECTIVE: To determine whether hyperpolarized MR using [1-13C]pyruvate can assess the local cardiac inflammatory response after MI. METHODS AND RESULTS: We performed hyperpolarized [1-13C]pyruvate MR studies in small and large animal models of MI and in macrophage-like cell lines and measured the resulting [1-13C]lactate signals. MI caused intense [1-13C]lactate signal in healing myocardial segments at both day 3 and 7 after rodent MI, which was normalized at both time points after monocyte/macrophage depletion. A near-identical [1-13C]lactate signature was also seen at day 7 after experimental MI in pigs. Hyperpolarized [1-13C]pyruvate MR spectroscopy in macrophage-like cell suspensions demonstrated that macrophage activation and polarization with lipopolysaccharide almost doubled hyperpolarized lactate label flux rates in vitro; blockade of glycolysis with 2-deoxyglucose in activated cells normalized lactate label flux rates and markedly inhibited the production of key proinflammatory cytokines. Systemic administration of 2-deoxyglucose after rodent MI normalized the hyperpolarized [1-13C]lactate signal in healing myocardial segments at day 3 and also caused dose-dependent improvement in IL (interleukin)-1ß expression in infarct tissue without impairing the production of key reparative cytokines. Cine MRI demonstrated improvements in systolic function in 2-DG (2-deoxyglucose)-treated rats at 3 months. CONCLUSIONS: Hyperpolarized MR using [1-13C]pyruvate provides a novel method for the assessment of innate immune cell-driven inflammation in the heart after MI, with broad potential applicability across other cardiovascular disease states and suitability for early clinical translation.

Designing Integrated Courses in an RN-to-BSN Program.

Three faculty members and an instructional designer collaborated to develop and implement first-term courses in a newly revised RN-to-bachelor of science in nursing curriculum. The ADDIE model served as the organizing framework for course development. Student assessment was approached in a novel manner, using integrated assignments that spanned each course. Students were able to demonstrate that objectives for all three courses were met, while synthesizing and applying their newly gained knowledge and skills. J Contin Educ Nurs. 2017;48(8):369-372.

Molecular Mechanisms of Obesity-Induced Osteoporosis and Muscle Atrophy.

Obesity and osteoporosis are two alarming health disorders prominent among middle and old age populations, and the numbers of those affected by these two disorders are increasing. It is estimated that more than 600 million adults are obese and over 200 million people have osteoporosis worldwide. Interestingly, both of these abnormalities share some common features including a genetic predisposition, and a common origin: bone marrow mesenchymal stromal cells. Obesity is characterized by the expression of leptin, adiponectin, interleukin 6 (IL-6), interleukin 10 (IL-10), monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), macrophage colony stimulating factor (M-CSF), growth hormone (GH), parathyroid hormone (PTH), angiotensin II (Ang II), 5-hydroxy-tryptamine (5-HT), Advance glycation end products (AGE), and myostatin, which exert their effects by modulating the signaling pathways within bone and muscle. Chemical messengers (e.g., TNF-α, IL-6, AGE, leptins) that are upregulated or downregulated as a result of obesity have been shown to act as negative regulators of osteoblasts, osteocytes and muscles, as well as positive regulators of osteoclasts. These additive effects of obesity ultimately increase the risk for osteoporosis and muscle atrophy. The aim of this review is to identify the potential cellular mechanisms through which obesity may facilitate osteoporosis, muscle atrophy and bone fractures.

The von Hippel-Lindau Chuvash mutation in mice alters cardiac substrate and high-energy phosphate metabolism.

Hypoxia-inducible factor (HIF) appears to function as a global master regulator of cellular and systemic responses to hypoxia. HIF pathway manipulation is of therapeutic interest; however, global systemic upregulation of HIF may have as yet unknown effects on multiple processes. We used a mouse model of Chuvash polycythemia (CP), a rare genetic disorder that modestly increases expression of HIF target genes in normoxia, to understand what these effects might be within the heart. An integrated in and ex vivo approach was employed. Compared with wild-type controls, CP mice had evidence (using in vivo magnetic resonance imaging) of pulmonary hypertension, right ventricular hypertrophy, and increased left ventricular ejection fraction. Glycolytic flux (measured using [(3)H]glucose) in the isolated contracting perfused CP heart was 1.8-fold higher. Net lactate efflux was 1.5-fold higher. Furthermore, in vivo (13)C-magnetic resonance spectroscopy (MRS) of hyperpolarized [(13)C1]pyruvate revealed a twofold increase in real-time flux through lactate dehydrogenase in the CP hearts and a 1.6-fold increase through pyruvate dehydrogenase. (31)P-MRS of perfused CP hearts under increased workload (isoproterenol infusion) demonstrated increased depletion of phosphocreatine relative to ATP. Intriguingly, no changes in cardiac gene expression were detected. In summary, a modest systemic dysregulation of the HIF pathway resulted in clear alterations in cardiac metabolism and energetics. However, in contrast to studies generating high HIF levels within the heart, the CP mice showed neither the predicted changes in gene expression nor any degree of LV impairment. We conclude that the effects of manipulating HIF on the heart are dose dependent.

Risk of Neurological Injuries in Spinal Deformity Surgery.

STUDY DESIGN: A retrospective study. OBJECTIVE: Rate of neurological injuries is widely reported for spinal deformity surgery. However, few have included the influence of the subtypes and severity of the deformity, or anterior versus posterior corrections. The purpose of this study is to quantify these risks. SUMMARY OF BACKGROUND DATA: The risk of neurological injuries was examined in a single institution. Quantification of risk was made between operations, and for different subtypes of spinal deformity. METHODS: Prospectively entered neuromonitoring database between 2006 and 2012 was interrogated, including all deformity cases under 21 years of age. Tumor, fracture, infection, and revision cases were excluded. All major changes in monitoring ("red alerts") were identified and detailed examinations of the neuromonitoring records, clinical notes, and radiographs were made. Diagnosis, deformity severity, and operative details were recorded. RESULTS: Of 2291 deformity operations, there were 2068 scoliosis (1636 idiopathic, 204 neuromuscular, 216 syndromic, 12 others), 89 kyphosis, 54 growing rod procedures, and 80 operations for hemivertebra. Six hundred ninety-six anterior and 1363 posterior operations were performed for scoliosis (nine not recorded), and 38 anterior and 51 posterior kyphosis corrections. Sixty-seven "red alerts" were identified (62 posterior, five anterior). Average Cobb angle was 88°. There were 14 transient and six permanent neurological injuries. One permanent injury was sustained during kyphosis correction and five during scoliosis correction. Common surgeon reactions after "red alerts" were surgical pause with anesthetic interventions (n = 39) and the Stagnara wake-up test (n = 22). Metalwork was partially removed in 20, revised in 12, and completely removed in nine. Thirteen procedures were abandoned. CONCLUSION: The overall risk of permanent neurological injury was 0.2%. The highest risk groups were posterior corrections for kyphosis, and scoliosis associated with a syndrome. Four percent of all posterior deformity corrections had "red alerts," and 0.3% resulted in permanent injuries compared with 0.6% "red alerts" and 0.3% permanent injuries for anterior surgery. The overall risk for idiopathic scoliosis was 0.06%. LEVEL OF EVIDENCE: 3.