Drosophila melanogaster models of MPS IIIC (Hgsnat-deficiency) highlight the role of glia in disease presentation.

Sanfilippo syndrome (Mucopolysaccharidosis type III or MPS III) is a recessively inherited neurodegenerative lysosomal storage disorder. Mutations in genes encoding enzymes in the heparan sulphate degradation pathway lead to the accumulation of partially degraded heparan sulphate, resulting ultimately in the development of neurological deficits. Mutations in the gene encoding the membrane protein heparan-α-glucosaminide N-acetyltransferase (HGSNAT; EC2.3.1.78) cause MPS IIIC (OMIM#252930), typified by impaired cognition, sleep-wake cycle changes, hyperactivity and early death, often before adulthood. The precise disease mechanism that causes symptom emergence remains unknown, posing a significant challenge in the development of effective therapeutics. As HGSNAT is conserved in Drosophila melanogaster, we now describe the creation and characterisation of the first Drosophila models of MPS IIIC. Flies with either an endogenous insertion mutation or RNAi-mediated knockdown of hgsnat were confirmed to have a reduced level of HGSNAT transcripts and age-dependent accumulation of heparan sulphate leading to engorgement of the endo/lysosomal compartment. This resulted in abnormalities at the pre-synapse, defective climbing and reduced overall activity. Altered circadian rhythms (shift in peak morning activity) were seen in hgsnat neuronal knockdown lines. Further, when hgsnat was knocked down in specific glial subsets (wrapping, cortical, astrocytes or subperineural glia), impaired climbing or reduced activity was noted, implying that hgsnat function in these specific glial subtypes contributes significantly to this behaviour and targeting treatments to these cell groups may be necessary to ameliorate or prevent symptom onset. These novel models of MPS IIIC provide critical research tools for delineating the key cellular pathways causal in the onset of neurodegeneration in this presently untreatable disorder.

The Contribution of Psychological Resilience and Job Meaningfulness to Well-being of Working Cancer Survivors.

BACKGROUND: Although studies suggest that cancer survivors face workplace obstacles, to date there has been little empirical research regarding the personal and environmental factors that can help cancer survivors adjust to work. The purpose of this study was to examine how working survivors' resilience and job meaningfulness were related to their well-being outcomes, including lower cancer-related intrusive thoughts, fatigue, and presenteeism. METHODS: We recruited 200 full-time employed cancer survivors from online participant panels using Qualtrics. Participants responded to an online survey that measured their resilience, job meaningfulness, job-related psychological distress, and well-being outcomes. We conducted descriptive statistical analysis, confirmatory factor analysis, and moderated mediated analysis to examine the psychological process in which resilience and job meaning are associated with cancer survivors' mental health and work outcomes. Findings: The relationship between cancer survivors' resilience and their well-being outcomes depended on job meaningfulness. For survivors whose jobs were not highly meaningful, their resilience was related to reduced job-related psychological distress, which, in turn, was related to lower intrusive thoughts, fatigue, and presenteeism. For survivors with highly meaningful jobs, they did not need to rely on resilience to protect them from workplace psychological distress and other negative outcomes. Conclusion/Application to Practice: It is important for working cancer survivors to develop resilience, especially when they do not perceive their work as highly meaningful. Successful resilience-building interventions can buffer the negative impact of low job meaningfulness and help working survivors achieve better outcomes. In addition, organizations can actively help enrich survivors' jobs to increase perceived meaningfulness.

Antibiotic stewardship for urinary tract infection: A program evaluation.

Evidence supporting the use of antibiotic stewardship programs (ASP) is growing in a variety of healthcare settings for its association with improved patient outcomes, decreased resistance, and improved healthcare costs. There have been few studies supporting this evidence in long-term care facilities. This project involved a program evaluation of a long-term care facility's ASP for urinary tract infection (UTI) management. Improvement in appropriate diagnosing and antibiotic prescribing for UTI was noted, but no conclusions could be made regarding the effect on patient outcomes. The ASP was considered beneficial in this facility and highlighted areas for improvement, notably the need for sustained commitment by facility leadership and healthcare providers. Nurse practitioners are equipped with the skills necessary to assist facilities with education and implementation of systematic programs for judicious antibiotic prescribing.

Molecular Biology of the WWOX Gene That Spans Chromosomal Fragile Site FRA16D.

It is now more than 20 years since the FRA16D common chromosomal fragile site was characterised and the WWOX gene spanning this site was identified. In this time, much information has been discovered about its contribution to disease; however, the normal biological role of WWOX is not yet clear. Experiments leading to the identification of the WWOX gene are recounted, revealing enigmatic relationships between the fragile site, its gene and the encoded protein. We also highlight research mainly using the genetically tractable model organism Drosophila melanogaster that has shed light on the integral role of WWOX in metabolism. In addition to this role, there are some particularly outstanding questions that remain regarding WWOX, its gene and its chromosomal location. This review, therefore, also aims to highlight two unanswered questions. Firstly, what is the biological relationship between the WWOX gene and the FRA16D common chromosomal fragile site that is located within one of its very large introns? Secondly, what is the actual substrate and product of the WWOX enzyme activity? It is likely that understanding the normal role of WWOX and its relationship to chromosomal fragility are necessary in order to understand how the perturbation of these normal roles results in disease.

Does a Behavioral Parent Training Program for Parents of ADHD Children Improve Outcomes? A Pilot Project.

Attention Deficit Hyperactivity Disorder (ADHD) is the most common chronic neurobehavioral disorder of childhood. Research suggests increased parent-child conflict exists in families with an ADHD child. The evidence indicates links between child behavior problems and parenting practices. Behavioral Parent Training (BPT) is an evidence-based intervention recommended for the treatment of ADHD. BPT is recommended as first-line treatment in ADHD children under age six and as a combination treatment approach for children older than the age six. BPT programs have demonstrated significant improvement in frequency of the problem behaviors of inattention, hyperactivity, and impulsivity associated with ADHD. Pre- and Post-BPT Parenting Scales and Vanderbilt ADHD Diagnostic Rating Scales for Parents and Teachers were used to evaluate the efficacy of the BPT program. Percent changes for each participant pre- and post-BPT were calculated. The Parenting Scale overall score and overreactivity factor score showed significant improvement post-BPT (p = .05). Participation in a BPT program can affect parenting practices and improve outcomes for ADHD children. BPT programs are effective in reducing negative parenting practices and improving outcomes for this population.

Drosophila as a model to understand autophagy deregulation in human disorders.

Autophagy has important functions in normal physiology to maintain homeostasis and protect against cellular stresses by the removal of harmful cargos such as dysfunctional organelles, protein aggregates and invading pathogens. The deregulation of autophagy is a hallmark of many diseases and therapeutic targeting of autophagy is highly topical. With the complex role of autophagy in disease it is essential to understand the genetic and molecular basis of the contribution of autophagy to pathogenesis. The model organism, Drosophila, provides a genetically amenable system to dissect out the contribution of autophagy to human disease models. Here we review the roles of autophagy in human disease and how autophagy studies in Drosophila have contributed to the understanding of pathophysiology.

Choosing the right inhaler for the right patient: Considerations for effective management of patients with chronic obstructive pulmonary disease or asthma.

BACKGROUND AND PURPOSE: Effective management of chronic respiratory disorders such as chronic obstructive pulmonary disease and asthma necessitates that patients inhale their medication. However, lack of detailed guidelines on the technological and mechanical functions of inhalers limits the ability of health care providers (HCPs) to personalize inhaler choice for patients. Numerous types of inhalers are currently available which offer their own distinct advantages and disadvantages. Independent of the drug class, the choice of inhaler may be influenced by many factors (e.g., inhaler attributes and the efficiency with which it delivers the medication, patient characteristics and preferences, dosing regimen, clinical setting, and support available for both patients and HCPs). This article attempts to summarize the inhalation technology and factors influencing inhaler choice and use and to provide an approach for matching the right inhaler to the right patient. CONCLUSIONS: Identifying factors related to inhaler choice is critical to ensuring adherence to treatment and patients' ability to use their inhaler correctly. IMPLICATIONS FOR PRACTICE: This review will help HCPs engage their patients in decision-making for inhaler choice and facilitate selection of the correct inhaler for each patient (i.e., one that they will use).

Non-self mutation: double-stranded RNA elicits antiviral pathogenic response in a Drosophila model of expanded CAG repeat neurodegenerative diseases.

Inflammation is activated prior to symptoms in neurodegenerative diseases, providing a plausible pathogenic mechanism. Indeed, genetic and pharmacological ablation studies in animal models of several neurodegenerative diseases demonstrate that inflammation is required for pathology. However, while there is growing evidence that inflammation-mediated pathology may be the common mechanism underlying neurodegenerative diseases, including those due to dominantly inherited expanded repeats, the proximal causal agent is unknown. Expanded CAG.CUG repeat double-stranded RNA causes inflammation-mediated pathology when expressed in Drosophila. Repeat dsRNA is recognized by Dicer-2 as a foreign or 'non-self' molecule triggering both antiviral RNA and RNAi pathways. Neither of the RNAi pathway cofactors R2D2 nor loquacious are necessary, indicating antiviral RNA activation. RNA modification enables avoidance of recognition as 'non-self' by the innate inflammatory surveillance system. Human ADAR1 edits RNA conferring 'self' status and when co-expressed with expanded CAG.CUG dsRNA in Drosophila the pathology is lost. Cricket Paralysis Virus protein CrPV-1A is a known antagonist of Argonaute-2 in Drosophila antiviral defense. CrPV-1A co-expression also rescues pathogenesis, confirming anti-viral-RNA response. Repeat expansion mutation therefore confers 'non-self' recognition of endogenous RNA, thereby providing a proximal, autoinflammatory trigger for expanded repeat neurodegenerative diseases.

Innovations in Worksite Diagnosis of Urinary Tract Infections and the Occupational Health Nurse.

Occupational health nurses play a key role in evaluating innovative technologies that can aid in providing safe and rapid care and reduce lost work time. A nurse-led employee health clinic participated in a validation study of a novel pathogen detection technique developed by GeneCapture, Inc. Their proposed portable urinary tract infection (UTI) in vitro diagnostic test was challenged with discarded, deidentified urine samples from patients presenting with typical UTI symptoms collected at two university clinics and two multiphysician practices. GeneCapture's panel for this study was designed to rapidly identify the genetic signature of seven organisms: gram-negative Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa; gram-positive Enterococcus faecalis and Staphylococcus aureus; and fungal Candida species. The results from 40 clinical samples were in 95% agreement (90% specificity, 100% sensitivity) with traditional urine culture results from routine analysis. This successful occupational health nursing collaboration and validation study shows promise for point-of-care diagnoses and earlier treatment for workers with UTIs.

Regulation of the Elongation Phase of Protein Synthesis Enhances Translation Accuracy and Modulates Lifespan.

Maintaining accuracy during protein synthesis is crucial to avoid producing misfolded and/or non-functional proteins. The target of rapamycin complex 1 (TORC1) pathway and the activity of the protein synthesis machinery are known to negatively regulate lifespan in many organisms, although the precise mechanisms involved remain unclear. Mammalian TORC1 signaling accelerates the elongation stage of protein synthesis by inactivating eukaryotic elongation factor 2 kinase (eEF2K), which, when active, phosphorylates and inhibits eEF2, which mediates the movement of ribosomes along mRNAs, thereby slowing down the rate of elongation. We show that eEF2K enhances the accuracy of protein synthesis under a range of conditions and in several cell types. For example, our data reveal it links mammalian (m)TORC1 signaling to the accuracy of translation. Activation of eEF2K decreases misreading or termination readthrough errors during elongation, whereas knocking down or knocking out eEF2K increases their frequency. eEF2K also promotes the correct recognition of start codons in mRNAs. Reduced translational fidelity is known to correlate with shorter lifespan. Consistent with this, deletion of the eEF2K ortholog or other factors implicated in translation fidelity in Caenorhabditis elegans decreases lifespan, and eEF2K is required for lifespan extension induced by nutrient restriction. Our data uncover a novel mechanism linking nutrient supply, mTORC1 signaling, and the elongation stage of protein synthesis, which enhances the accuracy of protein synthesis. Our data also indicate that modulating translation elongation and its fidelity affects lifespan.

Successfully Incorporating Interprofessional Education in a Nonacademic Health Sciences Center.

Enhanced patient outcomes have led the health sciences to seek ways in which to incorporate interprofessional education in their curricula. This article presents a unique and innovative strategy for interprofessional education among nursing, medicine, and pharmacy in a nonacademic health science center setting. Nurse practitioner students from the University of Alabama in Huntsville College of Nursing, medical interns from the University of Alabama at Birmingham School of Medicine, and pharmacy students from Auburn University School of Pharmacy and their respective faculty participated in collaboratively designed simulations and skills experiences.

Using Drosophila Models of Amyloid Toxicity to Study Autophagy in the Pathogenesis of Alzheimer's Disease.

Autophagy is a conserved catabolic pathway that involves the engulfment of cytoplasmic components such as large protein aggregates and organelles that are delivered to the lysosome for degradation. This process is important in maintaining neuronal function and raises the possibility of a role for autophagy in neurodegenerative diseases. Alzheimer's disease (AD) is the most prevalent form of these diseases and is characterized by the accumulation of amyloid plaques in the brain which arise due to the misfolding and aggregation of toxic peptides, including amyloid beta (Aß). There is substantial evidence from both AD patients and animal models that autophagy is dysregulated in this disease. However, it remains to be determined whether this is protective or pathogenic as there is evidence that autophagy can act to promote the degradation as well as function in the generation of toxic Aß peptides. Understanding the molecular details of the extensive crosstalk that occurs between the autophagic and endolysosomal cellular pathways is essential for identifying the molecular details of amyloid toxicity. Drosophila models that express the toxic proteins that aggregate in AD have been generated and have been shown to recapitulate hallmarks of the disease. Here we focus on what is known about the role of autophagy in amyloid toxicity in AD from mammalian models and how Drosophila models can be used to further investigate AD pathogenesis.

Neuronal-specific impairment of heparan sulfate degradation in Drosophila reveals pathogenic mechanisms for Mucopolysaccharidosis type IIIA.

Mucopolysaccharidosis type IIIA (MPS IIIA) is a lysosomal storage disorder resulting from the deficit of the N-sulfoglucosamine sulfohydrolase (SGSH) enzyme that leads to accumulation of partially-degraded heparan sulfate. MPS IIIA is characterized by severe neurological symptoms, clinically presenting as Sanfilippo syndrome, for which no effective therapy is available. The lysosomal SGSH enzyme is conserved in Drosophila and we have identified increased levels of heparan sulfate in flies with ubiquitous knockdown of SGSH/CG14291. Using neuronal specific knockdown of SGSH/CG14291 we have also observed a higher abundance of Lysotracker-positive puncta as well as increased expression of GFP tagged Ref(2)P supporting disruption to lysosomal function. We have also observed a progressive defect in climbing ability, a hallmark of neurological dysfunction. Genetic screens indicate proteins and pathways that can functionally modify the climbing phenotype, including autophagy-related proteins (Atg1 and Atg18), superoxide dismutase enzymes (Sod1 and Sod2) and heat shock protein (HSPA1). In addition, reducing heparan sulfate biosynthesis by knocking down sulfateless or slalom expression significantly worsens the phenotype; an important observation given that substrate inhibition is being evaluated clinically as a treatment for MPS IIIA. Identifying the cellular pathways that can modify MPS IIIA neuropathology is an essential step in the development of novel therapeutic approaches to prevent and/or ameliorate symptoms in children with Sanfilippo syndrome.

Screening for Colorectal Cancer at the Worksite.

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths among men and women in the United States. To increase statewide CRC screening rates, the Alabama Department of Public Health (through a Centers for Disease Control and Prevention [CDC] Colorectal Cancer Control Program grant) partnered with The University of Alabama in Huntsville (UAH) and The University of South Alabama (USA) to provide free CRC screening opportunities to eligible University employees and dependents. Resources were invested at both universities to ensure participant education, tracking, and monitoring. In total, 86 fecal immunochemical tests (FITs) were distributed at the UAH campus and 62 were returned for testing; 146 FITs were distributed on the USA campus with 111 returned. Fecal immunochemical test return rates were over 70% at each site. Most notably, 21 positive FITs were identified among UAH participants and 25 at USA. Findings from both efforts suggest that employer-based screening initiatives are a systematic and replicable means of improving CRC screening.

Providers' Attitudes and Knowledge of Lesbian, Gay, Bisexual, and Transgender Health.

A survey of community-based outpatient clinic health care providers suggests the need for additional education and training to increase their cultural competencies.

Leadership Initiatives in Patient-Centered Transgender Care.

Advanced practice nurses develop solutions that can improve health care access and services for transgender persons in the VA.

Nurse faculty as international research collaborators.

Nursing faculty who desire to expand their research portfolios will benefit from collaboration with researchers with complimentary interests from different universities across the world. International collaboration can enhance the productivity of researchers who seek to conduct studies with similar populations in different environments, and who desire a larger impact based on the findings of their studies. International collaborative teams have the potential to make important discoveries that affect the health of populations across the world. Communication is a critical step in defining the roles and professional relationships of researchers involved in international collaboration. Researchers need to be cognizant of rules affecting data security, intellectual property, data ownership, and funding sources in each country. International collaborative research can be exciting and rewarding, especially when participants are culturally aware, respect universities' policies, and are mindful of the ethical and legal principles for the countries in which the research is conducted. This article describes ways to enhance the success of nursing faculty who desire a rich experience with international research collaborators.

The Enemy within: Innate Surveillance-Mediated Cell Death, the Common Mechanism of Neurodegenerative Disease.

Neurodegenerative diseases comprise an array of progressive neurological disorders all characterized by the selective death of neurons in the central nervous system. Although, rare (familial) and common (sporadic) forms can occur for the same disease, it is unclear whether this reflects several distinct pathogenic pathways or the convergence of different causes into a common form of nerve cell death. Remarkably, neurodegenerative diseases are increasingly found to be accompanied by activation of the innate immune surveillance system normally associated with pathogen recognition and response. Innate surveillance is the cell's quality control system for the purpose of detecting such danger signals and responding in an appropriate manner. Innate surveillance is an "intelligent system," in that the manner of response is relevant to the magnitude and duration of the threat. If possible, the threat is dealt with within the cell in which it is detected, by degrading the danger signal(s) and restoring homeostasis. If this is not successful then an inflammatory response is instigated that is aimed at restricting the spread of the threat by elevating degradative pathways, sensitizing neighboring cells, and recruiting specialized cell types to the site. If the danger signal persists, then the ultimate response can include not only the programmed cell death of the original cell, but the contents of this dead cell can also bring about the death of adjacent sensitized cells. These responses are clearly aimed at destroying the ability of the detected pathogen to propagate and spread. Innate surveillance comprises intracellular, extracellular, non-cell autonomous and systemic processes. Recent studies have revealed how multiple steps in these processes involve proteins that, through their mutation, have been linked to many familial forms of neurodegenerative disease. This suggests that individuals harboring these mutations may have an amplified response to innate-mediated damage in neural tissues, and renders innate surveillance mediated cell death a plausible common pathogenic pathway responsible for neurodegenerative diseases, in both familial and sporadic forms. Here we have assembled evidence in favor of the hypothesis that neurodegenerative disease is the cumulative result of chronic activation of the innate surveillance pathway, triggered by endogenous or environmental danger or damage associated molecular patterns in a progressively expanding cascade of inflammation, tissue damage and cell death.