Contributions of Chondroitin Sulfate, Keratan Sulfate and N-linked Oligosaccharides to Inhibition of Neurite Outgrowth by Aggrecan.

The role of proteoglycans in the central nervous system (CNS) is a rapidly evolving field and has major implications in the field of CNS injury. Chondroitin sulfate proteoglycans (CSPGs) increase in abundance following damage to the spinal cord and inhibit neurite outgrowth. Major advances in understanding the interaction between outgrowing neurites and CSPGs has created a need for more robust and quantitative analyses to further our understanding of this interaction. We report the use of a high-throughput assay to determine the effect of various post-translational modifications of aggrecan upon neurite outgrowth from NS-1 cells (a PC12 cell line derivative). Aggrecan contains chondroitin sulfate, keratan sulfate, and N-linked oligosaccharides (N-glycans), each susceptible to removal through different enzymatic digestions. Using a sequential digestion approach, we found that chondroitin sulfate and N-glycans, but not keratan sulfate, contribute to inhibition of neurite outgrowth by substrate-bound aggrecan. For the first time, we have shown that N-linked oligosaccharides on aggrecan contribute to its inhibition of neuritogenesis.

A Retrospective Descriptive Study of Nurses With Substance Use Disorders in Texas.

There are approximately 3.1 million nurses in the Unites States (U.S. Census Bureau, 2016), and approximately 8% of them experience substance use disorders (Kunyk, 2015). Nurses with impaired practice are referred to peer assistance programs as they seek rehabilitation. As of 2016, 348 nurses in Texas Peer Assistance Program for Nurses were actively participating in the program for substance-abuse-related offenses. Over the last 6 years (2010-2016), 1,553 nurses were referred to Texas Peer Assistance Program for Nurses specifically for substance-abuse-related problems. These represent 2% of the population of nurses in Texas. The average age of participants was 40.1 years. Women represented 75% of participants, and 76% were registered nurses. About 41% successfully completed the program without relapsing, and 32% reported at least one relapse. Varieties of drugs were abused including prescription drugs and illegal drugs. Opioids were the most frequently abused class of drugs, followed by alcohol and stimulants. Most nurses obtained their drugs by diverting from patients. Contrary to what is in the literature, nurses working in long-term care, medical-surgical units, and home health care had the highest prevalence of impaired practice. Psychiatric comorbidity was not significantly associated with relapse, but self-report status was significantly associated with gender, age category, license type, relapse, and drug of choice. There was a significant inverse relationship between time it takes to enroll and number of abstinent days. Men were also more likely to be employed while in the program.

Personal Factors as Correlates and Predictors of Relapse in Nurses With Impaired Practice.

Relapse is the unauthorized use of any mind-altering substance, prescribed or not, after an individual has entered treatment for substance use (Darbro, 2011). Among nurses with impaired practice, the 5-year relapse rate is estimated at about 40% (Zhong, Kenward, Sheets, Doherty, & Gross, 2009), and the risk of relapse is highest in the first year of recovery (Clark & Farnsworth, 2006). Many factors influence susceptibility to relapse among nurses including presence of psychiatric comorbidities (Schellekens, de Jong, Buitelaar, & Verkes, 2015), history of criminal background (Zhong et al., 2009), spirituality and religiosity (Allen & Lo, 2010), and receiving prelicensure education in the United States (Waneka, Spetz, & Keane, 2011). The purpose of this study was to examine the correlates and predictors of relapse among nurses and to establish at what point they are most susceptible to relapse. This study was a retrospective secondary data analysis of nurses in Texas with impaired practice. The total number of participants was 1,553. The time it takes participants to enroll in a peer assistance program is negatively associated with length in program (p < .001). Conversely, there is a strong, positive, significant relationship between the number of days abstinent and the length in program (p < .001). More men compared with women (p = .037) were likely to be employed while participating in the program. Finally, participants who were referred for substance use disorders alone had 55% less risk of relapse. Those who used alcohol as their primary drug of choice had 1.7 times higher risk of relapse.

Treatment Options for Opioid Use Disorders: A Review of the Relevant Literature.

Approximately 10% of the 20 million Americans who are suffering from substance use disorders are suffering from prescription opioid and heroine misuse. This has led to a rise in overdoses as well as emergency room visits, with over 1000 individuals across the United States being seen in emergency rooms every day. Unfortunately, about 90% of drug overdoses are unintentional. Therefore, finding effective ways to treat opioid use disorders and preventing relapse has now become a national priority. This review of the relevant literature highlights current treatment options available for opioid use disorders, including motivational interviewing, cognitive behavioral therapy, mindfulness meditation, mindfulness based relapse prevention, medication assisted therapies, and combination therapies. Lastly, a discussion on ways to address challenges related to the treatment of opioid use disorders is provided.

Integrating the 2013 Psychiatric Mental Health NP Competencies Into Educational Programs: Where Are We Now?

Since the introduction of the revised National Organization of Nurse Practitioner Faculties (NONPF) Nurse Practitioner Core Competencies and Population Focused Psychiatric Mental Health Nurse Practitioner (PMHNP) Competencies, a national forum took place to hear from many PMHNP program directors in the field comparing how they have integrated the lifespan competencies and the master's (MS)/or doctor of nurse practice (DNP) essentials into their curriculum. In this paper, we will report first on the major areas of change in the structure and content of the PMHNP-lifespan curriculum as well as the comments made by many faculty from across the country as to challenges and innovative strategies used to meet these challenges. We will review some of the major issues in content, pedagogy, and evaluation methods as well as examples of how these curricular elements have been infused into select programs across the country. We conclude highlighting several key areas, suggested foci for change, and how the specialty might focus attention and accelerate the significant growth we are seeing in PMHNP programs.

Effective Strategies for Nurses Empowering Clients With Schizophrenia: Medication Use as a Tool in Recovery.

Clients with schizophrenia require maintenance treatment with antipsychotic medication and psychosocial therapy to maintain symptom control. Rates of medication adherence or follow-through are low in clients with schizophrenia. This increases the risk of relapse and contributes to poor quality of life. As educators and advisers, psychiatric nurses can collaborate with clients to improve adherence and other outcomes using shared decision-making techniques and tools that engage and empower clients to actively participate in decisions about their treatment. This article outlines effective strategies used by psychiatric nurses to improve outcomes in clients with schizophrenia and uses a case example for demonstrating this strategy in a client with schizophrenia.

Proteoglycans of reactive rat cortical astrocyte cultures: abundance of N-unsubstituted glucosamine-enriched heparan sulfate.

"Reactive" astrocytes and other glial cells in the injured CNS produce an altered extracellular matrix (ECM) that influences neuronal regeneration. We have profiled the glycosaminoglycan (GAG) component of proteoglycans (PGs) produced by reactive neonatal rat cortical astrocytes, and have quantified their neurite-outgrowth inhibitory activity. PGs extracted from cell layers and medium were fractionated on DEAE-Sephacel with a gradient of NaCl from 0.15 to 1.0 M. Monosaccharide analysis of the major peaks eluting at 0.6 M NaCl indicated an excess of GlcNH2 to GalNH2, suggesting an approximate HS/CS ratio of 6.2 in the cell layer and 4.2 in the medium. Chondroitinase ABC-generated disaccharide analysis of cell and medium PGs showed a >5-fold excess of chondroitin 4-sulfate over chondroitin 6-sulfate. Heparin lyase-generated disaccharides characteristic of the highly sulfated S-domain regions within HS were more abundant in cell layer than medium-derived PGs. Cell layer and medium HS disaccharides contained ~20% and ~40% N-unsubstituted glucosamine respectively, which is normally rare in HS isolated from most tissues. NGF-stimulated neurite outgrowth assays using NS-1 (PC12) neuronal cells on adsorbed substrata of PGs isolated from reactive astrocyte medium showed pronounced inhibition of neurite outgrowth, and aggregation of NS-1 cells. Cell layer PGs from DEAE-Sephacel pooled fractions having high charge density permitted greater NGF-stimulated outgrowth than PGs with lower charge density. Our results indicate the synthesis of both inhibitory and permissive PGs by activated astrocytes that may correlate with sulfation patterns and HS/CS ratios.

Neuronal growth cones and regeneration: gridlock within the extracellular matrix.

The extracellular matrix is a diverse composition of glycoproteins and proteoglycans found in all cellular systems. The extracellular matrix, abundant in the mammalian central nervous system, is temporally and spatially regulated and is a dynamic "living" entity that is reshaped and redesigned on a continuous basis in response to changing needs. Some modifications are adaptive and some are maladaptive. It is the maladaptive responses that pose a significant threat to successful axonal regeneration and/or sprouting following traumatic and spinal cord injuries, and has been the focus of a myriad of research laboratories for many years. This review focuses largely on the extracellular matrix component, chondroitin sulfate proteoglycans, with certain comparisons to heparan sulfate proteoglycans, which tend to serve opposite functions in the central nervous system. Although about equally as well characterized as some of the other proteoglycans such as hyaluronan and dermatan sulfate proteoglycan, chondroitin sulfate proteoglycans are the most widely researched and discussed proteoglycans in the field of axonal injury and regeneration. Four laboratories discuss various aspects of chondroitin sulfate proteoglycans and proteoglycans in general with respect to their structure and function (Beller and Snow), the recent discovery of specific chondroitin sulfate proteoglycan receptors and what this may mean for increased advancements in the field (Shen), extracellular matrix degradation by matrix metalloproteinases, which sculpt and resculpt to provide support for outgrowth, synapse formation, and synapse stability (Phillips et al.), and the perilesion microenvironment with respect to immune system function in response to proteoglycans and central nervous system injuries (Jakeman et al.).

Proteoglycans: road signs for neurite outgrowth.

Proteoglycans in the central nervous system play integral roles as "traffic signals" for the direction of neurite outgrowth. This attribute of proteoglycans is a major factor in regeneration of the injured central nervous system. In this review, the structures of proteoglycans and the evidence suggesting their involvement in the response following spinal cord injury are presented. The review further describes the methods routinely used to determine the effect proteoglycans have on neurite outgrowth. The effects of proteoglycans on neurite outgrowth are not completely understood as there is disagreement on what component of the molecule is interacting with growing neurites and this ambiguity is chronicled in an historical context. Finally, the most recent findings suggesting possible receptors, interactions, and sulfation patterns that may be important in eliciting the effect of proteoglycans on neurite outgrowth are discussed. A greater understanding of the proteoglycan-neurite interaction is necessary for successfully promoting regeneration in the injured central nervous system.

Minimum information about a spinal cord injury experiment: a proposed reporting standard for spinal cord injury experiments.

The lack of reproducibility in many areas of experimental science has a number of causes, including a lack of transparency and precision in the description of experimental approaches. This has far-reaching consequences, including wasted resources and slowing of progress. Additionally, the large number of laboratories around the world publishing articles on a given topic make it difficult, if not impossible, for individual researchers to read all of the relevant literature. Consequently, centralized databases are needed to facilitate the generation of new hypotheses for testing. One strategy to improve transparency in experimental description, and to allow the development of frameworks for computer-readable knowledge repositories, is the adoption of uniform reporting standards, such as common data elements (data elements used in multiple clinical studies) and minimum information standards. This article describes a minimum information standard for spinal cord injury (SCI) experiments, its major elements, and the approaches used to develop it. Transparent reporting standards for experiments using animal models of human SCI aim to reduce inherent bias and increase experimental value.

Comparison of sensory neuron growth cone and filopodial responses to structurally diverse aggrecan variants, in vitro.

Following spinal cord injury, a regenerating neurite encounters a glial scar enriched in chondroitin sulfate proteoglycans (CSPGs), which presents a major barrier. There are two points at which a neurite makes contact with glial scar CSPGs: initially, filopodia surrounding the growth cone extend and make contact with CSPGs, then the peripheral domain of the entire growth cone makes CSPG contact. Aggrecan is a CSPG commonly used to model the effect CSPGs have on elongating or regenerating neurites. In this study, we investigated filopodia and growth cone responses to contact with structurally diverse aggrecan variants using the common stripe assay. Using time-lapse imaging with 15-s intervals, we measured growth cone area, growth cone width, growth cone length, filopodia number, total filopodia length, and the length of the longest filopodia following contact with aggrecan. Responses were measured after both filopodia and growth cone contact with five different preparations of aggrecan: two forms of aggrecan derived from bovine articular cartilage (purified and prepared using different techniques), recombinant aggrecan lacking chondroitin sulfate side chains (produced in CHO-745 cells) and two additional recombinant aggrecan preparations with varying lengths of chondroitin sulfate side chains (produced in CHO-K1 and COS-7 cells). Responses in filopodia and growth cone behavior differed between the structurally diverse aggrecan variants. Mutant CHO-745 aggrecan (lacking chondroitin sulfate chains) permitted extensive growth across the PG stripe. Filopodia contact with the CHO-745 aggrecan caused a significant increase in growth cone width and filopodia length (112.7% ± 4.9 and 150.9% ± 7.2 respectively, p<0.05), and subsequently upon growth cone contact, growth cone width remained elevated along with a reduction in filopodia number (121.9% ± 4.2; 72.39% ± 6.4, p<0.05). COS-7 derived aggrecan inhibited neurite outgrowth following growth cone contact. Filopodia contact produced an increase in growth cone area and width (126.5% ± 8.1; 150.3% ± 13.31, p<0.001), and while these parameters returned to baseline upon growth cone contact, a reduction in filopodia number and length was observed (73.94% ± 5.8, 75.3% ± 6.2, p<0.05). CHO-K1 derived aggrecan inhibited neurite outgrowth following filopodia contact, and caused an increase in growth cone area and length (157.6% ± 6.2; 117.0% ± 2.8, p<0.001). Interestingly, the two bovine articular cartilage aggrecan preparations differed in their effects on neurite outgrowth. The proprietary aggrecan (BA I, Sigma-Aldrich) inhibited neurites at the point of growth cone contact, while our chemically purified aggrecan (BA II) inhibited neurite outgrowth at the point of filopodia contact. BA I caused a reduction in growth cone width following filopodia contact (91.7% ± 2.5, p<0.05). Upon growth cone contact, there was a further reduction in growth cone width and area (66.4% ± 2.2; 75.6% ± 2.9; p<0.05), as well as reductions in filopodia number, total length, and max length (75.9% ± 5.7, p<0.05; 68.8% ± 6.0; 69.6% ± 3.5, p<0.001). Upon filopodia contact, BA II caused a significant increase in growth cone area, and reductions in filopodia number and total filopodia length (115.9% ± 5.4, p<0.05; 72.5% ± 2.7; 77.7% ± 3.2, p<0.001). In addition, filopodia contact with BA I caused a significant reduction in growth cone velocity (38.6 nm/s ± 1.3 before contact, 17.1 nm/s ± 3.6 after contact). These data showed that neuron morphology and behavior are differentially dependent upon aggrecan structure. Furthermore, the behavioral changes associated with the approaching growth cone may be predictive of inhibition or growth.

First controlled treatment trial of bipolar II hypomania with mixed symptoms: quetiapine versus placebo.

OBJECTIVES: To compare the efficacy and safety of adjunctive quetiapine (QTP) versus placebo (PBO) for patients with bipolar II disorder (BDII) currently experiencing mixed hypomanic symptoms in a 2-site, randomized, placebo-controlled, double-blind, 8-week investigation. METHODS: Participants included 55 adults (age 18-65 years) who met criteria for BDII on the Structured Clinical Interview for DSM-IV-TR (SCID). Entrance criteria included a stable medication regimen for ≥2 weeks and hypomania with mixed symptoms (>12 on the Young Mania Rating Scale [YMRS] and >15 on the Montgomery Asberg Depression Rating Scale [MADRS] at two consecutive visits 1-3 days apart). Participants were randomly assigned to receive adjunctive quetiapine (n=30) or placebo (n=25). RESULTS: Adjunctive quetiapine demonstrated significantly greater improvement than placebo in Clinical Global Impression for Bipolar Disorder Overall Severity scores (F(1)=10.12, p=.002) and MADRS scores (F(1)=6.93, p=.0138), but no significant differences were observed for YMRS scores (F(1)=3.68, p=.069). Side effects of quetiapine were consistent with those observed in previous clinical trials, with sedation/somnolence being the most common, occurring in 53.3% with QTP and 20.0% with PBO. CONCLUSIONS: While QTP was significantly more effective than PBO for overall and depressive symptoms of BDII, there was no significant difference between groups in reducing symptoms of hypomania. Hypomania improved across both groups throughout the study.

Quality and safety graduate competencies in psychiatric mental health nurse practitioner education.

Education of the psychiatric mental health nurse practitioner (PMHNP) is undergoing massive change, partially driven by practice requirements and national certification changes, the development of new nurse practitioner competencies, and the development of the graduate quality and safety in nursing (QSEN) competencies. We are in the middle of a paradigm shift of expectations, not only just from these new competencies but also from the context of care and the impact PMHNP graduates will have on policy and health care delivery in the future. In this review article, the authors will discuss the general categories of the graduate QSEN competencies and how they relate to PMHNP education, competency development, and the application to curricular development in PMHNP programs across the United States. Importantly, these changes into PMHNP education, while remaining true to the fundamental tenants of advanced practice psychiatric nursing, prepare the PMHNP to meet the challenges of health care reform and service delivery.