The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis.

The nucleus accumbens is a major input structure of the basal ganglia and integrates information from cortical and limbic structures to mediate goal-directed behaviors. Chronic exposure to several classes of drugs of abuse disrupts plasticity in this region, allowing drug-associated cues to engender a pathologic motivation for drug seeking. A number of alterations in glutamatergic transmission occur within the nucleus accumbens after withdrawal from chronic drug exposure. These drug-induced neuroadaptations serve as the molecular basis for relapse vulnerability. In this review, we focus on the role that glutamate signal transduction in the nucleus accumbens plays in addiction-related behaviors. First, we explore the nucleus accumbens, including the cell types and neuronal populations present as well as afferent and efferent connections. Next we discuss rodent models of addiction and assess the viability of these models for testing candidate pharmacotherapies for the prevention of relapse. Then we provide a review of the literature describing how synaptic plasticity in the accumbens is altered after exposure to drugs of abuse and withdrawal and also how pharmacological manipulation of glutamate systems in the accumbens can inhibit drug seeking in the laboratory setting. Finally, we examine results from clinical trials in which pharmacotherapies designed to manipulate glutamate systems have been effective in treating relapse in human patients. Further elucidation of how drugs of abuse alter glutamatergic plasticity within the accumbens will be necessary for the development of new therapeutics for the treatment of addiction across all classes of addictive substances.

Glutamatergic mechanisms of comorbidity between acute stress and cocaine self-administration.

There is substantial comorbidity between stress disorders and substance use disorders (SUDs), and acute stress augments the locomotor stimulant effect of cocaine in animal models. Here we endeavor to understand the neural underpinnings of comorbid stress disorders and drug use by determining whether the glutamatergic neuroadaptations that characterize cocaine self-administration are induced by acute stress. Rats were exposed to acute (2 h) immobilization stress, and 3 weeks later the nucleus accumbens core was examined for changes in glutamate transport, glutamate-mediated synaptic currents and dendritic spine morphology. We also determined whether acute stress potentiated the acquisition of cocaine self-administration. Acute stress produced an enduring reduction in glutamate transport and potentiated excitatory synapses on medium spiny neurons. Acute stress also augmented the acquisition of cocaine self-administration. Importantly, by restoring glutamate transport in the accumbens core with ceftriaxone the capacity of acute stress to augment the acquisition of cocaine self-administration was abolished. Similarly, ceftriaxone treatment prevented stress-induced potentiation of cocaine-induced locomotor activity. However, ceftriaxone did not reverse stress-induced synaptic potentiation, indicating that this effect of stress exposure did not underpin the increased acquisition of cocaine self-administration. Reversing acute stress-induced vulnerability to self-administer cocaine by normalizing glutamate transport poses a novel treatment possibility for reducing comorbid SUDs in stress disorders.

Molecular characterization of Fusarium resistance from Elymus repens introgressed into bread wheat.

A cross was made of Elymus repens onto the wheat cultivar Crocus and BC1 progeny advanced to BC1F7 by single seed descent. Sixteen lines were selected based on agronomic performance and evaluated in an FHB epiphytotic nursery. Eight lines with FHB resistance were selected. Based on GISH analysis, line P1142-3-1-5 had 42 chromosomes with one pair of chromosomes showing telomeric translocations on both arms. This chromosome was identified as 3D by using SSR markers. An evaluation of lines with single translocations revealed that FHB resistance was contributed by the translocation on the long arm of chromosome 3D. That line has minimal linkage drag and should be amenable to applications in breeding for disease resistance.

The CanPain SCI Clinical Practice Guidelines for Rehabilitation Management of Neuropathic Pain after Spinal Cord: introduction, methodology and recommendation overview.

STUDY DESIGN: Clinical practice guidelines. OBJECTIVES: The objective was to develop the first Canadian clinical practice guidelines for the management of neuropathic pain in people with spinal cord injury (SCI). SETTING: The guidelines are relevant for inpatient and outpatient SCI rehabilitation settings in Canada. METHODS: The guidelines were developed in accordance with the Appraisal of Guidelines for Research and Evaluation II tool. A Steering Committee and Working Group reviewed the relevant evidence on neuropathic pain management (encompassing screening and diagnosis, treatment and models of care) after SCI. The quality of evidence was scored using Grading of Recommendations Assessment, Development and Evaluation (GRADE). A consensus process was followed to achieve agreement on recommendations and clinical considerations. RESULTS: The Working Group developed 12 recommendations for screening and diagnosis, 12 recommendations for treatment and 5 recommendations for models of care. Important clinical considerations accompany each recommendation. CONCLUSIONS: The Working Group recommendations for the management of neuropathic pain after SCI should be used to inform practice.

The CanPain SCI Clinical Practice Guidelines for Rehabilitation Management of Neuropathic Pain after Spinal Cord: Recommendations for treatment.

STUDY DESIGN: Clinical practice guidelines. OBJECTIVES: To develop the first Canadian clinical practice guidelines for treatment of neuropathic pain in people with spinal cord injury (SCI). SETTING: The guidelines are relevant for inpatient and outpatient SCI rehabilitation settings in Canada. METHODS: The CanPainSCI Working Group reviewed the evidence for different treatment options and achieved consensus. The Working Group then developed clinical considerations for each recommendation. Recommendations for research are also included. RESULTS: Twelve recommendations were developed for the management of neuropathic pain after SCI. The recommendations address both pharmacologic and nonpharmacologic treatment modalities. CONCLUSIONS: An expert Working Group developed recommendations for the treatment of neuropathic pain after SCI that should be used to inform practice.

The CanPain SCI Clinical Practice Guideline for Rehabilitation Management of Neuropathic Pain after Spinal Cord: recommendations for model systems of care.

STUDY DESIGN: Clinical practice guidelines. OBJECTIVES: The project objectives were to develop the first Canadian recommendations on a model of care for the management of at- and below-level neuropathic pain in people with spinal cord injury (SCI). SETTING: The guidelines are relevant for inpatient and outpatient SCI rehabilitation settings in Canada. METHODS: On the basis of a review of the Accreditation Canada standards, the Steering Committee developed questions to guide the CanPainSCI Working Group when developing the recommendations. The Working Group agreed on recommendations through a consensus process. RESULTS: The Working Group developed five recommendations for the organization of neuropathic pain rehabilitation care in people with SCI. CONCLUSIONS: The Working Group recommendations for a model of care for at- and below-level neuropathic pain after SCI should be used to inform clinical practice.

The CanPain SCI Clinical Practice Guidelines for Rehabilitation Management of Neuropathic Pain after Spinal Cord: screening and diagnosis recommendations.

STUDY DESIGN: Clinical practice guidelines. OBJECTIVES: To develop the first Canadian clinical practice guidelines for screening and diagnosis of neuropathic pain in people with spinal cord injury (SCI). SETTING: The guidelines are relevant for inpatient and outpatient SCI rehabilitation settings in Canada. METHODS: The CanPainSCI Working Group reviewed evidence to address clinical questions regarding screening and diagnosis of neuropathic pain after SCI. A consensus process was followed to achieve agreement on recommendations and clinical considerations. RESULTS: Twelve recommendations, based on expert consensus, were developed for the screening and diagnosis of neuropathic pain after SCI. The recommendations address methods for assessment, documentation tools, team member accountability, frequency of screening and considerations for diagnostic investigation. Important clinical considerations accompany each recommendation. CONCLUSIONS: The expert Working Group developed recommendations for the screening and diagnosis of neuropathic pain after SCI that should be used to inform practice.

Does an evidence-based healthy relationships program for 9th graders show similar effects for 7th and 8th graders? Results from 57 schools randomized to intervention.

Integrating social and emotional learning (SEL) programming throughout curricula to support the development of healthy behaviors and prevent violence is critical for a comprehensive approach to school health. This study used a post-test comparison design to evaluate a healthy relationships program for eighth grade students that applies a SEL approach. The program was adapted from the Fourth R, an evidence-based program for ninth graders, but matches the curriculum and developmental context for eighth graders. Surveys were collected post-intervention from 1012 students within 57 schools randomized to intervention or control conditions. Multivariate multilevel analysis accounted for the nested nature of students within schools. There were significant group differences on three of four outcomes following intervention, including improved knowledge about violence, critical thinking around the impact of violence, and identification of more successful coping strategies. There was no group difference on general acceptance of violence. Overall, students learned relevant information and strategies and were able to apply that knowledge to demonstrate critical thinking, suggesting that adapting an evidence-based approach for use with younger students provided similar benefits. These findings build a case for 2 years of consecutive evidence-based healthy relationships programming in grades 8 and 9, consistent with best practice guidelines.

Knowledge translation and implementation in spinal cord injury: a systematic review.

OBJECTIVE: To conduct a systematic review examining the effectiveness of knowledge translation (KT) interventions in changing clinical practice and patient outcomes. METHODS: MEDLINE/PubMed, CINAHL, EMBASE and PsycINFO were searched for studies published from January 1980 to July 2012 that reported and evaluated an implemented KT intervention in spinal cord injury (SCI) care. We reviewed and summarized results from studies that documented the implemented KT intervention, its impact on changing clinician behavior and patient outcomes as well as the facilitators and barriers encountered during the implementation. RESULTS: A total of 13 articles featuring 10 studies were selected and abstracted from 4650 identified articles. KT interventions included developing and implementing patient care protocols, providing clinician education and incorporating outcome measures into clinical practice. The methods (or drivers) to facilitate the implementation included organizing training sessions for clinical staff, introducing computerized reminders and involving organizational leaders. The methodological quality of studies was mostly poor. Only 3 out of 10 studies evaluated the success of the implementation using statistical analyses, and all 3 reported significant behavior change. Out of the 10 studies, 6 evaluated the effect of the implementation on patient outcomes using statistical analyses, with 4 reporting significant improvements. The commonly cited facilitators and barriers were communication and resources, respectively. CONCLUSION: The field of KT in SCI is in its infancy with only a few relevant publications. However, there is some evidence that KT interventions may change clinician behavior and improve patient outcomes. Future studies should ensure rigorous study methods are used to evaluate KT interventions.

Comparative effectiveness of antinociceptive gene therapies in animal models of diabetic neuropathic pain.

Peripheral neuropathic pain is one of the most common and debilitating complications of diabetes. Several genes have been shown to be effective in reducing neuropathic pain in animal models of diabetes after transfer to the dorsal root ganglion using replication-defective herpes simplex virus (HSV)1-based vectors, yet there has never been a comparative analysis of their efficacy. We compared four different HSV1-based vectors engineered to produce one of two opioid receptor agonists (enkephalin or endomorphin), or one of two isoforms of glutamic acid decarboxylase (GAD65 or GAD67), alone and in combination, in the streptozotocin-induced diabetic rat and mouse models. Our results indicate that a single subcutaneous hindpaw inoculation of vectors expressing GAD65 or GAD67 reduced diabetes-induced mechanical allodynia to a degree that was greater than daily injections of gabapentin in rats. Diabetic mice that developed thermal hyperalgesia also responded to GAD65 or endomorphin gene delivery. The results suggest that either GAD65 or GAD67 vectors are the most effective in the treatment of diabetic pain. The vector combinations, GAD67+endomorphin, GAD67+enkephalin or endomorphin+enkephalin also produced a significant antinociceptive effect but the combination did not appear to be superior to single gene treatment. These findings provide further justification for the clinical development of antinociceptive gene therapies for the treatment of diabetic peripheral neuropathies.

The effects of exercise training on physical capacity, strength, body composition and functional performance among adults with spinal cord injury: a systematic review.

STUDY DESIGN: Systematic review. OBJECTIVES: To conduct a systematic review of evidence surrounding the effects of exercise on physical fitness in people with spinal cord injury (SCI). SETTING: Canada. METHODS: The review was limited to English-language studies (published prior to March 2010) of people with SCI that evaluated the effects of an exercise intervention on at least one of the four main components of physical fitness (physical capacity, muscular strength, body composition and functional performance). Studies reported at least one of the following outcomes: oxygen uptake/consumption, power output, peak work capacity, muscle strength, body composition, exercise performance or functional performance. A total of 166 studies were identified. After screening, 82 studies (69 chronic SCI; 13 acute SCI) were included in the review. The quality of evidence derived from each study was evaluated using established procedures. RESULTS: Most studies were of low quality; however, the evidence was consistent that exercise is effective in improving aspects of fitness. There is strong evidence that exercise, performed 2-3 times per week at moderate-to-vigorous intensity, increases physical capacity and muscular strength in the chronic SCI population; the evidence is not strong with respect to the effects of exercise on body composition or functional performance. There were insufficient high-quality studies in the acute SCI population to draw any conclusions. CONCLUSIONS: In the chronic SCI population, there is good evidence that exercise is effective in improving both physical capacity and muscular strength, but insufficient quality evidence to draw meaningful conclusions on its effect on body composition or functional capacity.

The development of evidence-informed physical activity guidelines for adults with spinal cord injury.

OBJECTIVES: To systematically develop evidence-informed physical activity guidelines to improve physical fitness in people with spinal cord injury (SCI). SETTING: This study was conducted in Canada. METHODS: The Appraisal of Guidelines, Research and Evaluation II guideline development protocol was used to develop exercise guidelines to improve physical capacity and muscular strength. The evidence base for the guideline development process consisted of a systematic review and quality appraisal of research examining the effects of exercise on physical fitness among people with SCI. A multidisciplinary expert panel deliberated the evidence and generated the guidelines. Pilot testing led to refinement of the wording and presentation of the guidelines. RESULTS: The expert panel generated the following guidelines: for important fitness benefits, adults with a SCI should engage in (a) at least 20 min of moderate to vigorous intensity aerobic activity two times per week and (b) strength training exercises two times per week, consisting of three sets of 8-10 repetitions of each exercise for each major muscle group. CONCLUSION: People with SCI, clinicians, researchers and fitness programmers are encouraged to adopt these rigorously developed guidelines.

A human trial of HSV-mediated gene transfer for the treatment of chronic pain.

Gene transfer to the dorsal root ganglion using replication defective herpes simplex virus (HSV)-based vectors reduces pain-related behaviors in rodent models having inflammatory pain, neuropathic pain and pain caused by cancer in bone. HSV vectors engineered to produce inhibitory neurotransmitters, including the delta opioid agonist peptide enkephalin, the mu opioid agonist peptide endomorphin-2 and glutamic acid decarboxylase (GAD), to effect the release of gamma amino butyric acid (GABA) act to inhibit nociceptive neurotransmission at the first synapse between primary nociceptive and second-order neuron in the dorsal horn of the spinal cord. HSV vectors engineered to release anti-inflammatory peptides, including interleukin (IL)-4, IL-10 and the p55 soluble tumor necrosis factor alpha (TNFalpha) receptor reduce neuroimmune activation in the spinal dorsal horn. The path leading from preclinical animal studies to the ongoing phase 1 human trial of the enkephalin-producing vector in patients with pain from cancer, and plans for an efficacy trial with an opioid-producing vector in inflammatory pain and an efficacy trial with a GAD-producing vector in diabetic neuropathic pain are outlined.

Herpes simplex virus vector-mediated delivery of neurturin rescues erectile dysfunction of cavernous nerve injury.

Neurturin (NTN), a member of glial cell line-derived neurotrophic factor (GDNF) family, is known as an important neurotrophic factor for penis-projecting neurons. We recently demonstrated significant protection from erectile dysfunction (ED) following a replication-defective herpes simplex virus (HSV) vector-mediated GDNF delivery to the injured cavernous nerve. Herein, we applied HSV vector-mediated delivery of NTN to this ED model. Rat cavernous nerve was injured bilaterally using a clamp and dry ice. For HSV-treated groups, 20 microl of vector stock was administered directly to the damaged nerve. Delivery of an HSV vector expressing both green fluorescent protein and lacZ (HSV-LacZ) was used as a control. Intracavernous pressure along with systemic arterial pressure (ICP/AP) was measured 2 and 4 weeks after the nerve injury. Fluorogold (FG) was injected into the penile crus 7 days before being killed to assess neuronal survival. Four weeks after nerve injury, rats treated with HSV-NTN exhibited significantly higher ICP/AP compared with untreated or control vector-treated groups. The HSV-NTN group had more FG-positive major pelvic ganglion neurons than the control group following injury. HSV vector-mediated delivery of NTN could be a viable approach for the improvement of ED following cavernous nerve injury.

Herpes simplex virus vector-mediated gene delivery of glutamic acid decarboxylase reduces detrusor overactivity in spinal cord-injured rats.

We examined whether replication-defective herpes simplex virus (HSV) vectors encoding the 67 kDa form of the glutamic acid decarboxylase (GAD(67)) gene product, the gamma-aminobutyric acid (GABA) synthesis enzyme, can suppress detrusor overactivity (DO) in rats with spinal cord injury (SCI). One week after spinalization, HSV vectors expressing GAD and green fluorescent protein (GFP) (HSV-GAD) were injected into the bladder wall. Rats with SCI without HSV injection (HSV-untreated) and those injected with lacZ-encoding reporter gene HSV vectors (HSV-LacZ) were used as controls. Three weeks after viral injection, continuous cystometry was performed under awake conditions in all three groups. In the HSV-GAD group, the number and amplitude of non-voiding contractions (NVCs) were significantly decreased (40-45% and 38-40%, respectively) along with an increase in voiding efficiency, compared with HSV-untreated and HSV-LacZ groups, but micturition pressure was not different among the three groups. Intrathecal application of bicuculline partly reversed the decreased number and amplitude of NVCs, and decreased voiding efficiency in the HSV-GAD group. In the HSV-GAD group, GAD(67) mRNA and protein levels were significantly increased in the L6-S1 dorsal root ganglia (DRG) compared with the HSV-LacZ group, while 57% of DRG cells were GFP-positive, and these neurons showed increased GAD(67)-like immunoreactivity compared with the HSV-LacZ group. These results indicate that GAD gene therapy effectively suppresses DO after SCI predominantly through the activation of spinal GABA(A) receptors. Thus, HSV-based GAD gene transfer to bladder afferent pathways may represent a novel approach for treatment of neurogenic DO.

Transformation of rat cerebral endothelial cells by Rous sarcoma virus.

Rat cerebral microvascular endothelial cells were infected with Schmidt-Ruppin Rous sarcoma virus-strain D (SR-RSV-D), an avian retrovirus. A single focus of transformed cells was isolated and the resultant cell line designated RCE-T1. The specificity for SR-RSV-D transformation was determined by virus rescue assay and demonstration of virus-specific antigens. RCE-T1 cells are virogenic when fused with chicken embryo fibroblasts (CEF) and do not produce infectious virus as demonstrated by the absence of detectable virus in culture fluid from these cells alone. Studies using an enzyme-linked immunosorbent assay (ELISA) for avian retrovirus-coded internal proteins show that RSV-transformed endothelial cells contain mainly p27 and react to some extent to p19 and p15 viral antigens. These data demonstrate conclusively that the transformation event was indeed due to SR-RSV-D. In addition, chromosome analysis confirmed these cells to be of rat origin. RSV-transformed endothelial cells express the typical array of transformation-related properties such as anchorage-independent cell growth in soft agar, decreased cell adhesiveness, ability to grow in low serum, and capability of producing tumors in newborn rats. Demonstration of differentiated endothelial characteristics included positive immunofluorescent staining for factor VIII antigen and angiotensin-converting enzyme and histochemical localization of gamma-glutamyl transpeptidase activity. This cell line should provide a useful model to study not only specialized biochemical and other functional characteristics of cerebrovascular endothelium but also the cellular mechanisms that involve the transition from normal to neoplastic expression.

The fate of amoco cadiz oil.

The Amoco Cadiz oil spill (223,000 metric tons) of March 1978 is the largest and best studied tanker spill in history. Of the total oil lost, 30,000 tons (13.5 percent) rapidly became incorporated into the water column, 18,000 tons (8 percent) were deposited in subtidal sediments, 62,000 tons (28 percent) washed into the intertidal zone, and 67,000 tons (30 percent) evaporated. While still at sea, approximately 10,000 tons of oil were degraded microbiologically. After 3 years, the most obvious effects of the spill have passed, although hydrocarbon concentrations remain elevated in those estuaries and marshes that were initially most heavily oiled.

A systematic review of depression and anxiety measures used with individuals with spinal cord injury.

STUDY DESIGN: A systematic review. OBJECTIVES: To review and assess the psychometric properties of depression and anxiety instruments used with populations with spinal cord injury (SCI). SETTING: Vancouver, Canada. METHODS: Electronic databases were searched for papers reporting psychometric properties of depression and anxiety instruments. Pre-established criteria were used to assess the psychometric properties. RESULTS: Thirteen papers reporting on the psychometric properties of 13 depression and anxiety instruments are used in this review, and include BDI, BSI, CESD-20, CESD-10, DASS-21, GHQ-28, HADS, Ilfeld-PSI, MEDS, PHQ-9, PHQ-9-Short, SCL-90-R, and the Zung SRS. Reliability data are available for 10 instruments, and validity results are available for 12 instruments. Evidence spanned the spectrum of evaluation criteria varying from poor to excellent. Responsiveness data are generally lacking. CONCLUSION: Given that the reliability and validity findings range for the most part from adequate to excellent, and the large amount of work to develop cutoff scores specific for populations with SCI, at present there is no need to develop SCI-specific instruments. As psychometric properties of one measure do not clearly stand out, it is difficult to recommend the use of one over another. Overall, more psychometric data are needed, and if the instruments are to be used to evaluate treatment outcomes or change over time, responsiveness data are also required. Administering the instruments in tandem with each other and with clinical diagnostic interviews would provide valuable information, as would comparison of results to normative data specific to individuals with SCI.

Knowledge Synthesis in Evidence-Based Medicine.

Systematic reviews are the most common form of knowledge synthesis and remain a cornerstone of the practice of evidence-based medicine. They offer enhanced rigor and validity relative to traditional narrative review articles by reducing bias and increasing objectivity. In answering focused research questions, systematic reviews are directly applicable to clinical practice as well as the development of clinical guidelines and the identification of knowledge gaps, which may drive future primary research directions. Typically, such a rigorous process necessarily requires substantive time to carefully and systematically identify, screen, and synthesize all relevant available primary research on a topic. Further, other knowledge synthesis methods have emerged to address the varying needs of decision makers with respect to condensed timelines and more diverse research questions, as well as to allow incorporation of already synthesized evidence into reviews. These alternative methods include rapid reviews, scoping reviews, and overviews of systematic reviews, which are being used with increasing frequency by clinicians, decision-makers, and researchers. We encourage clinicians and researchers in nuclear medicine and other imaging sciences to acquire a greater familiarity with these methods and to consider them in clinical decision making, the development of clinical guidelines, and the planning of future research activities.

Of mice and men: asymmetric interactions between Bordetella pathogen species.

In a recent experiment, we found that mice previously infected with Bordetella pertussis were not protected against a later infection with Bordetella parapertussis, while primary infection with B. parapertussis conferred cross-protection. This challenges the common assumption made in most mathematical models for pathogenic strain dynamics that cross-immunity between strains is symmetric. Here we investigate the potential consequences of this pattern on the circulation of the two pathogens in human populations. To match the empirical dominance of B. pertussis, we made the additional assumption that B. parapertussis pays a cost in terms of reduced fitness. We begin by exploring the range of parameter values that allow the coexistence of the two pathogens, with or without vaccination. We then track the dynamics of the system following the introduction of anti-pertussis vaccination. Our results suggest that (1) in order for B. pertussis to be more prevalent than B. parapertussis, the former must have a strong competitive advantage, possibly in the form of higher infectivity, and (2) because of asymmetric cross-immunity, the introduction of anti-pertussis vaccination should have little effect on the absolute prevalence of B. parapertussis. We discuss the evidence supporting these predictions, and the potential relevance of this model for other pathogens.