Activity-regulated genes as mediators of neural circuit plasticity

Modifications of neuronal circuits allow the brain to adapt and change with experience. This plasticity manifests during development and throughout life, and can be remarkably long lasting. Evidence has linked activity-regulated gene expression to the long-term structural and electrophysiological adaptations that take place during developmental critical periods, learning and memory, and alterations to sensory map representations in the adult. In all these cases, the cellular response to neuronal activity integrates multiple tightly coordinated mechanisms to precisely orchestrate long-lasting, functional and structural changes in brain circuits. Experience-dependent plasticity is triggered when neuronal excitation activates cellular signaling pathways from the synapse to the nucleus that initiate new programs of gene expression. The protein products of activity-regulated genes then work via a diverse array of cellular mechanisms to modify neuronal functional properties. Synaptic strengthening or weakening can reweight existing circuit connections, while structural changes including synapse addition and elimination create new connections. Posttranscriptional regulatory mechanisms, often also dependent on activity, further modulate activity-regulated gene transcript and protein function. Thus, activity-regulated genes implement varied forms of structural and functional plasticity to fine-tune brain circuit wiring.National Institutes of Health (U.S.). Ruth L. Kirschstein National Research Service Award (F31 NS069510)RO1 EY01189

Regulation of mammalian neuronal circuit development by CPG 15

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2012.Cataloged from PDF version of thesis.Includes bibliographical references.The orderly assembly of neuronal circuits is specified by developmental programs of gene expression, however, the final stage in circuit development, maturation and refinement of specific synaptic connections, is strongly influenced by neuronal activity. It is thus not surprising that the products of many activity-regulated genes have been implicated in synapse development and plasticity. The extracellular signaling protein CPG15 is one such activity-regulated gene product that promotes the maturation and growth of synapses, dendrites, and axonal arbors during development. Expression of cpg15 mRNA is spatiotemporally correlated with periods of synapse maturation and refinement, posing it to play a central role in the wiring of developing brain circuits. Here we utilize a mouse mutant, which is null for the cpg15 gene (cpg15 KO), to elucidate the mechanism of CPG15 function in the developing brain. Analysis of the cpg15 KO mouse suggests that CPG15 signaling leads to the selection and stabilization of synapses in the developing brain, as well as in the adult. Loss of CPG 15 results in reduced synapse numbers and synapse maturation with a corresponding reduction in the complexity and growth of neuronal arbors. This is most pronounced during early periods of promiscuous synapse formation and arbor growth that provide a physical substrate upon which subsequent experience-dependent processes act to sculpt mature patterns of neuronal connectivity. Consequently, cpg]5 KO mice do not appear to undergo the same extensive refinement as their wild type (WT) counterparts. cpg15 KO mice are also slow learners, requiring repeated training in learning tasks to perform at WT levels. These results led us to propose that the selection and stabilization of synapses by CPG15 mediates optimal wiring of developing neuronal circuits important for brain function throughout life. To test this possibility we investigated the function of CPG15 in the developing thalamocortical circuit in the visual system. The thalamus is the major hub for sensory information flow (minus olfaction) en route from the periphery to the cortex. As CPG15 is expressed in both input and target structures in this circuit we compared cortical synapse development in the global cpg15 KO mouse which lacks CPG15 expression in both the cortex and thalamus to a cortex-specific cpg15 KO mouse which retains thalamic expression of CPG15. Previous work has shown the importance of cortically-derived signaling factors in the maturation of thalamocortical circuits, however, we were surprised to find that CPG15 signaling by the thalamus has a stronger contribution to cortical synapse development than cortical CPG 15. This work reveals a novel function for thalamic signaling in the maturation of cortical circuits.by Jennifer H. Leslie.Ph.D

Building Capacity for Sustainability through Curricular and Faculty Development: A Learning Outcomes Approach

Portland State University has made integration of sustainability across its academic programs an institutional priority. This article describes the strategies that have been used to engage faculty in developing sustainability curricula, including adopting sustainability as one of eight campus-wide learning outcomes, incorporating sustainability into the general education program, providing faculty development, and developing a Graduate Certificate in Sustainability. The article shares lessons learned and next steps planned to advance Portland State\u27s sustainability curricula

Knowledge of and perceived need for evidence-based educational materials about antipsychotic medication safety by nursing home staff

Background: Given the widespread overuse of antipsychotic medications among US nursing home (NH) residents, we sought to identify knowledge of and perceived need for the AHRQ Comparative Effectiveness Research Summary Guide (CERSG) “Off-Label Use of Atypical Antipsychotic Drugs”. Methods: We conducted a baseline needs assessment with 12 NHs participating in a randomized controlled trail evaluating evidence dissemination strategies. Using a mixed method approach, we conducted in-depth assessments of knowledge, attitudes, and practice behavior using telephone interviews with NH leadership (administrators, directors of nursing [DON], and medical directors), and questionnaires with NH leadership, consultant pharmacists and direct care staff. Interviews were transcribed, verbatim responses were coded independently by 2 project staff. The coding scheme was revised after each round until substantial agreement (85%) was reached. Results: Interviews revealed that 70% of medical directors and 46% of DON and administrators believed that antipsychotics decreased agitation and controlled harmful behavior; 50% of medical directors and 7% of DONs & administrators reported knowledge of the increased risk of morbidity and mortality due to atypical antipsychotics. Half of administrators and DONs expressed interest in receiving information for NH staff pertaining to understanding dementia and dementia-related behaviors, 42% believed families would benefit from information about antipsychotic use for dementia-related behaviors. Questionnaire results were similar. When leaders were asked to list any risks associated with antipsychotic use for residents with dementia, only 17% reported death as a possible adverse event; licensed nursing staff (RN and LPNs) reported death 5% of the time. Over half of consultant pharmacists identified that their biggest barrier to improving medication use in challenging NHs was physician resistance to accepting recommendations. Conclusions: The responses of the NH leaders, staff and consultant pharmacists suggest widespread knowledge gaps regarding antipsychotic benefits and risks, and suggest a need for increase evidence dissemination and broad organizational change

Policy change to improve pathology turnaround time and reduce costs – possible to do both?

Background: Overcrowding and prolonged length of stay in emergency departments (ED) are increasing problems in hospitals. Rapid availability of all laboratory results has an impact on clinical decision-making, admissions or discharge decisions and resource utilisation. Increasing number of our urinary drugs of abuse (DOA) screens had a turnaround time (TAT) of up to 33 days after the discharge of the patient. Materials and methods: Following an audit and a consultation period with clinicians using the service, a policy change was implemented to reduce the use of gas chromatography mass spectroscopy (GCMS): all requests would have a standard immunoassay (IA) test panel undertaken unless specifically they requested GCMS (including medico-legal) analysis. Results: Almost all of the clinicians interviewed had no understanding of the DOA screening or the difference in the information generated between a confirmatory GCMS urine toxicology screen and IA DOA panel. It appeared none of the patients surveyed in the audit would have had a different clinical decision made if a GCMS had not been undertaken. Post change audit showed only 4.3% of drug requests for IA also received a confirmatory GCMS testing. The estimated saving post change implementation was $127,000 (AU$) in test costs alone over a two year period. The TAT of GCMS results was reduced to 3-4 days. Conclusion: A laboratory-led behavioural change in test requesting is possible and sustainable provided the reason is clinically sound and accompanied by consultation and availability of advice by phone when requested on test requesting or interpretation

Reducing Rehospitalizations through Automated Alerts to Primary Care Providers and Staff When Older Patients are Discharged from the Hospital: A Randomized Trial

Background: Inadequate continuity of care places older patients at very high risk during transitions from the hospital to ambulatory setting. Methods: We conducted a randomized controlled trial of an HIT-based transitional care intervention in patients aged 65 and older discharged from hospital to home. All patients were senior plan members of a Massachusetts-based health plan, and cared for by a multispecialty medical group using the EpicCare Ambulatory Medical Record. In addition to notifying providers about the patient’s recent transition, the system provided information about new drugs added during the inpatient stay, warnings about drug-drug interactions, recommendations for dose changes and laboratory monitoring of high-risk medications, and reminded the primary care provider’s support staff to schedule a post-hospitalization office visit. Randomization occurred at the time of hospital discharge during a one-year intervention period beginning in August 2010. Alerts were automatically delivered to the provider and staff in-basket within the EMR. The primary outcomes were: 1) having an outpatient office visit with the primary care provider within 30 days following discharge; and 2) having a rehospitalization within 30 days following discharge. Results: The study included 3667 discharges of which 1877 discharges were randomly assigned to the intervention arm. Forty-nine percent of discharges in the intervention arm were followed by office visits with the primary care provider within 30 days, compared to 51% in the comparison arm (RR 0.96, 95% CI 0.90, 1.03). Eighteen percent of discharges in the intervention arm were followed by a rehospitalization within 30 days compared to 20% in the comparison arm (RR 0.92, 95% CI 0.80, 1.05). Conclusions: This HIT-based intervention was not effective in increasing the percentage of hospital discharges of older patients that were followed by timely office visits to primary care providers or reducing the percentage with rehospitalization

Adverse Drug Events Post-Hospital Discharge in Older Patients: Types, Severity, and Involvement of Beers Criteria Medications

Objective: To characterize adverse drug events (ADEs) occurring within the high-risk 45-day period post-hospitalization in older adults. Design: Clinical pharmacists reviewed the ambulatory records of 1000 consecutive discharges. Setting: A large multispecialty group practice closely aligned with a Massachusetts-based health plan. Participants: Hospitalized patients aged 65 years and older who were discharged to home. Measurements: Possible drug-related incidents occurring during the 45-day period post-hospitalization were identified and presented to a pair of physician-reviewers who classified incidents as to whether an ADE was present, whether the event was preventable, and the severity of the event. Medications implicated in ADEs were further characterized according to their inclusion in the 2012 Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. Results: At least one ADE was identified during the 45-day period in 18.7% (187) of the 1000 discharges. Of the 242 ADEs identified, 35% (n=84) were deemed preventable, of which 32% (n=27) were characterized as serious, and 5% (n=4) as life threatening. Over half of all ADEs occurred within the first 14 days post-hospitalization. The percentage of ADEs in which Beers Criteria medications were implicated was 16.5% (n=40). Beers Criteria medications with both a high quality of evidence and strong strength of recommendation were implicated in 6.6% (n=16) of the ADEs. Conclusion: ADEs are common and often preventable among older adults following hospital discharge, underscoring the need to address medication safety during this high-risk period in this vulnerable population. Beers Criteria medications played a small role in these events suggesting that efforts to improve the quality and safety of medication use during this critical transition period must extend beyond a singular focus on Beers criteria medications

A Mixed-Methods Study To Characterize Pharmaceutical Marketing in the Nursing Home Setting: Off-Label Use of Atypical Antipsychotics

Background: Despite FDA warnings that atypical antipsychotic medications are associated with an increased risk of death when used to treat behavioral disorders in older adults with dementia, they are prescribed to nearly one-third of older U.S. nursing home (NH) residents. Reasons for their high use in NHs are poorly understood, but may include pharmaceutical marketing efforts in the NH setting. Methods: This study is nested within an ongoing cluster randomized trial to improve the use of atypical antipsychotics in NHs. We analyzed semistructured interviews (n = 36) and surveys (n = 139) of administrators, directors of nursing and medical directors from 62 NHs in Connecticut. Using prescription drug claims from a national long-term care pharmacy, we arrayed study NHs into lowest to highest tertile of atypical antipsychotic use. We tested for differences in the receipt of information or clinical tools from pharmaceutical company representatives (PCRs) to manage dementia-related behaviors by medication use tertiles, adjusting for NH profit status, size, quality (overall, health inspections, staffing) and staffing measures (daily nurse hours per resident). Results: Average baseline use of atypical antipsychotics ranged from 6.6 to 44.3 percent of all residents in the facility. Approximately one-quarter of NH leaders presently receive information on dementia-related behavioral management strategies from PCRs through detailing, in-service training, written or Web-based material or sponsorship as speakers. However, we did not detect statistically significant differences in the receipt of information by level of atypical antipsychotic use, NH characteristics, quality and staffing measures. Conclusions: This first attempt to characterize pharmaceutical marketing within the NH setting did not find differences among reports of marketing efforts with respect to medication use and facility-level characteristics. However, studies across a wider geographic area should continue investigating the possible role of marketing efforts on overall use and choice of atypical antipsychotics in the NH setting

Potent and Broad Inhibition of HIV-1 by a Peptide from the gp41 Heptad Repeat-2 Domain Conjugated to the CXCR4 Amino Terminus.

HIV-1 entry can be inhibited by soluble peptides from the gp41 heptad repeat-2 (HR2) domain that interfere with formation of the 6-helix bundle during fusion. Inhibition has also been seen when these peptides are conjugated to anchoring molecules and over-expressed on the cell surface. We hypothesized that potent anti-HIV activity could be achieved if a 34 amino acid peptide from HR2 (C34) were brought to the site of virus-cell interactions by conjugation to the amino termini of HIV-1 coreceptors CCR5 or CXCR4. C34-conjugated coreceptors were expressed on the surface of T cell lines and primary CD4 T cells, retained the ability to mediate chemotaxis in response to cognate chemokines, and were highly resistant to HIV-1 utilization for entry. Notably, C34-conjugated CCR5 and CXCR4 each exhibited potent and broad inhibition of HIV-1 isolates from diverse clades irrespective of tropism (i.e., each could inhibit R5, X4 and dual-tropic isolates). This inhibition was highly specific and dependent on positioning of the peptide, as HIV-1 infection was poorly inhibited when C34 was conjugated to the amino terminus of CD4. C34-conjugated coreceptors could also inhibit HIV-1 isolates that were resistant to the soluble HR2 peptide inhibitor, enfuvirtide. When introduced into primary cells, CD4 T cells expressing C34-conjugated coreceptors exhibited physiologic responses to T cell activation while inhibiting diverse HIV-1 isolates, and cells containing C34-conjugated CXCR4 expanded during HIV-1 infection in vitro and in a humanized mouse model. Notably, the C34-conjugated peptide exerted greater HIV-1 inhibition when conjugated to CXCR4 than to CCR5. Thus, antiviral effects of HR2 peptides can be specifically directed to the site of viral entry where they provide potent and broad inhibition of HIV-1. This approach to engineer HIV-1 resistance in functional CD4 T cells may provide a novel cell-based therapeutic for controlling HIV infection in humans