scholarly journals Cell-type and region-specific nucleus accumbens AMPAR plasticity associated with morphine reward, reinstatement, and spontaneous withdrawal

2019 ◽  
Author(s):  
Aric C. Madayag ◽  
Devan Gomez ◽  
Eden M. Anderson ◽  
Anna E. Ingebretson ◽  
Mark J. Thomas ◽  
...  

ABSTRACTDespite evidence that morphine-related pathologies reflect adaptations in NAc glutamate signaling, substantial gaps in basic information remain. The current study examines the impact of non-contingent acute, repeated, and withdrawal-inducing morphine dosing regimens on glutamate transmission in D1- or D2-MSNs in the NAcSh and NAcC sub-regions in hopes of identifying excitatory plasticity that may contribute to differing facets of opioid addiction-related behavior. Three hours following an acute morphine injection (10 mg/kg), average miniature excitatory postsynaptic current (mEPSC) amplitude mediated by AMPA-type glutamate receptors was increased at D1-MSNs in the both the shell and core regions, whereas only the frequency of events was elevated at D2-MSNs in the shell. In contrast, somatic withdrawal induced by escalating dose of repeated morphine twice per day (20, 40, 60, 80, 100mg/kg) only enhanced mEPSC frequency at D2-MSNs in the shell 24 hrs following the final drug exposure. Further, drug re-exposure 10-14 days following a preference-inducing regimen of morphine produced a rapid and enduring endocytosis of GluA2-containing AMPARs at D1-MSNs in the shell, that when blocked by an intra-NAc shell infusion of the Tat-GluA23Y peptide, increased reinstatement of morphine place preference – a phenomenon distinctly different than effects previously found with cocaine. The present study is the first to directly identify unique circuit specific adaptations in NAc glutamate synaptic transmission associated with morphine-related acute reward and somatic withdrawal as well as post-abstinence short-term plasticity. While differing classes of abused drugs (i.e., psychostimulants and opioids) produce seemingly similar bidirectional plasticity in the NAc following exposure to relapse-linked stimuli, our findings indicate this plasticity has distinct behavioral consequences.Compliance with Ethical StandardsThe authors have no conflicts of interest to disclose. All authors have given their consent for manuscript submission. The research in the current study used mice single- or group-housed on a 12 h light/dark cycle with food and water available ad libitum with experiments run during the light portion. All experiments were approved by the University of Minnesota and Marquette University Institutional Animal Care and Use Committee. The following funding sources made the study possible: National Institute for Neurological Disorders and Stroke (P30 NS062158); National Institute on Drug Abuse grant K99 DA038706 (to M.H.), R00DA038706 (M.H.), R00DA038706-04S1 (A.C.M), R01DA019666 (M.J.T.), K02DA035459 (M.J.T.) and T32 DA007234 (A.E.I.).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3377-3377
Author(s):  
Michael Burke ◽  
Barb Trotz ◽  
Qing Cao ◽  
Brenda Weigel ◽  
Ashish Kumar ◽  
...  

Abstract Abstract 3377 Poster Board III-265 Introduction: Allo-HCT with best available donor for children with Philadelphia positive (Ph+) ALL has previously been considered standard practice. Since the introduction of imatinib into the treatment of this disease, the role of allo-HCT is more uncertain. Patients and Methods: We investigated the impact of remission status, graft source, and imatinib use on transplant outcomes for thirty-seven children with Ph+ ALL who received an allo-HCT at the University of Minnesota between 1990 and 2006. The median age at HCT was 7.47 (range; 1.4 -16.4) years. Thirteen patients received imatinib therapy pre and/or post-HCT (imatinib group) and 24 patients, received either no imatinib (n=23) or only after post-HCT relapse (n=1) (non-imatinib group). Results: There was no difference in disease-free survival (DFS) or relapse between the imatinib and non-imatinib groups at 3 years (62% / 15% vs. 53% / 26%; p=0.99; 0.81, respectively). There was no significant difference in transplant outcomes between matched related donor or unrelated donor (umbilical cord blood or matched unrelated marrow) recipients whereas patients receiving allo-HCT in first remission (CR1) had superior DFS and less relapse compared to patients transplanted in ≥CR2 (71% / 16% vs. 29% / 36%; p=0.01; p=0.05). Conclusions: Based on this retrospective analysis at a single institution, the use of imatinib either pre and/or post-transplant does not appear to significantly impact outcomes for children with Ph+ ALL and allo-HCT with the best available donor should be encouraged in CR1. Disclosures: No relevant conflicts of interest to declare.


2021 ◽  
Vol 28 (Supplement_1) ◽  
Author(s):  
S Pallikadavath ◽  
R Patel ◽  
CL Kemp ◽  
M Hafejee ◽  
N Peckham ◽  
...  

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Cardiovascular adaptations as a result of exercise conducted at high-intensity and high-volume are often termed the ‘Athlete’s heart’. Studies have shown that these cardiovascular adaptations vary between sexes. It is important that both sexes are well represented in this literature. However, many studies assessing the impact of high-dose exercise on cardiovascular outcomes under-recruit female participants. Purpose This scoping review aimed to evaluate the representation of females in studies assessing the impact of high-dose exercise on cardiovascular outcomes and demonstrate how this has changed over time. Methods The scoping review protocol as outlined by Arksey and O’Malley was used. OVID and EMBASE databases were searched and studies independently reviewed by two reviewers. Studies must have investigated the effects of high-dose exercise on cardiovascular outcomes. To assess how the recruitment of females has changed over time, two methods were used. One, the median study date was used to categorise studies into two groups. Two, studies were divided into deciles to form ten equal groups over the study period. Mean percentage of female recruitment and percentage of studies that failed to include females were calculated. Results Overall, 250 studies were included. Over half the studies (50.8%, n = 127) did not include female participants. Only 3.2% (n = 8) did not include male participants. Overall, mean percentage recruitment was 18.2%. The mean percentage of recruitment was 14.5% before 2011 and 21.8% after 2011. The most recent decile of studies demonstrated the highest mean percentage of female recruitment (29.3%) and lowest number of studies that did not include female participants (26.9%). Conclusion Female participants are significantly underrepresented in studies assessing cardiovascular outcomes caused by high-dose exercise. The most recent studies show that female recruitment may be improving, however, this still falls significantly short for equal representation. Risk factors, progression and management of cardiovascular diseases vary between sexes, hence, translating findings from male dominated data is not appropriate. Future investigators should aim to establish barriers and strategies to optimise fair recruitment. Mean percentage females recruited per study (%) Percentage studies that do not include women (%) Overall (n = 250) 18.2 50.8 (n = 127) Studies before 2011 (n = 121) 14.5 59.5 (n = 72) Studies after 2011 (n = 129) 21.8 42.6 (n = 55) Table 1: Female recruitment characteristics. The year 2011 (median study year) was chosen as this divides all included studies into two equal groups.


2020 ◽  
Vol 30 (Supplement_5) ◽  
Author(s):  
◽  

Abstract The role of the corporate sector in research sponsorship is growing. So too is the evidence that corporations whose products are potentially damaging to health or the environment influence science and the ways in which science is used in policy and practice. Such efforts are a key part of corporate attempts to maintain or increase the consumption or use of industry products, and to secure favourable policy outcomes. The products and practices of corporations are responsible for a growing proportion of the global disease burden. Non-communicable diseases, many driven by consumption of unhealthy commodities and exposure to chemicals, account for over 73 percent of global deaths. It is increasingly important to understand the complex and multifaceted ways corporations seek to influence science; the impact these strategies have; and the ways this influence can be addressed. This workshop brings together global experts to explore these issues. Drawing on examples from several industries (e.g. tobacco, alcohol, food, and pharmaceuticals), it aims to: Increase understanding of the ways corporations whose products are potentially damaging to health influence science. We present a newly developed, evidence-based typology which draws together the vast existing literature in this field, to present a simplified way of understanding corporate influence on science. Delegates will be provided with materials that provide a means for recognising such influence.Examine the influence that corporations have on the first stage in the research process - research agendas. We present examples from tobacco, food and pharmaceutical industries which illustrate the mechanism through which industry funding of science drives researchers to study questions that are favourable to industry. The desired outcome is to maximise research on the benefits of industry products (positioning these products as solutions to complex problems), minimise research on the harms of their products, support their policy and legal positions, and impede potential regulation of their products.Increase awareness of the involvement that corporations have had in altering the mechanisms though which science is used in policymaking. Delegates will hear how corporations promoted and embedded policymaking reforms which increase reliance on and provide a conduit for industry-favourable science.Suggest ways forward concerning management of conflicts of interest in the publication of health research. Here we will discuss the roles that journals can play in governing conflicts of interest and issues of transparency in the publication of academic research.Suggest ways forward for funding research on unhealthy commodities. We present criteria for tobacco industry-supported research funding programs, and discuss the applicability of similar programs for funding research on other unhealthy commodities, and on the practices of other industries such as the fossil fuels industry. Key messages Corporations have been seen to skew evidence bases, manipulate interpretations of science, and influence use of science in policy and practice – such influence is a major threat to public health. This workshop exposes industry tactics in this area and begins to identify ways for dealing with them.


Author(s):  
David Busse ◽  
André Schaeftlein ◽  
Alexander Solms ◽  
Luis Ilia ◽  
Robin Michelet ◽  
...  

Abstract Purpose Systematic comparison of analysis methods of clinical microdialysis data for impact on target-site drug exposure and response. Methods 39 individuals received a 500 mg levofloxacin short-term infusion followed by 24-h dense sampling in plasma and microdialysate collection in interstitial space fluid (ISF). ISF concentrations were leveraged using non-compartmental (NCA) and compartmental analysis (CA) via (ii) relative recovery correction at midpoint of the collection interval (midpoint-NCA, midpoint-CA) and (ii) dialysate-based integrals of time (integral-CA). Exposure and adequacy of community-acquired pneumonia (CAP) therapy via pharmacokinetic/pharmacodynamic target-attainment (PTA) analysis were compared between approaches. Results Individual AUCISF estimates strongly varied for midpoint-NCA and midpoint-CA (≥52.3%CV) versus integral-CA (≤32.9%CV) owing to separation of variability in PK parameters (midpoint-CA = 46.5%–143%CVPK, integral-CA = 26.4%–72.6%CVPK) from recovery-related variability only in integral-CA (41.0%–50.3%CVrecovery). This also led to increased variability of AUCplasma for midpoint-CA (56.0%CV) versus midpoint-NCA and integral-CA (≤33.0%CV), and inaccuracy of predictive model performance of midpoint-CA in plasma (visual predictive check). PTA analysis translated into 33% of evaluated patient cases being at risk of incorrectly rejecting recommended dosing regimens at CAP-related epidemiological cut-off values. Conclusions Integral-CA proved most appropriate to characterise clinical pharmacokinetics- and microdialysis-related variability. Employing this knowledge will improve the understanding of drug target-site PK for therapeutic decision-making.


Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2341-2341
Author(s):  
Kouzbari Karim ◽  
Gostynska Sandra ◽  
Sonia Elhadad ◽  
Dube Pratibha ◽  
Jeffrey Laurence ◽  
...  

Combination antiretroviral therapies (cART) have markedly reduced mortality in HIV infection. However, cardiovascular disease (CVD), including heart failure linked to fibrosis, remains a major cause of morbidity and mortality in HIV/cART patients. The magnitude of this risk increases with use of certain protease inhibitors (PI), but the underlying mechanism remains unclear. We showed that the PI ritonavir leads to increased plasma levels of the pro-fibrotic cytokine TGF-β1, cardiac dysfunction, and pathologic cardiac fibrosis in wild-type (wt) C57BL/6 mice. Mice with targeted depletion of platelet TGF-β1 had reduced cardiac fibrosis and partially preserved cardiac function following ritonavir exposure (Laurence, et al. PLoS One 2017;12:e0187185). Several groups have examined the effects of a variety of cART agents on agonist-induced platelet aggregation, but correlations with clinical CVD are weak. Since platelets are a rich source of TGF-β1, we hypothesized that ritonavir and other PIs linked clinically to an increased CVD risk directly activate platelets to release TGF-β1 and activate latent (L)TGF-β1 to initiate signaling for organ fibrosis. We examined the impact of clinically relevant doses of ritonavir, alone and in combination with two other contemporary PIs, atazanavir and darunavir, which are currently used along with low dose ritonavir in so-called PI-boosted cART regimens. We incubated human platelet-rich plasma and washed platelets with PIs alone or in combinations at various doses for 10 min at 37°C in a platelet aggregometer (BioData. Corp). Total and active TGF-β1 levels were measured by ELISA. For in vivo assessment, we treated wt mice with a low dose of ritonavir, as used in PI-boosted cART, and measured the levels of plasma TGF-β1 by ELISA, and TGF-β1 signaling in tissues by immunofluorescence imaging for pSmad2. We found that ritonavir dose-dependently increased total TGF-β1 release from freshly-isolated platelet-rich plasma and washed human platelets. This release was blocked by ceefurin-1 and MK517, potent inhibitors of the ATP binding cassette transporter ABCC4. Darunavir alone did not cause release of TGF-β1, and did not alter significantly ritonavir-induced TGF-β1 release (Figure-1A). Atazanavir alone did induce release of TGF-β1 from platelets and did not affect the extent of such release induced by ritonavir (Figure-1A). Since total TGF-β1 released from platelets must be activated in order to signal, we tested whether these PIs could activate LTGF-β1. Ritonavir alone, in low dose, activated TGF-β1 by 4-5-fold (Fig-1B). Darunavir alone did not activate LTGF-β1, and had only a minor effect on ritonavir-induced TGF-β1 activation (Fig-1B). In marked contrast, while atazanavir also did not activate LTGF-β1, it significantly inhibited ritonavir-induced LTGF-β1 activation (Fig-1B). For in vivo assessment, wt mice were injected daily for 8 weeks with ritonavir, which dose-dependently increased plasma TGF-β1 levels (mean levels with vehicle 2.1 ng/ml; 6.4 ng/ml with 5 mg/kg ritonavir; 8.5 ng/ml with 10 mg/kg ritonavir). Increased TGF-β1 levels correlated with development of pathologic fibrosis and increased phosphorylated Smad signaling in hearts of ritonavir-treated vs. vehicle-treated mice. Clinical correlations with these in vitro and in vivo mouse studies are important. The fact that ritonavir effected both release and activation of platelet TGF-β1 is consistent with its ability to induce cardiac fibrosis and dysfunction in mice, and its association with accelerated CVD in HIV-infected individuals. Our findings that low dose ritonavir in combination with darunavir induced release and activation of platelet TGF-β1, whereas atazanavir blocked TGF-β1 activation, are consistent with the strong association of ritonavir-boosted darunavir, but not ritonavir-boosted atazanavir, with CVD in the setting of HIV (Ryom, et al. Lancet-HIV 2018;5:e291-e300). Future work will examine the effects of other contemporary cART agents, including cobicistat, which is currently replacing ritonavir in many PI-boosted therapies and some integrase-boosted regimens, on TGF-β1 release and activation, for which correlations with clinical CVD are not yet available. Identification of the mechanism of pathologic fibrosis in the heart, and potentially other organs affected by certain cART regimens, such as the kidney, may suggest specific therapeutic interventions. Disclosures No relevant conflicts of interest to declare.


EP Europace ◽  
2021 ◽  
Vol 23 (Supplement_3) ◽  
Author(s):  
A Cueva-Parra ◽  
G Munoz-Benavides ◽  
W Ortiz-Solis ◽  
J Gomez-Flores ◽  
MF Marquez ◽  
...  

Abstract Funding Acknowledgements Type of funding sources: None. Background - Introduction: The COVID-19 pandemic has generated serious repercussions on the health system, reducing the number of all cardiology procedures worldwide. Objectives Describe the impact of the COVID-19 pandemic on the procedures performed by the electrophysiology department in a national referral center.  Methods We made a retrospective review of our data base and we compared procedures made in the last 3 years since 2017 to 2019 with the procedures made in the 2020. We divide the procedures into two large groups: Cardiac Implantable Electronic Devices (CIED) related procedures (which included implants, revisions, changes, upgrades and extractions) and electrophysiological studies and ablations (which included conventional and complex procedures). Other types of procedures were no included. Results There was a significant reduction in all procedures, the average of procedures performed in the last 3 previous years was 467 (there were 479 in 2017, 411 in 2018 and 511 in 2019), while in 2020 we performed only 319 (p = 0.01); this represents a reduction of 33.4% in the total number of procedures performed in our center. There was no statistical difference regarding the CIED related procedures, the average of procedures of the last 3 previous years was 174 (there were 186 in 2017, 148 in 2018 and 188 in 2019), and in 2020 we performed 189 procedures, this value is near to the average of the last 3 previous years and very close to the value of the 2019 (p = 0.46). Regarding the electrophysiological studies and ablations, the average of procedures of the last 3 previous years was 293 (there were 293 in 2017, 263 in 2018 and 323 in 2019), while in 2020 we performed only 129 procedures, considerably decreasing compared to the previous years (p < 0.01). The reduction in the electrophysiological studies and ablations was 55.97%. The most affected months were April, May and June. Conclusions The COVID-19 pandemic considerably affected the number of electrophysiological procedures in our center, reducing it by 33.4% compared to the previous years. The reduction of procedures fundamentally affected the electrophysiological studies and ablations, reducing them by 55.97%. The number of CIED related procedures were no affected. Electrophysiological procedures Procedures2017201820192017-2019 average2020CIED related procedures186148188174189Electrophysiological studies and ablations293263323293129Total479411511467319Comparative table of the electrophysiological procedures performed in our center in recent years.Abstract Figure. Comparison of the procedures.


Author(s):  
Clifford Nangle ◽  
Stuart McTaggart ◽  
Margaret MacLeod ◽  
Jackie Caldwell ◽  
Marion Bennie

ABSTRACT ObjectivesThe Prescribing Information System (PIS) datamart, hosted by NHS National Services Scotland receives around 90 million electronic prescription messages per year from GP practices across Scotland. Prescription messages contain information including drug name, quantity and strength stored as coded, machine readable, data while prescription dose instructions are unstructured free text and difficult to interpret and analyse in volume. The aim, using Natural Language Processing (NLP), was to extract drug dose amount, unit and frequency metadata from freely typed text in dose instructions to support calculating the intended number of days’ treatment. This then allows comparison with actual prescription frequency, treatment adherence and the impact upon prescribing safety and effectiveness. ApproachAn NLP algorithm was developed using the Ciao implementation of Prolog to extract dose amount, unit and frequency metadata from dose instructions held in the PIS datamart for drugs used in the treatment of gastrointestinal, cardiovascular and respiratory disease. Accuracy estimates were obtained by randomly sampling 0.1% of the distinct dose instructions from source records, comparing these with metadata extracted by the algorithm and an iterative approach was used to modify the algorithm to increase accuracy and coverage. ResultsThe NLP algorithm was applied to 39,943,465 prescription instructions issued in 2014, consisting of 575,340 distinct dose instructions. For drugs used in the gastrointestinal, cardiovascular and respiratory systems (i.e. chapters 1, 2 and 3 of the British National Formulary (BNF)) the NLP algorithm successfully extracted drug dose amount, unit and frequency metadata from 95.1%, 98.5% and 97.4% of prescriptions respectively. However, instructions containing terms such as ‘as directed’ or ‘as required’ reduce the usability of the metadata by making it difficult to calculate the total dose intended for a specific time period as 7.9%, 0.9% and 27.9% of dose instructions contained terms meaning ‘as required’ while 3.2%, 3.7% and 4.0% contained terms meaning ‘as directed’, for drugs used in BNF chapters 1, 2 and 3 respectively. ConclusionThe NLP algorithm developed can extract dose, unit and frequency metadata from text found in prescriptions issued to treat a wide range of conditions and this information may be used to support calculating treatment durations, medicines adherence and cumulative drug exposure. The presence of terms such as ‘as required’ and ‘as directed’ has a negative impact on the usability of the metadata and further work is required to determine the level of impact this has on calculating treatment durations and cumulative drug exposure.


2021 ◽  
Author(s):  
Raphaelle Delattre ◽  
Jeremy Seurat ◽  
Feyrouz Haddad ◽  
Thu-Thuy Nguyen ◽  
Baptiste Gaborieau ◽  
...  

The clinical (re)development of phage therapy to treat antibiotic resistant infections requires grasping specific biological properties of bacteriophages (phages) as antibacterial. However, identification of optimal dosing regimens is hampered by the poor understanding of phage-bacteria interactions in vivo. Here we developed a general strategy coupling in vitro and in vivo experiments with a mathematical model to characterize the interplay between phage and bacterial dynamics during pneumonia induced by a pathogenic strain of Escherichia coli. The model estimates some key parameters for phage therapeutic efficacy, in particular the impact of dose and route of administration on phage dynamics and the synergism of phage and the innate immune response on the bacterial clearance rate. Simulations predict a low impact of the intrinsic phage characteristics in agreement with the current semi-empirical choices of phages for compassionate treatments. Model-based approaches will foster the deployment of future phage therapy clinical trials.


2019 ◽  
Vol 4 (2) ◽  
pp. 50-63
Author(s):  
Achraf Haddad ◽  
Anis El Ammari ◽  
Abdelfattah Bouri

According to the literature of corporate governance, ownership structure is advanced as a non-dissociable mechanism of control intended to follow the stakeholders and especially used by shareholders to monitor the conflicts of interest and the opportunistic behavior of managers. Several previous studies have focused on the impact of ownership structure on financial performance separately in conventional or in Islamic banks. However, the comparative studies between these two impacts are non-existent. In this research, we compared the impacts of this governance mechanism on the financial performance in the two types of banks by using the Ordinary Least Squares method. Data relating to financial performance and ownership structure of banks come from 16 countries. Two samples were collected: the first one included 63 conventional banks, whereas the second one integrated 63 Islamic banks whose data are available over the period (2010-2018). Panel results showed that partial effect of each determinant of ownership structure on each measure of financial performance varied from one banks’ type to another and from one performance measure to another. Besides, the reconciliation of similar models revealed many differences between the same impacts’ signs. Therefore, we concluded that in both banks’ types the ownership structure has a positive impact on the financial performance. While, the negative part of the same impact is less significant in Islamic banks. JEL Classification:  F33, G20, G21, G24, G30.


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