Search

Background: The Biobanque québécoise de la COVID-19 (Quebec Biobank for COVID-19, or BQC19) is a provincial initiative that aims to manage the longitudinal collection, storage, and sharing of biological samples and clinical data related to COVID-19. During the study, BQC19 investigators reported a high loss-to-follow-up rate. The current study aimed to explore motivational and attrition factors from the perspective of BQC19 participants and health care and research professionals., Methods: This was an inductive exploratory qualitative study. Using a theoretical sampling approach, a sample of BQC19 participants and professionals were invited to participate via semi-structured interviews. Topics included motivations to participate; participants' fears, doubts, and barriers to participation; and professionals' experiences with biobanking during the COVID-19 pandemic., Results: Interviews were conducted with BQC19 participants (n = 23) and professionals (n = 17) from 8 clinical data collection sites. Motivations included the contribution to science and society in crisis, self-worth, and interactions with medical professionals. Reasons for attrition included logistical barriers, negative attitudes about public health measures or genomic studies, fear of clinical settings, and a desire to move on from COVID-19. Motivations and barriers seemed to evolve over time and with COVID-19 trends and surges. Certain situations were associated with attrition, such as when patients experienced indirect verbal consent during hospitalization. Barriers related to human and material resources and containment/prevention measures limited the ability of research teams to recruit and retain participants, especially in the ever-evolving context of crisis., Conclusion: The pandemic setting impacted participation and attrition, either by influencing participants' motivations and barriers or by affecting research teams' ability to recruit and retain participants. Longitudinal and/or biobanking studies in a public health crisis setting should consider these factors to limit attrition., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved.)

Introduction: In mild asthma, as-needed budesonide-formoterol offers similar protection from severe exacerbations as daily inhaled corticosteroids (ICS), with lower ICS exposure but slightly increased symptoms. We sought to develop an electronic decision aid to guide discussions about the pros and cons of these first-line options, while identifying and integrating user preferences., Methods: Following International Patient Decision Aid Standards, we created a mild asthma decision aid prototype comparing convenience, clinical outcomes, cumulative ICS dose exposure, costs, and side-effects of each option. After face validation, the prototype was iteratively adapted through rapid-cycle development. Each cycle consisted of a patient focus group and a primary care physician interview. We made user preference-based improvements after each round, until reaching a pre-set stopping criterion (no new critical issues identified). We then performed a summative qualitative content analysis., Results: Over 5 cycles, we recruited 21 asthma patients (12/21 women, 10/21 ≥ 60 years old) and 5 physicians. Serial changes included simplification and reduction of text and reading level, inclusion of an ICS "myths" section and elaboration of patient-friendly infographics for numerical comparisons. User preferences fell within Content, Format, and tool use Process themes. In response to decision-making preferences, we created a complementary one-page conversation aid for patient-provider use at the point-of-care., Conclusions: We present preference-based electronic patient decision and conversation aids for treatment of mild asthma. Our user preference analyses offer useful insights for development of such tools in other chronic diseases. These tools now require integration into point-of-care workflows for measurement of real-world uptake and impact., Competing Interests: Declaration of competing interest MG, JLSC, AK, PMO, LPB, and AG declare that they have no competing interests in this work. JMF declares participating in advisory boards and receiving honoraria for lectures from AstraZeneca, GlaxoSmithKline, TEVA, Novartis, and Sanofi. JMF also reports the following research funding, paid directly to UBC: CIHR, NIH, AllerGen NCE and Astra Zeneca, GlaxoSmithKline, TEVA, Novartis, and Sanofi. SG owns the intellectual property for a practice-based asthma management decision support system called the Electronic Asthma Management System., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The aim of this study was to assess the impact of exposure to tap water lead concentration ([Pb] TW ) occurring in schools or daycares on blood lead level (BLL) of attending children. Given the potentially wide variations in space and time of ([Pb] TW ) documented in the literature, a simple probabilistic toxicokinetic (STK) model that allows the simulation of the time-varying evolution of BLL in response to these variations was developed. Thus, basic toxicokinetic equations were assembled to simulate BLL in a typical infant, toddler and pupil. The STK model's steady-state BLL predictions showed good correspondence when validated against Integrated Exposure and Uptake BioKinetic model predictions for comparable [Pb] TW values. Exposures to three distributions of [Pb] TW in specific sets of Canadian schools and daycares documented in the scientific literature were simulated probabilistically with Monte Carlo simulations. For the highest distribution of [Pb] TW simulated (median, 90th percentile = 24, 412 μg/L), average annual BLL (median, 97.5th percentile) varies between 1.5 and 6.4 μg/dL in infant and 1.1 and 3 μg/dL in pupils. Toddler's results were midway between those from the infants and pupils. Under this exposure scenario, the infant may present BLL > 5 μg/dL for a significant number of days over the course of the academic year (median; 97.5th: 17; 227 days). However, peak exposure may remain unnoticed if rare and drowned out by the background BLL. In conclusion, even if they may be sparse, peak exposure episodes to [Pb] TW in schools and daycares may suffice to increased BLL in attending individuals. This finding emphasizes the need for further characterization of [Pb] TW in schools and daycares in order to identify potentially problematic institutions and therefore avoid undesirable exposures for the children attending them., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: We sought to describe training activities on self-management support (SMS) for asthma educators and the effects of SMS provided by trained educators on asthma patient outcomes., Methods: We conducted a systematic review of six medical databases and sought for trials assessing SMS provided for adults with asthma by trained educators. Two reviewers independently selected and extracted data on asthma educators' training activities and patient outcomes. We performed meta-analyses for asthma-related quality of life (QoL) and asthma control., Results: We screened 3217 records and included 16 trials. Learning activities and assessments were reported in 8/16 and 4/16 trials, respectively. Compared to usual care, trained asthma educators provided SMS that resulted in clinically important improvements in QoL (pooled mean difference [MD] = 0.52; 95% confidence interval [95%CI]: 0.19 to 0.83) and asthma control (pooled MD= -0.68; 95%CI: -0.99 to -0.38)., Conclusion: Although asthma-specific SMS provided by trained educators had a beneficial effect over the current care, our results highlight the need to better describe training activities for asthma educators., Practice Implications: This systematic review provides key elements of efficient training activities for asthma educators and reaffirms the importance of training educators to provide SMS in order to improve asthma patients' QoL and asthma control., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Traditional approaches for chemical risk assessment cannot keep pace with the number of substances requiring assessment. Thus, in a global effort to expedite and modernize chemical risk assessment, New Approach Methodologies (NAMs) are being explored and developed. Included in this effort is the OECD Integrated Approaches for Testing and Assessment (IATA) program, which provides a forum for OECD member countries to develop and present case studies illustrating the application of NAM in various risk assessment contexts. Here, we present an IATA case study for the prediction of estrogenic potential of three target phenols: 4-tert-butylphenol, 2,4-di-tert-butylphenol and octabenzone. Key features of this IATA include the use of two computational approaches for analogue selection for read-across, data collected from traditional and NAM sources, and a workflow to generate predictions regarding the targets' ability to bind the estrogen receptor (ER). Endocrine disruption can occur when a chemical substance mimics the activity of natural estrogen by binding to the ER and, if potency and exposure are sufficient, alters the function of the endocrine system to cause adverse effects. The data indicated that of the three target substances that were considered herein, 4-tert-butylphenol is a potential endocrine disruptor. Further, this IATA illustrates that the NAM approach explored is health protective when compared to in vivo endpoints traditionally used for human health risk assessment., (Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.)

Objective: To assess whether adding a video on atrial fibrillation (AF) to a face-to-face educational session improves quality of life (QoL), knowledge, and health resource utilization (HRU) among AF patients., Methods: In this parallel clinical trial, adults with AF received a face-to-face educational session on AF and were randomly allocated to watch an educational video or not. Self-reported questionnaires measured QoL (primary outcome; score 0-100), AF knowledge (score 0-25), and HRU. Data were collected before and after interventions. Within- and between-group changes were estimated by mixed models., Results: Sixty participants (age: 56 ± 13 years; men: n = 41) were allocated to watch the video after education (n = 30) or to receive education only (n = 30). Within groups over time, QoL and knowledge significantly improved. Knowledge increased by 2.3 units (95% confidence interval: 0.5-4.1) more in participants who watched the video than in others (P = 0.014). Changes in QoL and HRU were not different between groups., Conclusion: Complementing education with a video on AF did not result in additional positive impacts on QoL and HRU among AF adults but led to greater improvements in AF knowledge., Practice Implications: The video on AF could be used as part of educational sessions to increase AF knowledge in AF patients., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Mitral valve replacement is technically challenging in the context of mitral annular calcification. A new surgical strategy is described that was used in a 71-year-old obese patient, where intraatrial prosthesis insertion and valve fixation into native uncalcified structures were performed without calcium debridement., (Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Few data are available on population-based access to specialised trauma care and its influence on patient outcomes in an integrated trauma system. We aimed to evaluate the influence of access to an integrate trauma system on in-hospital mortality and length of stay (LOS)., Methods: All adults admitted to acute care hospitals for major trauma [International Classification of Diseases Injury Severity Score (ICISS<0.85)] in a Canadian province with an integrated trauma system between 2006 and 2011 were included using an administrative hospital discharge database. The influence of access to an integrated trauma system on in-hospital mortality and LOS was assessed globally and for critically injured patients (ICISS<0.75), according to the type of injury [traumatic brain injury (TBI), abdominal/thoracic, spine, orthopaedic] using logistic and linear multivariable regression models., Results: We identified 22,749 injury admissions. In-hospital mortality was 7% and median LOS was 9 days for all injuries. Overall, 92% of patients were treated within the trauma system. Globally, patients who did not have access had similar mortality and LOS compared to patients who had access. However, we observed a 62% reduction in mortality for critical abdominal/thoracic injuries (odds ratio=0.38; 95% CI, 0.16-0.92) and an 8% increase in LOS for TBI patients (geometric mean ratio=1.08; 95% CI, 1.02-1.14) treated within the trauma system., Conclusions: Results provides evidence that in a health system with an integrated mature trauma system, access to specialised trauma care is high and the small proportion of patients treated outside the system, have similar mortality and LOS compared to patients treated within the system. This study suggests that the Québec trauma system performs well in its mandate to offer appropriate treatment to victims of injury that require specialised care., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Access to specialised trauma care is an important measure of trauma system efficiency. However, few data are available on access to integrated trauma systems. We aimed to describe access to trauma centres (TCs) in an integrated Canadian trauma system and identify its determinants., Methods: We conducted a population-based cohort study including all injured adults admitted to acute care hospitals in the province of Québec between 2006 and 2011. Proportions of injured patients transported directly or transferred to TCs were assessed. Determinants of access were identified through a modified Poisson regression model and a relative importance analysis was used to determine the contribution of each independent variable to predicting access., Results: Of the 135,653 injury admissions selected, 75% were treated within the trauma system. Among 25,522 patients with major injuries [International Classification of diseases Injury Severity Score (ICISS<0.85)], 90% had access to TCs. Access was higher for patients aged under 65, men and among patients living in more remote areas (p-value <0.001). The region of residence followed by injury mechanism, number of trauma diagnoses, injury severity and age were the most important determinants of access to trauma care., Conclusions: In an integrated, mature trauma system, we observed high access to TCs. However, problems in access were observed for the elderly, women and in urban areas where there are many non-designated hospitals. Access to trauma care should be monitored as part of quality of care improvement activities and pre-hospital guidelines for trauma patients should be applied uniformly throughout the province., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The ongoing need for public sector organizations to enhance their internal evaluation capacity is increasingly resulting in the use of hybrid evaluation project models, where internal evaluators work with external contracted evaluators to complete evaluative work. This paper first seeks to identify what is currently known about internal evaluation through a synthesis of the literature in this area. It then presents a case narrative illustrating how internal and external evaluation approaches may be used together to strengthen an evaluation project and to develop the evaluation capacity of the organization. Lessons learned include the need to integrate internal and external resources throughout the evaluation and to clarify expectations at the outset of the project., (Crown Copyright © 2011. Published by Elsevier Ltd. All rights reserved.)

Recent efforts worldwide have resulted in a growing database of measured concentrations of chemicals in blood and urine samples taken from the general population. However, few tools exist to assist in the interpretation of the measured values in a health risk context. Biomonitoring Equivalents (BEs) are defined as the concentration or range of concentrations of a chemical or its metabolite(s) in a biological medium (blood, urine, or other medium) consistent with an existing health-based exposure guideline, and are derived by integrating available data on pharmacokinetics with existing chemical risk assessments. This study reviews available health-based exposure guidance values for triclosan based on recent evaluations from the United States Environmental Protection Agency (US EPA), the European Commission's Scientific Committee on Consumer Products (EC SCCP) and the Australian National Industrial Chemicals Notification and Assessment Scheme (NICNAS). BE values corresponding to the reference dose (RfD) or margin of safety (MOS) targets from these agencies were derived based on kinetic data (urinary excretion and plasma clearance) from human studies and measured blood concentration data in animal studies. Estimated BE values for urinary total triclosan (free plus conjugates) corresponding to the US EPA RfD and the EC-identified margin of safety target from the NOAEL are 6.4 and 2.6 mg/L, respectively (corresponding to 8.3 and 3.3mg/g creatinine, respectively). Plasma BE values corresponding to the US EPA, EC, and Australian NICNAS values are 0.3, 0.9, and 0.4 mg/L, respectively. These values may be used as screening tools for evaluation of population biomonitoring data for triclosan in a risk assessment context., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Recent efforts worldwide have resulted in a growing database of measured concentrations of chemicals in blood and urine samples taken from the general population. However, few tools exist to assist in the interpretation of the measured values in a health risk context. Biomonitoring Equivalents (BEs) are defined as the concentration or range of concentrations of a chemical or its metabolite in a biological medium (blood, urine, or other medium) that is consistent with an existing health-based exposure guideline. BE values are derived by integrating available data on pharmacokinetics with existing chemical risk assessments. This study reviews available health-based exposure guidance values for bisphenol A (BPA) from Health Canada, the United States Environmental Protection Agency (USEPA) and the European Food Safety Authority (EFSA). BE values were derived based on data on BPA urinary excretion in humans. The BE value corresponding to the oral provisional tolerable daily intake (pTDI) of 25 microg/kg-d from Health Canada is 1mg/L (1.3mg/g creatinine); value corresponding to the US EPA reference dose (RfD) and EFSA tolerable daily intake (TDI) estimates (both of which are equal to 50 microg/kg-d) is 2mg/L (2.6 mg/g creatinine). These values are estimates of the 24-h average urinary BPA concentrations that are consistent with steady-state exposure at the respective exposure guidance values. These BE values may be used as screening tools for evaluation of central tendency measures of population biomonitoring data for BPA in a risk assessment context and can assist in prioritization of the potential need for additional risk assessment efforts for BPA relative to other chemicals., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

This paper presents Biomonitoring Equivalents (BEs) for inorganic arsenic. Biomonitoring Equivalents (BEs) are defined as the concentration or range of concentrations of a chemical or its metabolite in a biological medium (blood, urine, or other medium) that is consistent with an existing health-based exposure guideline, and are derived by integrating available data on pharmacokinetics with existing chemical risk assessments. This study reviews available health-based exposure guidance values for arsenic based on recent evaluations from the United States Environmental Protection Agency (US EPA), US Agency for Toxic Substances and Disease Registry (ATSDR) and Health Canada (HC). BE values corresponding to the Reference Dose (RfD) or risk-specific doses for cancer endpoints from these agencies were derived based on kinetic data (urinary excretion) from controlled dosing studies in humans. The BE values presented here provide estimates of the sum of inorganic arsenic-derived urinary biomarkers (inorganic arsenic, monomethylated arsenic, and dimethylated arsenic). The BE associated with the United States Environmental Protection Agency's Reference Dose and the Agency for Toxic Substances and Disease Registry's Minimal Risk Level is 6.4 microg arsenic/L urine. The BEs associated with the various cancer risk assessments are significantly lower. These BE values may be used as screening tools for evaluation of biomonitoring data for inorganic arsenic in a public health risk context., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Recent efforts worldwide have resulted in a growing database of measured concentrations of chemicals in blood and urine samples taken from the general population. However, few tools exist to assist in the interpretation of the measured values in a health risk context. Biomonitoring equivalents (BEs) are defined as the concentration or range of concentrations of a chemical or its metabolite in a biological medium (blood, urine, or other medium) that is consistent with an existing health-based exposure guideline. This study reviews available health-based exposure guidance values for hexachlorobenzene (HCB) from Health Canada, the United States Environmental Protection Agency (US EPA), the US Agency for Toxic Substances and Disease Registry (ATSDR) and World Health Organization (WHO). HCB liver tissue concentrations in chronic rodent bioassays and information on human elimination rates and tissue distribution of HCB were extrapolated to estimate serum lipid-adjusted HCB concentrations that are consistent with the exposure guidance values for HCB. Estimated serum lipid-adjusted HCB concentrations ranging from 16 to 250 ng/g lipid were consistent with non-cancer-based exposure guidance values from various agencies. Concentrations associated with cancer risk-specific doses at target risk levels of interest were also estimated. These BE values may be used as screening tools for evaluation of population biomonitoring data for HCB in a risk assessment context and can assist in prioritization of the potential need for additional risk assessment efforts for HCB relative to other chemicals., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Recent efforts worldwide have resulted in a growing database of measured concentrations of chemicals in blood and urine samples taken from the general population. However, few tools exist to assist in the interpretation of the measured values in a health risk context. Biomonitoring Equivalents (BEs) are defined as the concentration or range of concentrations of a chemical or its metabolite in a biological medium (blood, urine, or other medium) that is consistent with an existing health-based exposure guideline, and are derived by integrating available data on pharmacokinetics with existing chemical risk assessments. This study reviews available health-based exposure guidance values for cyfluthrin from Health Canada, the United States Environmental Protection Agency (USEPA), and the World Health Organization/Food and Agriculture Organization. BE values corresponding to the oral reference dose (RfD), or acceptable daily intake (ADI) estimates from these agencies were derived based on data on excretion fractions of the urinary metabolite 4-fluoro-3-phenoxybenzoic acid (FPBA), which is a metabolite specific to cyfluthrin. These values may be used as screening tools for evaluation of biomonitoring data for cyfluthrin as the metabolite FPBA in the context of existing risk assessments and for prioritization of the potential need for additional risk assessment efforts for cyfluthrin relative to other chemicals.

Recent efforts worldwide have resulted in a growing database of measured concentrations of chemicals in blood and urine samples taken from the general population. However, few tools exist to assist in the interpretation of the measured values in a health risk context. Biomonitoring Equivalents (BEs) are defined as the concentration or range of concentrations of an environmental chemical or its metabolite in a biological medium (blood, urine, or other medium) that is consistent with an existing health-based exposure guideline, and are derived by integrating available data on pharmacokinetics with existing chemical risk assessments. This study reviews available health-based exposure guidance values for di(2-ethylhexyl)phthalate (DEHP) from Health Canada, the United States Environmental Protection Agency (U.S. EPA), the Agency for Toxic Substances and Disease Registry (ATSDR), the European Chemicals Bureau (ECB), and the European Food Safety Authority (EFSA). BE values corresponding to the oral reference dose (RfD), minimal risk level (MRL) or tolerable daily intake (TDI) estimates from these agencies were derived based on data on excretion fractions of key urinary metabolites. BE values based on the sum of three, four, and five of the most predominant and commonly-measured metabolites of DEHP are presented. These values may be used as screening tools for evaluation of biomonitoring data for DEHP metabolites in the context of existing risk assessments and for prioritization of the potential need for additional risk assessment efforts for DEHP relative to other chemicals.

Recent efforts worldwide have resulted in a growing database of measured concentrations of chemicals in blood and urine samples taken from the general population. However, few tools exist to assist in the interpretation of the measured values in a health risk context. Biomonitoring Equivalents (BEs) are defined as the concentration or range of concentrations of a chemical or its metabolite in a biological medium (blood, urine, or other medium) that is consistent with an existing health-based exposure guideline, and are derived by integrating available data on pharmacokinetics with existing chemical risk assessments. This study reviews available health-based exposure guidance values for di-n-butyl phthalate (DBP), benzylbutyl phthalate (BzBP), and diethyl phthalate (DEP) from Health Canada, the United States Environmental Protection Agency (U.S. EPA), the Agency for Toxic Substances and Disease Registry (ATSDR), and the European Food Safety Authority (EFSA). BE values corresponding to the oral reference dose (RfD), minimal risk level (MRL) or tolerable daily intake (TDI) estimates from these agencies were derived for each compound based on data on excretion fractions of key urinary metabolites. These values may be used as screening tools for evaluation of biomonitoring data for metabolites of these three phthalate compounds in the context of existing risk assessments and for prioritization of the potential need for additional risk assessment efforts for each of these compounds relative to other chemicals.

This study was designed to investigate the potential use of in vitro matured, in vitro fertilized bovine zygotes for producing transgenic calves by microinjection of foreign DNA. In Experiment 1, the effect of centrifugation (4 min, 15,000 x g, 20 degrees C) on in vitro derived bovine zygotes was evaluated. In vitro development from 2 to 8 cells was not affected (80 vs 78%) when control zygotes (n = 211) were compared with zygotes treated (n = 210) 18 h post insemination. In Experiment 2, the influence of the centrifugation alone on the developmental potential of embryos was evaluated in rabbit oviducts for 120 h. The percentage of control and treated zygotes that developed to 1, 2 to 8, 8 to 32 and more than 32 cells were 7, 54, 10 and 10% vs 7, 40, 11 and 10%, respectively. In Experiment 3, the effect of pronuclear injection with plasmid containing CRF (corticotropin releasing factor) gene or pOCAT 330 Delta 1 plasmids; 2 microg/ml in Tris 10 mM, EDTA 0.2 mM, 18 to 20 h post insemination was evaluated by in vivo development in the rabbit oviduct. The embryos submitted only to centrifugation and vortexing resulted in a morula-blastocyst (> 32 cells) rate of 25% (n = 226) compared with the injected zygotes of which only 5% (n = 206) achieved the same stage. We conclude that in vitro produced bovine zygotes have a reduced developmental potential following microinjection, and this effect is not due to the centrifugation process.

The effects of neurotensin, 7.5 or 30 micrograms, on concentrations of DA, DOPAC, (HVA), serotonin 5-HT and 5-HIAA were measured in 8 regions of the rat brain either 5 or 30 min following intracerebroventricular administration. Regions examined include the frontal cortex, striatum, nucleus accumbens, amygdala, septum, hypothalamus, ventral tegmentum and substantia nigra. Results indicate that both doses of neurotensin significantly elevated concentrations of dopamine in the striatum and amygdala 5 min following injection. The effects of the peptide on DOPAC and HVA were more pervasive and enduring, with significant increases in metabolite levels occurring in both mesolimbic and nigrostriatal terminal regions. In order to assess effects on turnover of dopamine, the ratios of each metabolic to dopamine concentrations were examined. Results indicate that, while the DOPAC/DA ratio was elevated in many regions, the HVA/DA ratio was increased in all regions examined. The effects of neurotensin on serotoninergic parameters were less pervasive and more variable, with both increases and decreases in 5-HT and 5-HIAA concentrations being observed. The effects of the peptide on 5-HIAA/5-HT were limited to the nucleus accumbens, where this ratio was increased, and the ventral tegmentum, where 5-HIAA/5-HT was decreased. These findings reveal that the effects of the neurotensin on dopaminergic transmission are more widespread than previously reported in that all major dopamine pathways are affected by the peptide. Also, the observed changes in the ratios of both DOPAC and HVA to DA suggest that neurotensin enhances the turnover of this transmitter.

The effects of neurotensin on the strong and persistent hyperactivity induced in rats by intra-accumbens administration of ADTN, a potent dopamine agonist, were examined. Neurotensin was administered intraventricularly as well as bilaterally into the accumbens. With both routes of administration neurotensin significantly decreased the hyperactivity produced by ADTN. However, important differences in doses required to produce this effect were noted between the two routes of administration. Whereas intraventricular injection of doses as small as 0.05 micrograms neurotensin was sufficient to reduce hyperactivity, bilateral intra-accumbens administration of at least 1.8 micrograms was required to replicate the effect. ADTN induced hyperactivity was also significantly decreased by intraventricular and intra-accumbens injections of the structural analog [D-Tyr11]-NT. In both routes of administration, the inhibitory action of the analog was more persistent than that observed with neurotensin. As was the case for neurotensin, intraventricular administration of [D-Tyr11]-NT was more potent than intra-accumbens injections. Finally, the results of a preliminary experiment indicate that neurotensin injected intraventricularly can also decrease hyperactivity elicited by intra-accumbens administration of dibutyryl cyclic AMP. Taken together, the results of the present study demonstrate that neurotensin can affect hyperactivity elicited by a strong and persistent activation of mesolimbic dopamine receptors or by stimulation of events beyond these receptors. The observed greater efficacy of intraventricularly administered neurotensin in decreasing ADTN induced hyperactivity suggests an action of the peptide on regions distant from the accumbens, probably on efferent outputs of mesolimbic stimulation.

Relationships between structure and duration of neurotensin's central action were examined. Included in the study were analogs containing amino acid substitutions at purported enzymatic cleavage sites of neurotensin: the arg8-arg9, the Pro10-Tyr11, and the Tyr11-Ile12 peptide bonds. Peptides were administered in rats via the cerebro-ventricular route and the ensuing hypothermia was monitored repeatedly until the effect dissipated. Results indicate that substitutions of the Tyr11 residue of the neurotensin molecule with either Dopa, Trp, D-Trp, or D-Tyr yielded analogs displaying markedly increased durations of action. Substitutions at other sites did not alter the time course of neurotensin's hypothermic effect. The longest acting analog was [Dopa11]-NT. At a dose of 7.5 micrograms the hypothermia induced by this analog persisted for 660 min while the effect of a same dose of neurotensin endured for only 90 min after injection. No clear correlation was found between the relative potency of analogs and their duration of action. Taken together, the results confirm the predominant role of Tyr11 in the inactivation of neurotensin by the brain, but do not support the hypothesis that relative potencies of structural analogs are solely dependent on differing susceptibilities to enzymatic degradation.