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IntroductionPostoperative delirium is common in older patients. Despite its prognostic significance, the pathophysiology is incompletely understood. Although many risk factors have been identified, no reversible factors, particularly ones potentially modifiable by anaesthetic management, have been identified. The goal of this prospective cohort study was to investigate whether intraoperative hypotension was associated with postoperative delirium in older patients undergoing major non-cardiac surgery.MethodsStudy subjects were patients >65 years of age, undergoing major non-cardiac surgery, who were enrolled in an ongoing prospective observational study of the pathophysiology of postoperative delirium. Intraoperative blood pressure was measured and predefined criteria were used to define hypotension. Delirium was measured by the Confusion Assessment Method on the first two postoperative days. Data were analysed using t-tests, two-sample proportion tests and ordered logistic regression multivariable models, including correction for multiple comparisons.ResultsData from 594 patients with a mean age of 73.6 years (sd 6.2) were studied. Of these 178 (30%) developed delirium on day 1 and 176 (30%) on day 2. Patients developing delirium were older, more often female, had lower preoperative cognitive scores, and underwent longer operations. Relative hypotension (decreases by 20, 30, or 40%) or absolute hypotension [mean arterial pressure (MAP)

Introduction: Postoperative delirium is common in older patients. Despite its prognostic significance, the pathophysiology is incompletely understood. Although many risk factors have been identified, no reversible factors, particularly ones potentially modifiable by anaesthetic management, have been identified. The goal of this prospective cohort study was to investigate whether intraoperative hypotension was associated with postoperative delirium in older patients undergoing major noncardiac surgery. Methods: Study subjects were patients >65 years of age, undergoing major non-cardiac surgery, who were enrolled in an ongoing prospective observational study of the pathophysiology of postoperative delirium. Intraoperative blood pressure was measured and predefined criteria were used to define hypotension. Delirium was measured by the Confusion Assessment Method on the first two postoperative days. Data were analysed using t-tests, two-sample proportion tests and ordered logistic regression multivariable models, including correction for multiple comparisons. Results: Data from 594 patients with a mean age of 73.6 years (SD 6.2) were studied. Of these 178 (30%) developed delirium on day 1 and 176 (30%) on day 2. Patients developing delirium were older, more often female, had lower preoperative cognitive scores, and underwent longer operations. Relative hypotension (decreases by 20, 30, or 40%) or absolute hypotension [mean arterial pressure (MAP)<50mmHg] were not significantly associated with postoperative delirium, nor was the duration of hypotension (MAP)<50mmHg). Conversely, intraoperative blood pressure variancewas significantly associated with postoperative delirium. Discussion: These results showed that increased blood pressure fluctuation, not absolute or relative hypotension, was predictive of postoperative delirium. [ABSTRACT FROM AUTHOR]

Plasma-derived therapeutic proteins are produced through an industrial fractionation process where proteins are purified from individual intermediates, some of which remain unused and are discarded. Relatively few plasma-derived proteins are exploited clinically, with most of available plasma being directed towards the manufacture of immunoglobulin and albumin. Although the plasma proteome provides opportunities to develop novel protein replacement therapies, particularly for rare diseases, the high cost of plasma together with small patient populations impact negatively on the development of plasma-derived orphan drugs. Enabling therapeutics development from unused plasma fractionation intermediates would therefore constitute a substantial innovation. To this objective, we characterized the proteome of unused plasma fractionation intermediates and prioritized proteins for their potential as new candidate therapies for human disease. We selected ceruloplasmin, a plasma ferroxidase, as a potential therapy for aceruloplasminemia, an adult-onset ultra-rare neurological disease caused by iron accumulation as a result of ceruloplasmin mutations. Intraperitoneally administered ceruloplasmin, purified from an unused plasma fractionation intermediate, was able to prevent neurological, hepatic and hematological phenotypes in ceruloplasmin-deficient mice. These data demonstrate the feasibility of transforming industrial waste plasma fraction into a raw material for manufacturing of new candidate proteins for replacement therapies, optimizing plasma use and reducing waste generation., (© 2024. The Author(s).)

Globally, noise exposure from occupational and nonoccupational sources is common, and, as a result, noise-induced hearing loss affects tens of millions of people. Occupational noise exposures have been studied and regulated for decades, but nonoccupational sound exposures are not well understood. The nationwide Apple Hearing Study, launched using the Apple research app in November 2019 (Apple Inc., Cupertino, CA), is characterizing the levels at which participants listen to headphone audio content, as well as their listening habits. This paper describes the methods of the study, which collects data from several types of hearing tests and uses the Apple Watch noise app to measure environmental sound levels and cardiovascular metrics. Participants, all of whom have consented to participate and share their data, have already contributed nearly 300 × 10 6  h of sound measurements and 200 000 hearing assessments. The preliminary results indicate that environmental sound levels have been higher, on average, than headphone audio, about 10% of the participants have a diagnosed hearing loss, and nearly 20% of the participants have hearing difficulty. The study's analyses will promote understanding of the overall exposures to sound and associated impacts on hearing and cardiovascular health. This study also demonstrates the feasibility of collecting clinically relevant exposure and health data outside of traditional research settings.

The opioid epidemic is the most significant modern-day, public health crisis. Physicians and lawmakers have developed methods and practices to curb opioid use. This article describes one method, prescription drug monitoring programs (PDMP), through the lens of how to optimize use for emergency departments (ED). EDs have rapidly become a central location to combat opioid abuse and drug diversion. PDMPs can provide emergency physicians with comprehensive prescribing information to improve clinical decisions around opioids. However, PDMPs vary tremendously in their accessibility and usability in the ED, which limits their effectiveness at the point of care. Problems are complicated by varying state-to-state requirements for data availability and accessibility. Several potential solutions to improving the utility of PDMPs in EDs include integrating PDMPs with electronic health records, implementing unsolicited reporting and prescription context, improving PDMP accessibility, data analytics, and expanding the scope of PDMPs. These improvements may help improve clinical decision-making for emergency physicians through better data, data presentation, and accessibility., Competing Interests: Conflicts of Interest: By the WestJEM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. No author has professional or financial relationships with any companies that are relevant to this study. There are no conflicts of interest or sources of funding to declare.

Drug dilution (MIC) and disk diffusion (DIA) are the 2 most common antimicrobial susceptibility assays used by hospitals and clinics to determine an unknown pathogen's susceptibility to various antibiotics. Since only one assay is commonly used, it is important that the 2 assays give similar results. Calibration of the DIA assay to the MIC assay is typically done using the error-rate bounded method, which selects DIA breakpoints that minimize the observed discrepancies between the 2 assays. In 2000, Craig proposed a model-based approach that specifically models the measurement error and rounding processes of each assay, the underlying pathogen distribution, and the true monotonic relationship between the 2 assays. The 2 assays are then calibrated by focusing on matching the probabilities of correct classification (susceptible, indeterminant, and resistant). This approach results in greater precision and accuracy for estimating DIA breakpoints. In this paper, we expand the flexibility of the model-based method by introducing a Bayesian 4-parameter logistic model (extending Craig's original 3-parameter model) as well as a Bayesian nonparametric spline model to describe the relationship between the 2 assays. We propose 2 ways to handle spline knot selection, considering many equally spaced knots but restricting overfitting via a random walk prior and treating the number and location of knots as additional unknown parameters. We demonstrate the 2 approaches via a series of simulation studies and apply the methods to 2 real data sets., (Copyright © 2017 John Wiley & Sons, Ltd.)

Purpose of the Study: This study determined whether self-reports of unmet need for help with activities of daily living (ADL) disabilities are prognostic of emergency department (ED) utilization., Design and Methods: This prospective cohort study of 2,194 community-living, ADL-disabled subjects combined 2004 National Long-Term Care Survey responses with linked Medicare data through 2005. A negative binomial count model was computed to assess the association between unmet ADL need and number of subsequent ED admissions while statistically adjusting for predisposing, enabling, and need characteristics associated with ED admissions among older adults., Results: The adjusted annual incidence rate (IR) for ED admissions was 19% higher for unmet versus met need (IR = 1.19; 95% confidence interval [CI] = 1.00-1.40; p = .047). The IR for ED admissions for falls and injuries was higher for those with unmet ADL versus met ADL need (IR = 1.43; 95% CI = 1.10-1.86), and trended toward significance for ED admissions for skin breakdown (IR = 2.02; 95% CI = 0.97-2.88), but was not significant for ED admissions for dehydration (IR = 1.13; 95% CI= 0.79-1.63)., Implications: Unmet ADL need is prognostic of ED admissions, especially for falls and injuries. Future research is needed to determine whether resolution of unmet ADL need reduces ED utilization., (© The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The determination of diffusion test breakpoints has become a challenging issue due to the increasing resistance of microorganisms to antibiotics. Currently, the most commonly-used method for determining these breakpoints is the modified error-rate bounded method. Its use has remained widespread despite the introduction of several model-based methods that have been shown superior in terms of precision and accuracy. However, the computational complexities associated with these new approaches has been a significant barrier for clinicians. To remedy this, we developed and examine the utility of a free online software package designed for the determination of diffusion test breakpoints: dBETS (diffusion Breakpoint Estimation Testing Software). This software package allows clinicians to easily analyze data from susceptibility experiments through visualization, error-rate bounded, and model-based approaches. We analyze four publicly available data sets from the Clinical and Laboratory Standards Institute using dBETS., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Whether postoperative subsyndromal delirium (SSD) is a separate syndrome from delirium and has clinical relevance is not well understood., Objectives: We sought to investigate SSD in older surgical patients and to determine its prognostic significance., Methods: We performed a prospective cohort study of patients who were 65 years or older and were scheduled for noncardiac surgery. Postoperative delirium was determined using the Confusion Assessment Method. SSD was defined as the presence of at least one of the possible 10 symptoms of delirium, as defined by the Confusion Assessment Method, but not meeting the criteria for delirium., Results: The number of features of SSD on the first postoperative day was associated with the subsequent development of delirium on the next day, after controlling for other risk factors. When compared with a patient with no SSD features, a patient with 1 SSD feature was 1.07 times more likely to have delirium on the next day (95% CI: 0.42-2.53), with 2 features was 3.32 times more likely to have it (95% CI: 1.42-7.57), and with ≥ 2 features was 8.37 times more likely to have it (95% CI: 4.98-14.53). Furthermore, there was a significant relationship between the number of features of SSD and increased length of hospital stay and worsened functional status at 1 month after surgery., Conclusions: SSD is prevalent in at-risk surgical patients and has prognostic significance. Only a single symptom of SSD was sufficient to cause a significant increase in hospital length of stay and further decline in functional status. These results suggest that monitoring for SSD is indicated in at-risk patients., (Copyright © 2015 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Postoperative delirium and cognitive dysfunction are frequent phenomena in older patients; however, few studies have examined the temporal relationship between these two conditions in the early postoperative period. Therefore, this study aimed to determine if postoperative delirium and postoperative cognitive dysfunction (POCD) coexist after major noncardiac surgery., Methods: This was a prospective cohort study of patients who were ≥ 65 yr of age undergoing noncardiac surgery. Patients were evaluated preoperatively and for two days postoperatively for delirium and POCD. Delirium was determined using the Confusion Assessment Method, and POCD was measured by three cognitive tests addressing changes in executive function, memory, attention, and concentration. For each postoperative day, patients' neurologic status was categorized into three mutually exclusive categories: delirium, POCD, or neither condition., Results: Four hundred sixty-one patients aged ≥ 65 yr of age were studied, and 421 patients with complete postoperative cognitive testing were reported. Eighty percent of patients experienced either delirium or POCD on the first day after surgery. Seventy percent of patients who had delirium on the first postoperative day also had delirium on the second postoperative day. Sixty-three percent of patients who had POCD on postoperative day one continued to have POCD on the next day. Sixteen percent of patients with delirium on day one were non-delirious on day two but met criteria for POCD on day two. Conversely, 15% of patients with POCD on day one became delirious on day two. Only 13% of patients did not experience delirium or POCD on either day after surgery., Conclusions: Eighty percent of surgical patients experienced some form of cognitive dysfunction the day after surgery, and few recovered by the second day after surgery.

Purpose: This study determined whether returning to the community from a recent hospitalization with unmet activities of daily living (ADL) need was associated with probability of readmission., Methods: A total of 584 respondents to the 1994, 1999, and/or 2004 National Long-Term Care Surveys (NLTCS) who were hospitalized within 90 days prior to the interview and reported ADL disability at the time of the interview were considered for analysis. Medicare claims linked to the NLTCS provided information about hospital episodes, so those enrolled in Health Maintenance Organizations or Veterans Affairs Medical Centers were not included (n = 62), resulting in a total sample size of 522. ADL disability was defined as needing human help or equipment to complete the task. Unmet ADL need was defined as receiving inadequate or no help for one or more ADL disabilities. Disability that began within 90 days of the interview was considered new disability., Results: After adjusting for demographic, health, and functioning characteristics, unmet ADL need was associated with increased risk for hospital readmission (HR: 1.37, 95% CI: 1.03-1.82). Risk of readmission was greater for those with unmet need for new disabilities than those with unmet need for disabilities that were present before the index hospitalization (HR: 1.66, 95% CI: 1.01-2.73)., Implications: Many older patients are discharged from the hospital with ADL disability. Those who report unmet need for new ADL disabilities after they return home from the hospital are particularly vulnerable to readmission. Patients' functional needs after discharge should be carefully evaluated and addressed.

We assessed the influence of serum 25-hydroxyvitamin D (25[OH]D) and parathyroid hormone (PTH) concentrations on oral glucose tolerance, body composition, and muscle strength in older, nondiabetic adults who performed resistance exercise training (RT) while consuming diets with either 0.9 or 1.2 g protein kg(-1) d(-1). We hypothesized that individuals with insufficient 25(OH)D and/or high PTH would have less improvement in glucose tolerance after 12 weeks of RT compared with individuals with sufficient 25(OH)D and lower PTH. Sixteen men and 19 women (aged 61 ± 8 years; range, 50-80 years; body mass index, 26.3 ± 3.6 kg/m(2)) performed RT 3 times/wk for 12 weeks, with oral glucose tolerance tests done at baseline and postintervention. Protein intake did not influence the responses described below. Plasma glucose area under the curve (P = .02) and 2-hour plasma glucose concentration (P = .03) were higher for vitamin D-insufficient subjects (25[OH]D <50 nmol/L, n = 7) vs vitamin D-sufficient subjects (25[OH]D ≥50 nmol/L, n = 28). These differences remained significant after adjustment for age and body mass index. Resistance exercise training reduced fat mass (mean ± SD, -6% ± 7%; P < .001) and increased lean body mass (2% ± 3%, P < .001) and whole-body muscle strength (32% ± 17%, P < .001) in these weight-stable subjects but did not affect 25(OH)D or PTH concentrations. Oral glucose tolerance improved after RT (-10% ± 16% in glucose area under the curve and -21% ± 40% in 2-hour glucose, P = .001), but baseline 25(OH)D and PTH did not influence these RT-induced changes. These findings indicate that vitamin D status and RT independently affect glucose tolerance, and a training-induced improvement in glucose tolerance does not offset the negative effect of insufficient vitamin D status in older, nondiabetic adults., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: There are a variety of techniques to handle missing data, such as removing observations with missing data from the analyses or estimating the missing values using various imputation algorithms. Dropping subjects from standard regression models and analyzing only completers, however, may bias results from the true value of reality. Likewise, 'last-observation-carried-forward' may not be an appropriate technique for studies measuring a particular variable over time., Methods: This dataset was part of a larger prospective cohort study that examined postoperative cognitive decline (POCD) after surgery in older adults. Data collectors had provided the reasons for data being missing using adjectives including 'confused', 'incapable', 'stuporous', 'comatose', and 'intubated'. Data having these qualitative notations were re-coded as 'incapable' and trial scores of zero were recorded. This value of '0' indicated that the patient was cognitively incapable of performing the neuropsychological test., Results: Missing data varied by cognitive test and postoperative day. Re-coding word list scores from missing to zero when a patient was too cognitively impaired to complete the tests improved sample size by 13.5% of postoperative day (POD) 1 and 12.8% on POD 2. Recoding missing data to zero for the digit symbol test resulted in 29.3% larger sample size on POD 1 and 22.7% on POD 2. Verbal fluency gained 15.7% sample size with re-coding for POD 1 and 13.7% for POD 2. Re-coding of each cognitive test reduced missing data sample size to 20-32% in all cognitive tests for each day., Discussion: Our data suggest that using a scoring system that enters a value of '0' when patients are unable to perform cognitive testing did significantly increase the number of patients that met the diagnosis of postoperative cognitive decline using the criteria that were determined a priori and may lessen chances of type II error (failure to detect a difference)., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objectives: To determine whether intraoperative blood transfusion, a known trigger and amplifier of inflammation, is an independent risk factor for early postoperative delirium (POD), an acute state of confusion with fluctuating consciousness and inattention after surgery, in older adults undergoing surgery., Design: Secondary analysis using a database created for a prospective cognitive outcomes study., Setting: University hospital., Participants: Four hundred seventy-two individuals aged 65 and older undergoing major noncardiac surgery., Measurements: Perioperative data were examined for association with POD on the first postoperative day. Multivariable logistic regression analysis was conducted to determine whether intraoperative blood transfusion independently predicts POD after adjusting for covariates known to be associated with onset of delirium and blood transfusions., Results: One hundred thirty-seven individuals (29%) developed delirium on the first postoperative day. The multivariable logistic regression model identified age, sex, history of central nervous system disorder, preoperative cognitive dysfunction, and pain, as well as blood transfusions, as independent risk factors for POD. Intraoperative administration of more than 1,000 mL of red blood cells (RBCs) was the strongest predictor of POD on the first postoperative day (odds ratio = 3.68; 95% confidence interval = 1.32–10.94; P < .001)., Conclusion: Intraoperative blood transfusion of more than 1,000 mL of RBCs increases the risk of delirium on the first postoperative day in older adults undergoing noncardiac surgery.

Surface enhanced Raman spectroscopy (SERS) is a rapid and highly sensitive spectroscopic technique that has the potential to measure chemical changes in bacterial cell surface in response to environmental changes. The objective of this study was to determine whether SERS had sufficient resolution to differentiate closely related bacteria within a genus grown on solid and liquid medium, and a single Arthrobacter strain grown in multiple chromate concentrations. Fourteen closely related Arthrobacter strains, based on their 16S rRNA gene sequences, were used in this study. After performing principal component analysis in conjunction with Linear Discriminant Analysis, we used a novel, adapted cross-validation method, which more faithfully models the classification of spectra. All fourteen strains could be classified with up to 97% accuracy. The hierarchical trees comparing SERS spectra from the liquid and solid media datasets were different. Additionally, hierarchical trees created from the Raman data were different from those obtained using 16S rRNA gene sequences (a phylogenetic measure). A single bacterial strain grown on solid media culture with three different chromate levels also showed significant spectral distinction at discrete points identified by the new Elastic Net regularized regression method demonstrating the ability of SERS to detect environmentally induced changes in cell surface composition. This study demonstrates that SERS is effective in distinguishing between a large number of very closely related Arthrobacter strains and could be a valuable tool for rapid monitoring and characterization of phenotypic variations in a single population in response to environmental conditions.

Cocaine-induced increases in dopamine (DA) contribute importantly to cocaine effects on behavior but, the role of concomitant increases in norepinephrine (NE) and serotonin (5-HT) is less well understood. In order to selectively block the increases in NE and 5-HT evoked by cocaine, autoreceptor preferring low doses (0.01, 0.025 and 0.05 mg/kg) of the a2 agonist, Clonidine or the 5-HT1A agonist, 8-OHDPAT were given as pretreatments 20 min prior to saline or cocaine (10.0 mg/kg) in separate groups of rats (N=10). With pharmacological stimulation of NE and 5-HT autoreceptors, release of these neurotransmitters would be suppressed and, therefore, less available for re-uptake blockade by cocaine. With increasing dose levels, Clonidine had marked inhibitory effects on spontaneous and cocaine-induced locomotion, grooming and rearing. 8-OHDPAT pretreatment also suppressed spontaneous locomotion, grooming and rearing; but, in contrast, did not reduce the cocaine locomotor stimulant effects. 8-OHDPAT, however, did suppress central zone entry and rearing in cocaine treated rats. Using ex vivo methods, we found that 8-OHDPAT selectively reduced 5-HT metabolism in the medial frontal cortex (MFC) and subcortical limbic brain. Clonidine selectively reduced NE metabolism in the MFC, but decreased both DA and 5-HT metabolism in the subcortical limbic brain without affecting NE metabolism. This diverse and broad spectrum of Clonidine effects upon neurotransmitters and behavior is striking and points-up the important, complex and integrative role of NE in brain function. While both Clonidine and 8-OHDPAT can substantially attenuate a number of cocaine behavioral effects, these inhibitory effects appear to be secondary to reductions in the behavioral baseline rather than reversals of cocaine effects.

Repeated cocaine treatments typically generate sensitization effects which are environment specific. In this study, we investigated whether drug treatments with highly selective receptor specificity can also function as contextual cues to control the expression of cocaine sensitization effects. Two experiments were conducted in which separate groups of rats (N=10) received ten paired or unpaired cocaine (10.0 mg/kg) treatments. In the experiments, autoreceptor preferring low doses of either the 5-HT1A agonist, 8-OHDPAT (8OH) (0.05 mg/kg) or the D1/D2 agonist apomorphine (APO) (0.05 mg/kg) were administered 20 min prior to cocaine administration and test environment placement (paired treatment). Under these conditions, the drug cues generated by the 8OH/APO treatments were associated with the cocaine stimulant effect in the test environment. The unpaired treatment groups received the same drug treatments but the cocaine was administered after testing, in the homecage. Consequently, for these groups, the 8OH/APO drug cues generated by the drug treatments would not become associated with the cocaine stimulant effect in the test environment. Critically, both 8OH and APO pretreatments elicited equivalent unconditioned response effects which were opposite to the cocaine unconditioned response effects; that is, behavioral inhibition vs. behavioral stimulation. Initially, the 8OH and APO pretreatments prevented the locomotor stimulant effects of cocaine; but, these inhibitory effects were reversed in the paired groups with repeated cocaine treatments, consistent with the emergence of cocaine sensitization effects. In the unpaired 8OH and APO pretreatment groups, behavioral suppression persisted throughout the treatment protocol. Subsequently, paired and unpaired groups were compared in four conditioning/sensitization tests. The conditioning tests included: a saline/saline test; and a 8OH/saline test (Experiment 1); and, a saline/saline test and a APO/saline test (Experiment 2). There were no paired/unpaired group differences in these conditioning tests. The sensitization tests included: a saline/cocaine test; and a 8OH/cocaine test (Experiment 1); and, a saline/cocaine test and a APO/cocaine test (Experiment 2). There were no paired/unpaired group differences in the saline/cocaine test for sensitization but paired/unpaired group differences were found in both the 8OH/cocaine and APO/cocaine sensitization tests. In these tests the paired but not the unpaired groups exhibited cocaine locomotor sensitization effects. Critically when, in an additional test, the pretreatments in the cocaine tests were reversed (i.e., 8OH paired group received APO and APO paired group received 8OH prior to cocaine), then there was no evidence for cocaine sensitization. Since the 8OH/APO pretreatments had equivalent inhibitory response effects, it was the stimulus properties of these drugs which controlled the expression of the cocaine locomotor sensitization effects. These findings support the critical role of associative processes in the stimulus-gating of psychostimulant drug sensitization. Importantly, this report incorporates a new methodology in which context can be specified in terms of highly specific brain receptor targets rather than in terms of global environmental situational cues.

Recently it was shown that the combined pretreatment with low autoreceptor preferring dose levels of apomorphine (0.05 mg/kg) and 8-OHDPAT (0.05 mg/kg), which decrease dopaminergic and serotonergic activity, induces a profound behavioral inhibition and also blocks the stimulant effects of cocaine. In two experiments, we report that the acute blockade of spontaneous and cocaine locomotor stimulant effects by pretreatment with 8-OHDPAT (0.05 mg/kg) plus apomorphine (0.05 mg/kg) is dose-dependently (0.0 2.5, 5.0, and 10.0 mg/kg cocaine) reversed with repeated cocaine treatments. Using a paired vs. unpaired Pavlovian conditioning protocol, we found that this reversal by cocaine (10 mg/kg) of the inhibition by the combined 8-OHDPAT plus apomorphine pretreatment occurred for the paired but not the unpaired cocaine treatment. The findings suggest that this reversal of behavioral inhibition is mediated by the transformation of the drug cues generated by 8-OHDPAT and apomorphine into cocaine-conditioned stimuli which can activate behavior.

The psychostimulant effects of cocaine critically depend on the serotonergic (5-HT) system, of which the 5-HT1A receptor is an essential component. We recently showed divergent contributions of various pre- and postsynaptic 5-HT1A receptor populations to the behavioral effects of cocaine. Here, we further investigate the role of 5-HT1A autoreceptors in the acute and chronic stimulant effects of cocaine using 5-HT1A receptor ligands in autoreceptor preferring doses. In experiment 1, four groups of rats (N = 10) received either saline or the 5-HT1A agonist, 8-OHDPAT (0.05 mg/kg) 20 min prior to a saline or cocaine (10 mg/kg) injection on 9 consecutive days. In experiment 2, six groups (N = 10) were given either saline, the 5-HT1A antagonist, WAY 100635 (0.05 mg/kg) or 8-OHDPAT (0.05 mg/kg) plus WAY 100635 (0.05 mg/kg) 20 min before a saline or cocaine (10.0 mg/kg) treatment on 9 consecutive days. Initially, both the 8-OHDPAT and WAY 100635 pretreatments completely blocked the locomotor stimulant effects of cocaine whereas the combined 8-OHDPAT plus WAY 100635 pretreatment had no effect. In saline treated groups, neither the WAY 100635 nor the 8-OHDPAT plus WAY 100635 pretreatment influenced spontaneous activity levels, whereas the 8-OHDPAT alone severely reduced spontaneous activity. These effects persisted over the course of the 9 test sessions. A different pattern of results was obtained for the cocaine treatment groups. With repeated treatments, the WAY 100635 treatment always blocked the locomotor activation effect of cocaine, whereas the effects of 8-OHDPAT were transformed from an inhibition to an enhancement of cocaine locomotor stimulation. The combined 8-OHDPAT plus WAY 100635 pretreatment did not affect the stimulant effect of cocaine. These findings demonstrate that low dose autoreceptor preferring treatments with a 5-HT1A agonist and antagonist can strongly modify the behavioral stimulant effects of cocaine and suggest that the 5-HT1A autoreceptor may be an important pharmacological target for the development of treatments for cocaine addiction.

Evidence, even if not univocal, of increase of systolic and diastolic blood pressure for Pb doses lower than 30 microg/dl stimulated studies in the last years and opened a discussion on a possible relapse in morbility and mortality, since hypertension is an important factor of cardiovascular risk. In this study, it was possible to investigate the relationship between lead and blood pressure of 303 subjects occupationally exposed to this metal with blood-Pb between 10 and 80 microg/dl and 206 subjects belonging to the general population with blood-Pb between 0.5 and 9 microg/dl. In both groups it resulted a positive and statistically significant correlation between blood-Pb values and systolic and diastolic blood pressure values, in detail in hypertensive subjects, belonging to the not-occupationally exposed group, this effect is proportionally higher. The effect of lead on blood pressure appears therefore proved, as confirmed by previous literature, but taking into consideration three specific information. It presents itself in a large range of doses, it is quantitatively very modest, it appears more evident at low doses, thus we could hypothesize different mechanisms for different doses.

The pairing of cocaine treatments with a specific test environment typically leads to cocaine-conditioned drug effects. In this study, we first pre-exposed rats 10 times to an open-field environment to establish an habituation asymptote in locomotor activity prior to the initiation of cocaine treatments. Two groups (N=10) equated for locomotion, grooming, central zone penetrations and rearing behavior were used. One group received five pairings of cocaine (10.0 mg/kg) and the second group five pairings of saline injections with placements in the open-field environment. Subsequently, both groups received a saline test to detect possible cocaine-conditioned behavioral effects. During the cocaine treatment phase, cocaine enhanced locomotion and central zone penetrations but decreased rearing and grooming. On the conditioning test, the cocaine group exhibited enhanced central zone penetrations and decreased grooming as compared to the saline group. There were no group differences in locomotion or rearing. When within group comparisons were performed between behavioral responses on the pre-conditioning test vs. the conditioning test, the saline group scores were essentially unchanged. In contrast, the cocaine group exhibited higher central zone penetrations and decreased grooming without changes in locomotion or rearing. In that a cocaine conditioning test can also be viewed as a cocaine withdrawal test, two additional experiments were conducted using an unpaired conditioning protocol to test for withdrawal effects without conditioning. These results indicated that the central zone and grooming effects observed in the conditioning protocol were not withdrawal effects. Altogether, these findings provide support for Pavlovian conditioning of cocaine-induced changes in emotion-related behavioral responses.

Rationale: The contribution of the 5-HT(1A) somato-dendritic autoreceptor populations to spontaneous and cocaine-induced locomotion is unclear., Objectives: To use a low dose range of +/-8-hydroxy-2-(di- n-propylamino)tetralin (8-OHDPAT) to preferentially stimulate 5-HT(1A) autoreceptors and a medium 8-OHDPAT dose range to stimulate both 5-HT(1A) autoreceptors and postsynaptic receptors as pretreatments prior to either saline or cocaine., Methods: In experiment 1, either a medium dose of 8-OHDPAT (0.4 mg/kg) or a low dose (0.05 mg/kg) was given as pretreatments 20 min before five separate 20-min open-field tests. In experiment 2, the pretreatments were changed to a low dose range of 8-OHDPAT (0.01-0.05 mg/kg), with or without WAY 100635 (0.01-0.05 mg/kg). In experiment 3, the 8-OHDPAT pretreatments (0.01, 0.025 or 0.05 mg/kg) were administered 20 min prior to saline or cocaine (10 mg/kg) tests. In experiment 4, a medium dose range (0.2-0.3 mg/kg) was given 20 min prior to saline or cocaine (10 mg/kg) tests., Results: Experiment 1 showed that 8-OHDPAT (0.4 mg/kg) tended to increase locomotor activity but that pretreatment with 0.05 mg/kg severely suppressed locomotor activity. In experiment 2, 8-OHDPAT in the low dose range inhibited locomotor activity and this effect was reversed by co-administration of WAY 100635. Experiment 3 showed that the low-dose 8-OHDPAT pretreatment reduced locomotor activity in saline but not cocaine tests. In experiment 4, 8-OHDPAT in the medium dose range enhanced locomotor activity in cocaine tests., Conclusions: It is suggested that the facilitatory effect of 8-OHDPAT on cocaine-induced locomotor stimulation is mediated by inhibition of 5-HT(1A) somato-dendritic autoreceptors.

We used the D(2) receptor agonist, apomorphine (APO) and the 5-HT(1A) receptor agonist, 8-OHDPAT (8OH) in a low dose range to stimulate autoreceptors and in this way assess the separate and combined effects of reduced DA and 5-HT activity upon spontaneous and cocaine induced locomotor behavior. Two separate experiments were conducted. In the first experiment, separate groups of rats (N=10) were tested with either saline, 8OH, APO or 8OH plus APO (0.01, 0.025, 0.05 mg/kg). At 0.05 mg/kg, 8OH and APO induced similar dose related decreases (up to approximately 50%) in locomotor activity. The combined 8OH plus APO treatment induced dose-related decreases in locomotion (approximately 90%). At the 0.05 mg/kg dose level, the drug treatments given separately blocked cocaine induced increases in activity and the 8OH and APO inhibitory effects were again additive. In the second experiment, separate groups (N=10) received saline, 0.05 mg/kg APO, 0.05 mg/kg 8OH or 0.05 mg/kg APO plus 0.05 mg/kg 8OH. As in the first experiment, the 8OH and APO given separately reduced locomotor activity by approximately 50% and when given together, locomotor activity was virtually eliminated (reduced 80-90%). When the combined APO/8OH group also received the 5-HT(1A) antagonist, WAY 100635 (0.05 mg/kg), the effect on activity was equivalent to 0.05 mg/kg APO alone. Ex vivo neurochemical measurement of dopamine (DA) and serotonin (5-HT) metabolism confirmed that the APO decreased DA turnover, 8OH decreased 5-HT turnover and the combined treatment reduced both the DA and 5-HT turnover. Thus, for both spontaneous and cocaine induced locomotor behavior, the low dose 8OH and APO treatments suppressed locomotor activity and these effects were additive. These findings indicate that DA and 5-HT systems contribute separately to motoric activation. These results suggest that it is important to consider both DA and 5-HT contributions to disorders of motoric impoverishment such as Parkinson's disease as well as to hyperkinetic states such as those induced by stimulant drugs.

Rationale: An animal's response to novelty has been suggested to be a predictor of its response to drugs of abuse. The possible relationship between an individual's behavioral response to novelty and its subsequent behavioral response to cocaine has not been subjected to a detailed correlational analysis., Objective: To use a repeated cocaine treatment protocol to induce cocaine sensitization and conditioned cocaine locomotor stimulant effects and to assess the relationship of these effects to pre-cocaine locomotor behavior in a novel environment., Methods: In two separate experiments, rats were given a 20-min test in a novel open-field environment. Subsequently, the rats were given a series of additional tests in conjunction with either saline or cocaine (10 mg/kg) treatments to induce cocaine sensitization and conditioned effects., Results: The repeated cocaine treatments induced cocaine behavioral sensitization and conditioned effects. Correlational analyses showed that the initial 20-min novel environment test proved to be a strong predictor of an animal's subsequent saline activity level but did not predict the rats' behavioral acute and sensitized response to cocaine. When change in activity was used as the dependent variable, initial activity level was reliably negatively correlated with activity changes on cocaine tests as well as cocaine conditioning tests., Conclusions: The negative correlation between initial activity in a novel environment and the change in activity induced by cocaine indicates that low responders to environmental novelty tend to have the strongest response to cocaine. These results appear consistent with the classic initial value and response rate dependent analyses of stimulant drug effects.

Foundry ambient air contains very high concentrations of noxious substances, such as particulate matter and gaseous pollutants, which can target the respiratory epithelium. Serum concentrations of the 16-kDa Clara cell protein (CC16-S) may reflect both the integrity of the epithelial barrier and smoke-induced Clara cell toxicity. To evaluate whether CC16-S is a sensitive biomarker of early respiratory disturbances, it was determined in a group of 35 foundry male workers (aged 41.1 +/- 6.9 years) examined both prior to and at the end of their work-shift (06:00 a.m.-02:00 p.m.). Exposure to inhalable/respirable dusts and PAH was characterized; urinary excretion of 1-hydroxypyrene (1-OH-P) and naphtol was measured to assess exposure to pyrene and naphthalene, respectively. CC16 serum levels decreased at the end of the shift (10.7 +/- 3.82 micrograms/L vs. 8.39 +/- 3.05 micrograms/L; p < 0.01); such decrements were significantly larger in more exposed workers. Although smokers had lower baseline values as compared to non smokers, both subgroups showed an average decrease of 30% in CC16-S concentrations at the end of shift. CC16-S was also negatively correlated with 1-OH-P, but not with naphtol concentrations. Decreased CC16-S levels can result from citotoxicity and would represent an useful biomarker of pneumotoxicity in foundry workers exposed to complex mixtures.

Cocaine has potent locomotor stimulant effects in rodents, which seemingly can become conditioned to test environment cues. In two experimental protocols, we measured the effects of cocaine on locomotor activity and grooming behavior, and subsequently tested whether these cocaine effects became conditioned to contextual cues. In the first experiment, three groups of rats received 14 injections of either saline or cocaine (10 mg/kg) paired or unpaired to the test environment. Cocaine increased locomotion and decreased grooming during treatment and on the conditioning test. Over the course of the treatment phase, however, the saline- and cocaine-unpaired groups but not the cocaine paired group developed progressively lower locomotion and higher grooming scores indicative of substantial habituation effects. To examine whether the cocaine may have impaired the acquisition of habituation effects rather than induce a Pavlovian cocaine conditioned response, an additional experiment was conducted in which two additional non-habituation saline and cocaine control groups were added to the experimental design. On a conditioning test, the two non-habituation control groups were equivalent in activity and grooming behavior to the cocaine-paired group. The findings were consistent with a failure by cocaine-paired animals to acquire habituation effects, which could transfer to the non-cocaine state. The connection between cocaine and novelty/habituation may have substantial importance for understanding cocaine effects.

An increase in the extracellular dopamine (DA) concentration is generally accepted as an important neurochemical mediator of the behavioral effects of cocaine. Cocaine induced increases in serotonergic (5-HT) activity also appears to be involved in these effects. Here we describe the effects of the 5-HT(1A)-receptor antagonist WAY 100635 on the behavioral and neurochemical effects of cocaine. In-vivo microdialysis was used in behaving rats to measure extracellular concentration of DA in the nucleus accumbens (Nac). Four groups of animals received one of the following drug combinations: WAY 100635 (0.4 mg/kg) and cocaine (10 mg/kg), saline and cocaine (10 mg/kg), WAY 100635 (0.4 mg/kg) and saline, or saline and saline. The injections were administered i.p. and spaced 20 min apart. The pretreatment with WAY 100635 significantly attenuated the locomotor stimulant effects of cocaine without altering the DA overflow in the Nac. WAY 100635 itself did not modify locomotion or the extracellular DA concentration in the Nac. These results indicate that (1) the 5-HT(1A)-receptor is an important component in the mediation of cocaine locomotor stimulant effects, and (2) an increase in the extracellular DA concentration in the Nac might be a necessary but is not a sufficient condition for the locomotor stimulant effects of cocaine., (Copyright 2002 Elsevier Science B.V.)

The effects of the 5-HT1A agonist, (+/-)-8-hydroxy-dipropylaminotetralin (8-OHDPAT) upon the unconditioned and conditioned behavior induced by cocaine were assessed in rats. Separate groups (n=7) received saline, cocaine (10 mg/kg), 8-OHDPAT (0.2 mg/kg), or 8-OHDPAT (0.2 mg/kg) plus cocaine (10 mg/kg) for eight treatment sessions (two per week) in which the rats were tested for 20 min in an open-field. On the eighth treatment session, cocaine enhanced locomotion and rearing but decreased grooming. 8-OHDPAT also decreased grooming and, when given in combination with cocaine, enhanced locomotion but attenuated cocaine-induced rearing. The two 8-OHDPAT groups differed substantially from each other and from the cocaine group in terms of locomotion during the drug treatment phase. Subsequently, all groups received a series of conditioning tests in which they received saline, 0.1, 0.2, or 0.4 mg/kg 8-OHDPAT prior to testing. Groups which had received either 8-OHDPAT or cocaine prior to the conditioning tests exhibited equivalent conditioned effects on the saline conditioning test. When conditioning tests were conducted with 8-OHDPAT, however, only the group which had previously received the combined 0.2 mg/kg 8-OHDPAT plus cocaine treatment exhibited a conditioned response and this effect only occurred at the 0.2 8-OHDPAT dose level. These observations indicate the important influence of the stimulus properties of drugs for the study of drug conditioning and for understanding drug interactions with cocaine.