Ancillary Finding Research Articles

Exploring the Potential Value of [ 68 Ga]Ga-FAPI-46 PET/CT for Molecular Assessment of Fibroblast Activation in Interstitial Lung Disease : A Single-Center Pilot Study.

The aim of the study was to evaluate the association of high-resolution computed tomography (HRCT) findings with pulmonary fibrotic activity in the corresponding regions using [ 68 Ga]Ga-fibroblast activation fibroblast inhibitor (FAPI) PET/CT in patients with interstitial lung disease (ILD). Additionally, the potential of [ 68 Ga]Ga-FAPI-46 PET/CT for evaluating the active fibrosis process and 99m Tc-MIBI scintigraphy for assessing the inflammatory process in ILD patients was also assessed. In this pilot study, 20 ILD patients underwent [ 68 Ga]Ga-FAPI-46 PET/CT and 99m Tc-MIBI SPECT/CT. Additionally, 10 patients without lung or thoracic involvement who were undergoing [ 68 Ga]Ga-FAPI PET/CT for cancer detection were enrolled in the control group. The images were evaluated both visually and semiquantitatively and also compared with HRCT and pulmonary function tests. Multiple quantitative parameters were derived from the lung segments in the PET scan, including SUV max , SUV mean , maximum target-to-liver ratio, mean target-to-liver ratio (TLR mean ), and total lesion FAPI expression for the entire lung, as well as its lobes and zones. Additionally, the maximum Hounsfield unit (HU) and mean HU in HRCT were calculated for the whole lung as well as its lobes and zones. Furthermore, an HRCT fibrosis score (HFS) was defined according to the HRCT findings. Twenty ILD patients with a mean age of 58.70 (SD, 11.09) years were enrolled. Additionally, 10 control patients were enrolled with a mean age of 57.70 (SD, 15.19) years. Based on visual assessment, the FAPI scan was positive in 12 (60%) patients. Similarly, the MIBI scan was positive in 12 (60%) patients. In the 20 ILD cases, both scans were positive in 6 cases, and both were negative in 2 cases. Six cases showed FAPI-negative and MIBI-positive results, whereas another 6 cases showed FAPI-positive and MIBI-negative results. Comparing the control and ILD patients, there was a significant difference in SUV max , SUV mean , total lesion FAPI expression, TLR mean , maximum HU, and mean HU ( P < 0.05). When comparing HFS with PET-derived parameters in zones, a significant positive correlation was found between HFS and SUV mean , SUV max , maximum target-to-liver ratio, and TLR mean ( P < 0.05). Additionally, a significant difference was noted between FAPI results and HFS ( P = 0.003). An ancillary finding, 9 of 20 (45%) ILD patients showed intense FAPI uptakes in gallbladder, whereas none of the 10 in the control group showed such uptake. The present study may suggest that combining [ 68 Ga]Ga-FAPI PET/CT and 99m Tc-MIBI SPECT/CT yields an additive effect for evaluating ILD-related fibrosis and inflammatory processes over using either modality alone. Furthermore, it appears that [ 68 Ga]Ga-FAPI PET/CT has the potential to ascertain levels of fibrotic activity from population of resident fibroblasts, active fibroblasts, and scar maturation among ILD patients based on their HRCT patterns.

Scandal at the Albrechtsburg: The Hoym–Lemaire affair and its impact on the early 18th‐century development of pigment technology at the Meissen Manufactory

AbstractWe present portable X‐ray fluorescence data on the composition of body, glaze and enamels of several Meissen porcelain objects associated with the Hoym–Lemaire Affair (1728–1731). In 1728, the French merchant Rodolphe Lemaire convinced the Meissen Porcelain Manufactory into making copies of Japanese Kakiemon porcelain for sale as originals in Paris, a dubious enterprise that depended on the development of additional pigments closely emulating the Kakiemon palette. We shall illustrate how the color formulations for these objects, designed to imitate Japanese porcelain, differ from those on earlier porcelain from 1723–24, as well as later (mid‐18th century) objects. In all cases, the colorant chemistry can be related to special recipes introduced by Johann Gregorius Höroldt specifically for this purpose and preserved in the Meissen archives. A surprising observation is the absence of antimony or tin in the yellow colorant. As an ancillary finding, we have confirmed analytically for the first time that unmarked, undecorated Meissen porcelain in storage since prior to 1725 was decorated around 1730 and became part of the Hoym–Lemaire shipment.

Weather risks, crop losses, and risk proneness: An examination of evolving risk preferences of rice farmers in Bangladesh

Changing climate poses significant challenges for smallholder rice farmers. Weather-related deviations from longer-term patterns and crop losses due to abiotic hazards can affect farmer risk preferences and drive adaptive responses. In addition, farmers’ proneness to and past experiences with crop risks such as drought, submergence, and excess soil salinity can impact their baseline risk preferences and their response to changing risks. Using data for Bangladesh from two waves of the Rice Monitoring Survey, climate-related data (precipitation and temperature), farmer reports of crop losses, and measures of proneness to abiotic risks, this article estimates how weather deviations from longer-term trends, crop losses, and proneness to crop risks (submergence, drought, and soil salinity) affect elicited risk preferences over time. This research finds evidence in favor of the hypothesis that larger absolute seasonal deviations from past patterns of seasonal mean daily minimum temperature and seasonal total precipitation yield increased risk aversion. In addition, the research provides mixed evidence with respect to risk proneness and farmers’ change in risk preferences over time. Contrary to our original hypothesis, individuals with land more prone to soil salinity become more risk averse rather than less, but, consistent with our hypothesis, those with land more prone to crop submergence become more risk preferring over time. Because of differences in crop experiences and degrees of proneness to risk, risk preferences for farmers in different regions are predicted to evolve along different pathways. This article contributes to the literature on risk preference formation by considering the possibility that less significant deviations than shocks might also contribute to evolving risk preferences. In addition, the article emphasizes the regional heterogeneity of changing preferences. An ancillary finding of this work suggests that risk preferences are only weakly related over time, contrary to other findings in the literature on the stability of risk preferences. Of policy relevance, the differential experiences in weather variability at the regional and local levels yield important differences in changes in preferences and should give rise to careful, regional-level policies to support adaptation to changing weather.

Windswept Deformity a Disease or a Symptom? A Systematic Review on the Aetiologies and Hypotheses of Simultaneous Genu Valgum and Varum in Children.

Objective: The objective of this study is to create an overview of the possible aetiologies of windswept deformity and to emphasize the points of attention when presented with a case. Methods: A systematic search according to the PRISMA statement was conducted using PubMed, African Journals Online, Cochrane, Embase, Google Scholar, and Web of Science. Articles investigating the aetiology of windswept deformity at the knee in children, and articles with windswept deformity as an ancillary finding were included. The bibliographic search was limited to English-language articles only. The level of evidence and methodological appraisal were assessed. Results: Forty-five articles discussing the aetiology of windswept deformity were included. A variety of aetiologies can be brought forward. These can be divided into the following groups: ‘Rickets and other metabolic disorders’, ‘skeletal dysplasias and other genetic disorders’, ‘trauma’ and ‘descriptive articles without specific underlying disorder’. With rickets being the largest group. Interestingly, in the group without a specific underlying disorder, all patients were from African descent, being otherwise healthy and presented with windswept deformity between two and three years of age. Conclusion: We have presented an overview that may help identify the underlying disorder in children with windswept deformity. A step-by-step guide for clinicians who see a child with windswept deformity is provided. Even though, according to the Oxford level of evidence, most articles have a low level of evidence.

Ancillary Finding on Myocardial Perfusion Imaging Due to Urinary Bladder Displacement.

When imaging patients are referred for single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) with technetium 99m (99mTc) agents, the attention is focused on the tracer activity in the myocardium. Apart from myocardial activity, the normal biodistribution of 99mTc Sestamibi and 99mTc Tetrofosmin is seen in the thyroid, liver, gastrointestinal tract, kidneys, and urinary bladder. These structures may be visualized when a large field of view (FOV) gamma camera is used for SPECT imaging. This brief report presents a serendipitous finding of a pelvic mass, which was identified because of the extended field-of-view afforded by the conventional gamma camera used for SPECT MPI and detected because of a review of the raw images by the nuclear medicine technologist (NMT). This case emphasizes the importance of the NMT training to review the raw data in the entire FOV prior to study completion.

Osteopontin as Candidate Biomarker of Coronary Disease despite Low Cardiovascular Risk: Insights from CAPIRE Study.

Stratification according high cardiovascular (CV) risk categories, still represents a clinical challenge. In this analysis of the CAPIRE study (NCT02157662), we investigate whether inflammation could fit between CV risk factors (RFs) and the presence of coronary artery disease (CAD). In total, 544 patients were included and categorized according with the presence of CAD and CV risk factor burden (low/multiple). The primary endpoint was to verify any independent association of neutrophil-related biomarkers with CAD across CV risk categories. The highest values of osteopontin (OPN) were detected in the low RF group and associated with CAD (23.2 vs. 19.4 ng/mL; p = 0.001), although no correlation with plaque extent and/or composition were observed. Conversely, myeloperoxidase (MPO) and resistin did not differ by CAD presence. Again, OPN was identified as independent variable associated with CAD but only in the low RF group (adjOR 8.42 [95% CI 8.42–46.83]; p-value = 0.015). As an ancillary finding, a correlation linked OPN with the neutrophil degranulation biomarker MPO (r = 0.085; p = 0.048) and resistin (r = 0.177; p = 3.4 × 10−5). In the present study, OPN further strengthens its role as biomarker of CAD, potentially bridging subclinical CV risk with development of atherosclerosis.

Assessing Language in Unstructured Conversation in People With Aphasia: Methods, Psychometric Integrity, Normative Data, and Comparison to a Structured Narrative Task.

Purpose This study evaluated interrater reliability (IRR) and test-retest stability (TRTS) of seven linguistic measures (percent correct information units, relevance, subject-verb-[object], complete utterance, grammaticality, referential cohesion, global coherence), and communicative success in unstructured conversation and in a story narrative monologue (SNM) in persons with aphasia (PWAs) and matched participants without aphasia (M-PWoAs). Furthermore, the relationship of language in unstructured conversation and SNM was investigated for these measures. Methods Twenty PWAs and 20 M-PWoAs participated in two unstructured conversations on different days with different speech-language pathologists trained as social conversation partners. An 8- to 12-min segment of each conversation was analyzed. Additionally, a wordless picture book was used to elicit an SNM sample at each visit. Correlational analyses were conducted to address the primary research questions. Normative range and minimal detectable change data were also calculated for the measures in both conditions. Results IRR and TRTS were moderate to good for parametric measures and moderate to excellent for nonparametric measures for both groups, except for TRTS for referential cohesion for the PWAs in conversation. Furthermore, in PWAs, a strong correlation was demonstrated for three of eight measures across conditions. Moderate or weaker correlations were demonstrated for three of eight measures, and correlations for two of eight measures were not significant. An ancillary finding was no significant differences occurred for sample-to-sample variability between the two conditions for any measure. Conclusions This study replicates previous research demonstrating the feasibility to reliably measure language in unstructured conversation in PWAs. Furthermore, this study provides preliminary evidence that language production varies for some measures between unstructured conversation and SNM, contributing to a literature base that demonstrates language variation between different types of monologue. Thus, these findings suggest that inclusion of the specific types of discourse of interest to the PWA may be important for comprehensive assessment of aphasia. Supplemental Material https://doi.org/10.23641/asha.16569360.

HOW GLOBAL IS YOUR BUSINESS SCHOOL? – THE 3 PS OF INTERNATIONALIZATION: PROGRAMS, PARTICIPANTS AND PURPOSE

In this paper, we introduce a three-factor framework that can be used to evaluate the internationality of universities offering international business by focusing on their programs, participants, and purpose. We illustrate how a prospective American student, and her parents could use the framework by applying it to four U.S. based business schools with international business programs, two large public schools and two smaller private schools. We argue that the framework may also be used by administrators and accreditors evaluating the institution from within. We gather our information from publicly available sources. We find that programs vary widely, both in depth and breath. Prospective students could use our framework to select the school that best fits their goals and skills. One ancillary finding is that the lack of transparency by most institutions makes gathering relevant information difficult.

Preoperative concurrent chemoradiotherapy MRI characteristics favouring pathologic complete response in patients with rectal cancer: Usefulness of MR T2-stage as an ancillary finding for predicting pathologic complete response.

This study sought to assess preoperative concurrent chemoradiotherapy (CRT) magnetic resonance imaging (MRI)-based findings according to a structured MRI report template for primary staging of rectal cancer, and to evaluate the prognostic relevance of the pre-CRT MRI-based findings in patients with rectal cancer after CRT. We retrospectively evaluated pre- and post-CRT MRI data of patients with pathologically proven rectal adenocarcinoma, between January 2008 and October 2019. Image interpretation was performed independently by two radiologists and each reviewer assessed the cancer characteristics on MRI, based on the structured MRI report for primary staging. MRI-based findings associated with pathologic complete tumour regression grade (TRG) after CRT were analysed by univariate and multivariate analysis. Significant factors from pre-CRT MRI were weighted to score mrTRG in post-CRT MRI. On univariate analysis, MR T-stage, tumour infiltration, mesorectal fascia involvement, extramural vascular invasion and serum carcinoembryonic antigen level correlated significantly with pathologic complete response (pCR). Multivariate analysis identified that only MR T-stage was independently associated with pCR (odds ratio, 3.89, 95% confidence interval, 1.18-12.84; P=0.0278). Adding MRI-based T2-stage as an ancillary finding to mrTRG statistically significantly improved the sensitivity as compared to using only mrTRG for considering a CR. T2_mrTRG was significantly different in terms of the time to tumour progression between the CR and non-CR group. The MR T2-stage was independently associated with pCR after CRT in patients with rectal cancer and was helpful as ancillary predictive factor, adding to mrTRG for prediction of pCR.

Developmental venous anomalies in patients with multiple sclerosis: is that a coincidence or an ancillary finding?

Developmental venous anomalies (DVAs) have been found to be more prevalent in patients with multiple sclerosis (MS). The aim of the study was to compare the prevalence of DVAs in a large population of patients with MS compared with controls and to investigate the correlation of 3D Fluid Attenuated Inversion Recovery (FLAIR) hyperintense signal abnormalities adjacent to DVAs between MS patients and controls having DVAs, as well as DVA potential role in differential diagnosis. Between January 2001 and December 2019, 349 patients who met the McDonald criteria for MS diagnosis (249 females, 100 males, age range 18-70 years) were retrospectively included in the study. All patients and 340 age-matched healthy controls had brain MRIs performed on a 1.5 Tesla MR system. Two radiologists reviewed all images to identify DVAs; their presence was compared between the MS and control groups. Among the subjects having DVAs, age, gender, adjacent FLAIR anomalies, and DVA location were compared between the two groups. Fifty (14.3%) out 349 patients presented 51 DVAs (35 supratentorial and 16 infratentorial), in comparison to 21/340 (6.2%) controls (P = 0.0005). One patient showed 2 simultaneous DVAs, while 3 patients had coexisting pontine capillary telangiectasias. FLAIR white matter changes adjacent to DVAs were found in 46.2% of patients and in 28.1% of controls (P = 0.0001). DVAs demonstrated a higher prevalence in the MS group in comparison to controls. We confirmed the association between DVAs and FLAIR anomalies in MS patients. However, currently there are no evidences that the presence of DVAs may be used in MS differential diagnosis.

Shedding light on the clinical recognition process of transient global amnesia.

Diagnostic uncertainty is common in the emergency evaluation of neurological conditions such as acute confusional states, particularly for non-neurologists. We aimed to investigate the clinical recognition process of transient global amnesia (TGA) before arrival at the hospital and in the emergency department (ED). In this retrospective observational study, medical records of 365 patients with TGA were analysed concerning mode of arrival, symptoms and suspected diagnosis made by pre-hospital medical care providers and the ED neurologist. More than half of the 248 patients who were evaluated before arrival at the hospital (N=157, 63.3%) received a diagnosis of suspected stroke, whereas TGA was considered in only 16 patients (6.5%), with recognition of acute amnesia in 150 patients (60.5%) and disturbed orientation in 86 patients (34.7%). Repetitive questions by the patient were noted in 28 patients (11.3%). In contrast, in 355 patients (97.3%), TGA was considered the primary diagnosis by the ED neurologist. Diagnosis in the ED was achieved by documenting ongoing impairment of episodic verbal memory (100.0%), repetitive questions as a prominent ancillary finding (95.5%) and the lack of focal neurological symptoms (100.0%) or by carefully obtaining collateral history suggestive of anterograde memory disturbance (89.9%) and/or repetitive questions (85.7%). Recognizing TGA crucially depends on identifying isolated anterograde episodic long-term memory disturbance or its observable effects such as repetitive questions and actions.

Early Sedation with Dexmedetomidine in Critically Ill Patients

BackgroundDexmedetomidine produces sedation while maintaining a degree of arousability and may reduce the duration of mechanical ventilation and delirium among patients in the intensive care unit (ICU). The use of dexmedetomidine as the sole or primary sedative agent in patients undergoing mechanical ventilation has not been extensively studied.MethodsIn an open-label, randomized trial, we enrolled critically ill adults who had been undergoing ventilation for less than 12 hours in the ICU and were expected to continue to receive ventilatory support for longer than the next calendar day to receive dexmedetomidine as the sole or primary sedative or to receive usual care (propofol, midazolam, or other sedatives). The target range of sedation-scores on the Richmond Agitation and Sedation Scale (which is scored from −5 [unresponsive] to +4 [combative]) was −2 to +1 (lightly sedated to restless). The primary outcome was the rate of death from any cause at 90 days.ResultsWe enrolled 4000 patients at a median interval of 4.6 hours between eligibility and randomization. In a modified intention-to-treat analysis involving 3904 patients, the primary outcome event occurred in 566 of 1948 (29.1%) in the dexmedetomidine group and in 569 of 1956 (29.1%) in the usual-care group (adjusted risk difference, 0.0 percentage points; 95% confidence interval, −2.9 to 2.8). An ancillary finding was that to achieve the prescribed level of sedation, patients in the dexmedetomidine group received supplemental propofol (64% of patients), midazolam (3%), or both (7%) during the first 2 days after randomization; in the usual-care group, these drugs were administered as primary sedatives in 60%, 12%, and 20% of the patients, respectively. Bradycardia and hypotension were more common in the dexmedetomidine group.ConclusionsAmong patients undergoing mechanical ventilation in the ICU, those who received early dexmedetomidine for sedation had a rate of death at 90 days similar to that in the usual-care group and required supplemental sedatives to achieve the prescribed level of sedation. More adverse events were reported in the dexmedetomidine group than in the usual-care group. (Funded by the National Health and Medical Research Council of Australia and others; SPICE III ClinicalTrials.gov number, NCT01728558.)

Maximizing botulinum toxin injections for cosmetic and therapeutic applications with a single use, disposable, exact dose injection assist device.

BackgroundAlthough freehand injection of botulinum toxin remains the status quo, it is an inaccurate technique for delivering precise amounts of neurotoxin at multiple injection sites with expediency. We developed an inexpensive, ergonomic, single-use, disposable exostructure device that rapidly converts a standard syringe into a highly accurate injection instrument.Materials and methodsBased on the results of two independent injectors, we determined the comparative delivery dose accuracy, precision, and amount of product waste associated with a standard syringe using the freehand injection technique vs a prototype injection assist device. Fifteen experienced injectors were also surveyed regarding their satisfaction using the device in a controlled research setting.ResultsThe average percentage difference from the expected dose value was <1% (0.00024 mL) for 1-unit doses (ie, 0.025 mL) with the injection assist device. In contrast, accuracy values with the freehand method were more than 10 times worse (ie, >10% or 0.0025 mL). Accuracy estimates were also superior with the device over freehand for 2- and 4-unit doses. Precision estimates favored the device for all comparisons and all dosing regimens. The magnitude of variability around the average difference ranged from 2.2 to 5.4 times worse for the freehand method compared to the device. The overall percentage of product waste was substantial with the freehand method (>10%) compared to the device (4.3%) (P=0.04) for 1-unit injections. The percentage of injections showing measurable product waste was also significantly lower with the device (78% vs 25%, P=0.01). Fourteen of 15 (93%) injectors surveyed would use the device in daily practice if it were included complimentary with the neurotoxin.ConclusionThe injection assist device offered superior accuracy and precision compared to the freehand method across the entire injection regimen. The ancillary finding of a significant reduction in product waste with the device was particularly notable.

Enter the Dragon: Import Penetration and Innovation

We examine the effect of Chinese import penetration on the innovation activities of US manufacturers. We find that firms boost innovation in response to greater import penetration. The boost in innovation builds on narrow focus and familiar technology and results in greater product differentiation. However, in the years after the import penetration, the firms gradually and significantly reduce innovation. As an ancillary finding, we document that import competition prompts firms to scale back capital expenditures. Combined, our evidence suggests that Chinese import penetration spurs US firms to rapidly, but temporarily, increase innovation to dodge price competition.

Tropical Cyclone Gale Wind Radii Estimates for the Western North Pacific

Abstract The Joint Typhoon Warning Center’s (JTWC) forecast improvement goals include reducing 34-kt (1 kt = 0.514 m s−1) wind radii forecast errors, so accurate real-time estimates and postseason analysis of the 34-kt wind radii are critical to reaching this goal. Accurate real-time 34-kt wind radii estimates are also critical for decisions regarding base preparedness and asset protection, but still represent a significant operational challenge at JTWC for several reasons. These reasons include a paucity of observations, the timeliness and availability of guidance, a lack of analysis tools, and a perceived shortage of personnel to perform the analysis; however, the number of available objective wind radii estimates is expanding, and the topic of estimating 34-kt wind radii warrants revisiting. In this work an equally weighted mean of real-time 34-kt wind radii objective estimates that provides real-time, routine operational guidance is described. This objective method is also used to retrospectively produce a 2-yr (2014–15) 34-kt wind radii objective analysis, the results of which compare favorably to the postseason National Hurricane Center data (i.e., the best tracks), and a newly created best-track dataset for the western North Pacific seasons. This equally weighted mean, when compared with the individual 34-kt wind radii estimate methods, is shown to have among the lowest mean absolute errors and smallest biases. In an ancillary finding, the western North Pacific basin average 34-kt wind radii calculated from the 2014–15 seasons are estimated to be 134 n mi (1 n mi = 1.852 km), which is larger than the estimates for storms in either the Atlantic (95 n mi) or eastern North Pacific (82 n mi) basins for the same years.

Enter the Dragon: Import Penetration and Innovation

We examine the effect of Chinese import penetration on the innovation activities of US manufacturers. We find that firms boost innovation in response to greater import penetration. The boost in innovation builds on narrow focus and familiar technology and results in greater product differentiation. However, in the years after the import penetration, the firms gradually and significantly reduce innovation. As an ancillary finding, we document that import competition prompts firms to scale back capital expenditures. Combined, our evidence suggests that Chinese import penetration spurs US firms to rapidly, but temporarily, increase innovation to dodge price competition.

Neural Mechanisms of the Transformation from Objective Value to Subjective Utility: Converting from Count to Worth.

When deciding, we aim to choose the “best” possible outcome. This is not just selection of the option that is the most numerous or physically largest, as options are translated from objective value (count) to subjective value (worth or utility). We localized the neural instantiation of the value-to-utility transformation to the dorsal anterior midcingulate cortex (daMCC), with independent replication. The daMCC encodes the context-specific information necessary to convert from count to worth. This encoding is not simply a representation of utility or preference, but the interaction of the two. Specifically, the relationship of brain activation to value is dependent on individual preference, with both positive and negative slopes across the population depending on whether each individual's preference results in enhancement or diminishment of the valuation. For a given value, across participants, enhanced daMCC activation corresponds to diminished subjective valuation, deactivation to enhanced subjective valuation, and non-modulated activation with non-modulated subjective valuation. Further, functional connectivity analyses identified brain regions (positive connectivity with the inferior frontal gyrus and negative connectivity with the nucleus accumbens) through which contextual information may be integrated into the daMCC and allow for outputs to modulate valuation signals. All analyses were replicated through an independent within-study replication, with initial testing in the gains domain and replication in the intermixed and mirrored losses trials. We also present and discuss an ancillary finding: we were unable to identify parametric value signals for losses through whole-brain analyses, and ROI analyses of the vmPFC presented non-modulation across loss value levels. These results identify the neural locus of the value-to-utility transformation, and provide a specific computational function for the daMCC in the production of subjective valuation through the integration of value, context, and preferences.

Reprint of: Locus coeruleus neuronal activity determines proclivity to consume alcohol in a selectively-bred line of rats that readily consumes alcohol.

Sprague-Dawley rats selectively-bred for susceptibility to stress in our laboratory (Susceptible, or SUS rats) voluntarily consume large amounts of alcohol, and amounts that have, as shown here, pharmacological effects, which normal rats will not do. In this paper, we explore neural events in the brain that underlie this propensity to readily consume alcohol. Activity of locus coeruleus neurons (LC), the major noradrenergic cell body concentration in the brain, influences firing of ventral tegmentum dopaminergic cell bodies of the mesocorticolimbic system (VTA-DA neurons), which mediate rewarding aspects of alcohol. We tested the hypothesis that in SUS rats alcohol potently suppresses LC activity to markedly diminish LC-mediated inhibition of VTA-DA neurons, which permits alcohol to greatly increase VTA-DA activity and rewarding aspects of alcohol. Electrophysiological single-unit recording of LC and VTA-DA activity showed that in SUS rats alcohol decreased LC burst firing much more than in normal rats and as a result markedly increased VTA-DA activity in SUS rats while having no such effect in normal rats. Consistent with this, in a behavioral test for reward using conditioned place preference (CPP), SUS rats showed alcohol, given by intraperitoneal (i.p.) injection, to be rewarding. Next, manipulation of LC activity by microinfusion of drugs into the LC region of SUS rats showed that (a) decreasing LC activity increased alcohol intake and increasing LC activity decreased alcohol intake in accord with the formulation described above, and (b) increasing LC activity blocked both the rewarding effect of alcohol in the CPP test and the usual alcohol-induced increase in VTA-DA single-unit activity seen in SUS rats. An important ancillary finding in the CPP test was that an increase in LC activity was rewarding by itself, while a decrease in LC activity was aversive; consequently, effects of LC manipulations on alcohol-related reward in the CPP test were perhaps even larger than evident in the test. Finally, when increased LC activity was associated with (i.e., conditioned to) i.p. alcohol, subsequent alcohol consumption by SUS rats was markedly reduced, indicating that SUS rats consume large amounts of alcohol because of rewarding physiological consequences requiring increased VTA-DA activity. The findings reported here are consistent with the view that the influence of alcohol on LC activity leading to changes in VTA-DA activity strongly affects alcohol-mediated reward, and may well be the basis of the proclivity of SUS rats to avidly consume alcohol.

Locus coeruleus neuronal activity determines proclivity to consume alcohol in a selectively-bred line of rats that readily consumes alcohol

Sprague–Dawley rats selectively-bred for susceptibility to stress in our laboratory (Susceptible, or SUS rats) voluntarily consume large amounts of alcohol, and amounts that have, as shown here, pharmacological effects, which normal rats will not do. In this paper, we explore neural events in the brain that underlie this propensity to readily consume alcohol. Activity of locus coeruleus neurons (LC), the major noradrenergic cell body concentration in the brain, influences firing of ventral tegmentum dopaminergic cell bodies of the mesocorticolimbic system (VTA-DA neurons), which mediate rewarding aspects of alcohol. We tested the hypothesis that in SUS rats alcohol potently suppresses LC activity to markedly diminish LC-mediated inhibition of VTA-DA neurons, which permits alcohol to greatly increase VTA-DA activity and rewarding aspects of alcohol. Electrophysiological single-unit recording of LC and VTA-DA activity showed that in SUS rats alcohol decreased LC burst firing much more than in normal rats and as a result markedly increased VTA-DA activity in SUS rats while having no such effect in normal rats. Consistent with this, in a behavioral test for reward using conditioned place preference (CPP), SUS rats showed alcohol, given by intraperitoneal (i.p.) injection, to be rewarding. Next, manipulation of LC activity by microinfusion of drugs into the LC region of SUS rats showed that (a) decreasing LC activity increased alcohol intake and increasing LC activity decreased alcohol intake in accord with the formulation described above, and (b) increasing LC activity blocked both the rewarding effect of alcohol in the CPP test and the usual alcohol-induced increase in VTA-DA single-unit activity seen in SUS rats. An important ancillary finding in the CPP test was that an increase in LC activity was rewarding by itself, while a decrease in LC activity was aversive; consequently, effects of LC manipulations on alcohol-related reward in the CPP test were perhaps even larger than evident in the test. Finally, when increased LC activity was associated with (i.e., conditioned to) i.p. alcohol, subsequent alcohol consumption by SUS rats was markedly reduced, indicating that SUS rats consume large amounts of alcohol because of rewarding physiological consequences requiring increased VTA-DA activity. The findings reported here are consistent with the view that the influence of alcohol on LC activity leading to changes in VTA-DA activity strongly affects alcohol-mediated reward, and may well be the basis of the proclivity of SUS rats to avidly consume alcohol.

Young Italian clinician wins Opitz award: Winner details evidence that conditions involving hypermobility are one entity.

Young Italian clinician wins Opitz award: Winner details evidence that conditions involving hypermobility are one entity.