Potential role of chitinase-3-like protein 1 (CHI3L1/YKL-40) in neurodegeneration and Alzheimer's disease.

Chitinase-3-like protein 1 (CHI3L1/YKL-40) has long been known as a biomarker for early detection of neuroinflammation and disease diagnosis of Alzheimer's disease (AD). In the brain, CHI3L1 is primarily provided by astrocytes and heralds the reactive, neurotoxic state triggered by inflammation and other stress signals. However, how CHI3L1 acts in neuroinflammation or how it contributes to AD and relevant neurodegenerative conditions remains unknown. In peripheral tissues, our group and others have uncovered that CHI3L1 is a master regulator for a wide range of injury and repair events, including the innate immunity pathway that resembles the neuroinflammation process governed by microglia and astrocytes. Based on assessment of current knowledge regarding CHI3L1 biology, we hypothesize that CHI3L1 functions as a signaling molecule mediating distinct neuroinflammatory responses in brain cells and misfunctions to precipitate neurodegeneration. We also recommend future research directions to validate such assertions for better understanding of disease mechanisms.

Examining the Link Between Intolerance of Uncertainty and Positive and Negative Urgency in Veterans With Comorbid Posttraumatic Stress Disorder and Substance Use Disorders.

Posttraumatic stress disorder (PTSD) and substance use disorders (SUD) are highly comorbid among the veteran population. Impulsivity, particularly negative and positive urgency, are prevalent within this dual-diagnosis population and associated with negative outcomes. One possible correlate of negative/positive urgency is intolerance of uncertainty (IU). IU is associated with exacerbated PTSD symptom severity and increased risk for substance use. However, few studies have examined the link between IU and negative/positive urgency in dual-diagnosis populations. This study aimed to examine whether there was a significant association between trait IU and baseline negative and positive urgency in veterans seeking treatment for both PTSD and SUD. In a sample of 114 veterans from a 6-week residential treatment program, IU was significantly associated with higher negative and positive urgency. Further research is warranted to extend these findings and examine whether IU plays an important role in negative/positive urgency for dual-diagnosis populations.

Increased Resilience is Associated with Positive Treatment Outcomes for Veterans with Comorbid PTSD and Substance Use Disorders.

OBJECTIVE: Resilience has been associated with less severe psychiatric symptomatology and better treatment outcomes among individuals with posttraumatic stress disorder (PTSD) and substance use disorders. However, it remains unknown whether resilience increases during psychotherapy within the comorbid PTSD and substance use disorder population with unique features of dual diagnosis, including trauma cue-related cravings. We tested whether veterans seeking psychotherapy for comorbid PTSD and substance use disorder reported increased resilience from pre- to posttreatment. We also tested whether increased resilience was associated with greater decreases in posttreatment PTSD and substance use disorder symptoms. METHODS: Participants were 29 male veterans (Mage = 49.07 years, SD = 11.24 years) receiving six-week residential day treatment including cognitive processing therapy for PTSD and cognitive behavioral therapy for substance use disorder. Resilience, PTSD symptoms, and trauma cue-related cravings were assessed at pre- and posttreatment. RESULTS: Veterans reported a large, significant increase in resilience posttreatment (Mdiff = 14.24, t = -4.22, p < .001, d = 0.74). Greater increases in resilience were significantly associated with fewer PTSD symptoms (ß = -0.37, p = .049, sr = -.36) and trauma-cued cravings (ß = -0.39, p = .006, sr = -.38) posttreatment when controlling for pretreatment scores and baseline depressive symptoms. CONCLUSIONS: Results suggest that evidence-based psychotherapy for comorbid PTSD and substance use disorder may facilitate strength-based psychological growth, which may further promote sustained recovery.

The Role of Impulsivity Dimensions in the Relation Between Probable Posttraumatic Stress Disorder and Aggressive Behavior Among Substance Users.

OBJECTIVE: Individuals with co-occurring posttraumatic stress disorder (PTSD) and substance use disorder report heightened levels of numerous risky and health-compromising behaviors, including aggressive behaviors. Given evidence that aggressive behavior is associated with negative substance use disorder treatment outcomes, research is needed to identify the factors that may account for the association between PTSD and aggressive behavior among patients with substance use disorder. Thus, the goal of this study was to examine the role of impulsivity dimensions (i.e., negative urgency, lack of premeditation, lack of perseverance, and sensation seeking) in the relations between probable PTSD status and both verbal and physical aggression. METHODS: Participants were 92 patients in residential substance use disorder treatment (75% male; 59% African American; M age = 40.25) who completed self-report questionnaires. RESULTS: Patients with co-occurring PTSD-substance use disorder (vs. substance use disorder alone) reported significantly greater verbal and physical aggression as well as higher levels of negative urgency and lack of premeditation. Lack of premeditation and lack of perseverance were significantly positively associated with verbal aggression, whereas negative urgency, lack of premeditation, and lack of perseverance were significantly positively associated with physical aggression. The indirect relation of probable PTSD status to physical aggression through negative urgency was significant. CONCLUSIONS: Results highlight the potential utility of incorporating skills focused on controlling impulsive behaviors in the context of negative emotional arousal in interventions for physical aggression among patients with co-occurring PTSD-substance use disorder.

The relation of PTSD symptoms to migraine and headache-related disability among substance dependent inpatients.

Despite emerging evidence for the comorbidity of posttraumatic stress disorder (PTSD) and migraine, few studies have examined the relation of PTSD and migraine, particularly among clinical populations at-risk for both conditions (e.g., substance-dependent patients). This study examined the role of PTSD symptoms in migraine and headache-related disability within a sample of 153 substance-dependent inpatients (37.25% female, Mean age 36.46). PTSD symptoms predicted both migraine and headache-related disability above and beyond gender, depression and anxiety symptoms, the experience of a Criterion A traumatic event, and current alcohol use disorder. Findings highlight the strong association between migraine and PTSD symptoms in a unique population at risk for both conditions.

Dataset: a social accounting matrix for Germany.

OBJECTIVES: The Social Accounting Matrix (SAM) is an extension of Input-Output tables that records macro and meso-economic accounts of a socio-economic system. Its main objective is to provide a comprehensive understanding of the interrelationships among different economic sectors and agents. The SAM can be used for various purposes, including economic analysis, policy evaluation, and economic modelling. It allows policymakers to make more informed decisions, understand potential consequences of different policy options and serve as the foundation for constructing Computable General Equilibrium (CGE) models. DATA DESCRIPTION: The SAM for Germany is a comprehensive source of data that reveals the incomes and expenditures of 163 different production sectors, along with data on factors of production, households, corporations, government, and external accounts with the rest of the world. Additionally, it provides information on gross fixed capital formation, changes in inventories, and natural capital accounts. This SAM was compiled by extending the EXIOBASE Input-Output (IO) accounts with data from the Federal Statistical Office of Germany. Balancing items were also used to ensure that the Total Income and Total Expenditure of the main transactors are in balance.

Structural requirements for inhibitory effects of bisphenols on the activity of the sarco/endoplasmic reticulum calcium ATPase.

Bisphenols (BPs) are a class of small organic compounds with widespread industrial applications. Previous studies have identified several BPs that interfere with the activity of the ion-translocating enzyme sarco/endoplasmic reticulum calcium ATPase (SERCA). In order to define the molecular determinants of BP-mediated SERCA inhibition, we conducted enzyme activity assays with rabbit SERCA to determine the inhibitory potencies of 27 commercially available BPs, which were the basis for structure-activity relationships. The most potent BPs inhibited SERCA at low micromolar concentrations and carried at their two phenyl rings multiple non-polar substituents, such as small alkyl groups or halides. Furthermore, the presence of methyl groups or a cyclohexyl group at the central carbon atom connecting the two phenyl moieties correlated with good potencies. For a characterization and visualization of enzyme/inhibitor interactions, molecular docking was performed, which suggested that hydrogen bonding with Asp254 and hydrophobic interactions were the major driving forces for BP binding to SERCA. Calcium imaging studies with a selection of BPs showed that these inhibitors were able to increase intracellular calcium levels in living human cells, a behavior consistent with that of a SERCA inhibitor.

The Generation and Functional Characterization of Human Microglia-Like Cells Derived from iPS and Embryonic Stem Cells.

The following protocol describes the generation of microglia cells from human-induced pluripotent stem cells (hiPSCs) using commercially available kits by StemCell Technologies. This protocol consists of three major steps: (1) Differentiation of hematopoietic precursor cells, (2) Microglia differentiation, and (3) Microglia maturation. Assays are described to characterize hematopoietic precursor cells and mature microglia.

Modeling Cellular Crosstalk of Neuroinflammation Axis by Tri-cultures of iPSC-Derived Human Microglia, Astrocytes, and Neurons.

Neuroinflammation is a common early pathological feature in many neurodegenerative disorders, including Alzheimer's disease (AD), which has been heavily implicated as a causative factor in disease pathology. However, the role neuroinflammation and inflammatory cells, including microglia and astrocytes, play in AD development and progression has not been fully defined. To try to better understand and study this neuroinflammatory role in AD pathogenesis, researchers use a variety of model systems, particularly in vivo animal models. Despite their usefulness, these models do come with a variety of limitations due to the inherent complexity of the brain and the human-specific nature of AD. Here, we describe a reductionist approach at modeling neuroinflammation by utilizing an in vitro tri-culture system of neurons, astrocytes, and microglia induced from human pluripotent stem cells. This tri-culture model is a powerful tool to dissect intercellular interactions that can facilitate future studies on neuroinflammation, particularly in the context of neurodegeneration and AD.

CHI3L1 signaling impairs hippocampal neurogenesis and cognitive function in autoimmune-mediated neuroinflammation.

Chitinase-3-like protein 1 (CHI3L1) is primarily secreted by activated astrocytes in the brain and is known as a reliable biomarker for inflammatory central nervous system (CNS) conditions such as neurodegeneration and autoimmune disorders like neuromyelitis optica (NMO). NMO is an astrocyte disease caused by autoantibodies targeting the astroglial protein aquaporin 4 (AQP4) and leads to vision loss, motor deficits, and cognitive decline. In this study examining CHI3L1's biological function in neuroinflammation, we found that CHI3L1 expression correlates with cognitive impairment in our NMO patient cohort. Activated astrocytes secrete CHI3L1 in response to AQP4 autoantibodies, and this inhibits the proliferation and neuronal differentiation of neural stem cells. Mouse models showed decreased hippocampal neurogenesis and impaired learning behaviors, which could be rescued by depleting CHI3L1 in astrocytes. The molecular mechanism involves CHI3L1 engaging the CRTH2 receptor and dampening ß-catenin signaling for neurogenesis. Blocking this CHI3L1/CRTH2/ß-catenin cascade restores neurogenesis and improves cognitive deficits, suggesting the potential for therapeutic development in neuroinflammatory disorders.

The therapeutic effect of histone deacetylase inhibitor PCI-24781 on gallbladder carcinoma in BK5.erbB2 mice.

BACKGROUND & AIMS: Gallbladder carcinoma (GBCa), a type of biliary tract cancer (BTC), has proven challenging to treat, demonstrating the need for more effective therapeutic strategies. In our current study, we examined the therapeutic effects of the histone deacetylase (HDAC) inhibitor PCI-24781 against GBCa that developed in BK5.erbB2 mice. METHODS: PCI-24781 [50 mg/kg/day] and control solutions were administered to BK5.erbB2 mice for 4 weeks. The therapeutic effect of PCI-24781 was evaluated by ultrasound biomicroscopy (USBM) throughout the experiment and histological analyses at the end of the experiment. To investigate potential mechanisms underlining the therapeutic effects of PCI-24781 on GBCa in BK5.erbB2 mice, PCI-24781-treated gallbladders were subjected to Western blot and RT-PCR analysis. The inhibitory effect of PCI-24781 on the growth of BTC cells was compared to the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) and gemcitabine. To study the role of miRNAs in GBCa tumorigenesis, the expression profile of 368 miRNAs in GBCas from BK5.erbB2 (both treated and untreated) and wild type mice was analyzed. RESULTS: Treatment of BK5.erbB2 mice with PCI-24781 for 1 month prevented 79% of GBCa cases from progression and showed a clinical effect in 47% of cases. We also confirmed a potent inhibitory effect on tumor cell growth in human BTC cell lines treated with PCI-24781. This effect was associated with downregulation of ErbB2 mRNA and ErbB2 protein/activity and upregulation of acetylated histone and acetylated tubulin. Treatment with PCI-24781 resulted in decreased expression of Muc4, an intramembrane ligand for ErbB2, in BTC cells. PCI-24781 had more effects on growth inhibition of BTC cells than SAHA. In addition, PCI-24781 effectively inhibited the growth of gemcitabine-resistant cells. miRNA profiling revealed that the expression of several miRNAs was significantly altered in GBCa in the BK5.erbB2 mouse compared to normal gallbladder, including upregulated miR21, which was downregulated by PCI-24781. CONCLUSIONS: These results indicate that PCI-24781 potently inhibits the growth of BTC cells by decreasing ErbB2 expression and activity as well as regulating altered miRNA expression. PCI-24781 may have a potential value as a novel chemotherapeutic agent against human BTC in which ErbB2 is overexpressed.

Emerging drugs for major depressive disorder.

INTRODUCTION: Major depressive disorder (MDD) remains a major public health concern, and one that continues to suffer an incompletely-met need for effective and acceptable treatments. The development of antidepressants, to date, has focused primarily on increasing monoamine neurotransmission with increasing efficacy while minimizing adverse effects. Medications currently recommended as 'first-line' are far more tolerable than the older medications they replaced, but as many as 70% of patients continue to suffer significant depressive symptoms after treatment with one of these agents, and as many as 50% will discontinue a trial due to issues with acceptability. This review will summarize antidepressants that have recently entered the market as well as those still in development to help characterize the current state of antidepressant development. AREAS COVERED: Currently available first-line antidepressants are reviewed with respect to efficacy and tolerability, and their weaknesses are discussed as targets for future development. The background, clinical trial data and potential significance of the three most recently introduced antidepressants (trazodone-ER, desvenlafaxine and vilazodone) and the most recently approved augmentation agents (aripiprazole and quetiapine) are discussed. Following a review of the current market, all medications currently in Phase II or later clinical trials are listed and discussed, based on a thorough review of the US National Institutes of Health clinicaltrials.gov index for trials using medications to treat MDD and a search of the Informa Pharmaprojects database for medications currently being developed for a depression indication. Compounds thus identified were then used as search terms in a PubMed search of each medication. Based on pharmacologic properties, medications in development were grouped into those acting on: i) monoamine neurotransmission; ii) cholinergic neurotransmission; iii) glutamatergic neurotransmission; iv) opioid receptors; v) sigma receptors; vi) neurokinin receptors; vii) corticotrophin-releasing factor receptors and viii) other mechanisms. In the discussion of each, a brief review of the pharmacology and physiology of the related system is provided. Potential issues for the future of antidepressant development and an expert opinion are discussed. EXPERT OPINION: The past decade has not yielded a large number of new antidepressants and, with the possible exception of agomelatine, none of the newer medications that have been introduced have decisively addressed the several unmet needs in this area of therapeutics. Among the various novel strategies that are being evaluated, results of several small studies of ketamine suggest that drugs that modulate glutamatergic neurotransmission may hold the greatest promise for exerting rapid and large antidepressant effects in patients who have not responded to SSRIs or SNRIs.

Percutaneous approach options for embolization of endoleak after iliac artery aneurysm repair: stick the sac or stick the gluteal artery.

Internal iliac artery aneurysms (IIAAs), isolated or associated with abdominal aortic aneurysms, are at rupture risk with growth. Treatment is recommended when symptomatic or greater than 3 cm. Surgical or endovascular therapy should exclude the arterial origin and outflow branches. If all outflow branches are not completely embolized, an endoleak can develop, pressurizing the sac leading to growth and rupture. Accessing the arteries involved can be technically challenging and understanding potential targets is critical. We describe two percutaneous approaches for treatment: percutaneously accessing the sac from an anterior trans-iliopsoas approach and percutaneously accessing the gluteal artery from a posterior approach.

Postoperative Recurrent Cholesteatoma in Rural Versus Urban Populations.

OBJECTIVE: Chronic ear disease presents a unique challenge to otolaryngologists in both rural and urban settings. Cholesteatoma remains a difficult disease to treat in rural populations due to limited healthcare access and high risk of recurrence. The purpose of this study was to determine if there are differences in surgical outcomes among patients with acquired cholesteatoma residing in rural versus urban settings. STUDY DESIGN: Single-surgeon retrospective case series with chart review. SETTING: Tertiary care private otolaryngology practice. PATIENTS: One hundred twenty-two patients presenting to the Kentuckiana ENT otology and neurotology practice from January 2011 to May 2017. MAIN OUTCOME MEASURES: Surgical outcomes including recurrence, air-bone gap improvement, ossicular integrity, and complications were reviewed and compared between the rural and urban cohorts. RESULTS: Presence of postoperative residual cholesteatoma (OR = 8.667, 95% CI = 2.022-37.141, p = 0.008) and number of surgeries per patient (OR = 5.185, 95% CI = 1.086-24.763, p = 0.024) were significantly increased among patients in rural nonmetropolitan areas. No significant differences were found when comparing risk of recurrence, size of cholesteatoma, presence of complications, air-bone gap improvement, and ossicular chain integrity. There were significantly more second-look surgeries performed in privately insured patients (OR = 8.582, 95% CI = 1.937-38.017, p = 0.001). CONCLUSIONS: Patients in rural communities have an increased number of surgeries and postoperative risk for residual cholesteatoma compared to patients residing in urban settings. This study provides the basis for larger, multicenter, prospective examinations of outcomes among urban versus rural patients, which would enable a better understanding of difference in surgical outcomes between rural and urban cohorts.Level of Evidence: IV.

Pre- to Posttreatment Changes in Trauma-Cued Negative Emotion Mediate Improvement in Posttraumatic Stress Disorder, Depression, and Impulsivity.

Posttraumatic stress disorder (PTSD) is characterized by strong negative emotions, often in response to trauma cues or reminders. Subsequent emotion regulation strategies impact the maintenance of PTSD symptoms and other trauma-related outcomes (depression, substance use). This study aimed to examine a range of trauma-cued emotions to enhance our understanding of changes following treatment and their potential role in improving relevant outcomes. Participants included 67 veterans diagnosed with PTSD and a substance use disorder who completed a dual diagnosis residential program that used cognitive processing therapy. At pre- and posttreatment, we measured 8 negative emotions following a trauma recall and PTSD symptoms, depressive symptoms, and negative urgency (impulsivity following negative emotions) as treatment outcomes. We used t-tests to assess changes at posttreatment and a within-subjects mediational analysis to test whether changes in trauma-cued emotions mediated treatment outcomes. Participants reported moderate, significant decreases for 5 emotions at posttreatment: anger at self, disgust at self, fear, guilt, and sadness (d ≥ 0.50), whereas nonsignificant changes were found for anger at others, disgust at others, and shame. Mediation analyses indicated greater reductions in trauma-cued sadness had a significant indirect effect on improvement in PTSD symptoms, depressive symptoms, and negative urgency. Reductions in disgust at self and fear also demonstrated a significant indirect effect on depressive symptom improvement. In this dual diagnosis program, veterans reported a significant reduction in some, but not all, trauma-cued emotions, and improvements in only select emotions accounted for a significant portion of improvement in relevant treatment outcomes.

Generation of Human Neurons and Oligodendrocytes from Pluripotent Stem Cells for Modeling Neuron-Oligodendrocyte Interactions.

In Alzheimer's disease (AD) and other neurodegenerative disorders, oligodendroglial failure is a common early pathological feature, but how it contributes to disease development and progression, particularly in the gray matter of the brain, remains largely unknown. The dysfunction of oligodendrocyte lineage cells is hallmarked by deficiencies in myelination and impaired self-renewal of oligodendrocyte precursor cells (OPCs). These two defects are caused at least in part by the disruption of interactions between neuron and oligodendrocytes along the buildup of pathology. OPCs give rise to myelinating oligodendrocytes during CNS development. In the mature brain cortex, OPCs are the major proliferative cells (comprising ~5% of total brain cells) and control new myelin formation in a neural activity-dependent manner. Such neuron-to-oligodendrocyte communications are significantly understudied, especially in the context of neurodegenerative conditions such as AD, due to the lack of appropriate tools. In recent years, our group and others have made significant progress to improve currently available protocols to generate functional neurons and oligodendrocytes individually from human pluripotent stem cells. In this manuscript, we describe our optimized procedures, including the establishment of a co-culture system to model the neuron-oligodendrocyte connections. Our illustrative results suggest an unexpected contribution from OPCs/oligodendrocytes to the brain amyloidosis and synapse integrity and highlight the utility of this methodology for AD research. This reductionist approach is a powerful tool to dissect the specific hetero-cellular interactions out of the inherent complexity inside the brain. The protocols we describe here are expected to facilitate future studies on oligodendroglial defects in the pathogenesis of neurodegeneration.

Effect of Fatigue on Equine Metacarpophalangeal Joint Kinematics-A Single Horse Pilot Study.

The objective was to validate a scientific method for characterizing equine metacarpophalangeal joint (MCPJ) motion in the nonfatigued and fatigued states using a single horse at trot, slow canter, and fast canter. One healthy Thoroughbred gelding exercised on a treadmill to exhaustion (fatigued state) (heart rate >190 BPM and blood lactate >10 mmol/L) while bilateral MCPJ angular data were acquired using electrogoniometry. Blood lactate and heart rate reflected transition from nonfatigued to fatigued states with increasing exercise duration and treadmill speed. Electrogoniometry consistently demonstrated: increase in mean MCPJ maximum extension angle with onset of fatigue; altered extension and flexion angular velocities with onset of fatigue; and increasing stride duration and decreasing stride frequency with onset of fatigue. The method allowed a preliminary but comprehensive characterization of the dynamic relationship between MCPJ kinematics and fatigue, prompting the need for multisubject studies that may enhance our ability to moderate exercise-related distal limb injury in equine athletes.

Targeted disruption of Bcl-xL in mouse keratinocytes inhibits both UVB- and chemically induced skin carcinogenesis.

Bcl-x(L) is one of several antiapoptotic proteins regulated by signal transducer and activator of transcription 3 (Stat3). We have recently shown that Stat3 is required for chemically induced and ultraviolet B (UVB)-induced skin carcinogenesis. In this study, the functional role of Bcl-x(L) in skin carcinogenesis was investigated using skin-specific Bcl-x(L)-deficient mice. In this model, Bcl-x(L) expression is disrupted in the basal compartment of mouse epidermis using the bovine keratin 5 (K5) promoter to drive expression of Cre recombinase (K5.Cre x Bcl-x(L) (fl/fl) mice). A significant increase in apoptosis induced by either UVB irradiation or 7,12-dimethylbenz[a]anthracene (DMBA) treatment was observed in the epidermis of Bcl-x(L)-deficient mice. Furthermore, an increase in apoptotic cells was noted in hair follicle keratinocytes, including those located in the bulge region. Cell proliferation was not affected by Bcl-x(L) deficiency following exposure to either UVB or 12-O-tetradecanoylphorbol-13-acetate (TPA). Bcl-x(L)-deficient mice were more resistant than wild-type controls to skin tumor development with delayed onset and reduced number of tumors using either UVB or the DMBA/TPA two-stage regimen. Moreover, Bcl-2, Mcl-1, and survivin protein levels were increased in the epidermis of Bcl-x(L)-deficient mice in the absence of stimuli. Furthermore, levels of these antiapoptotic proteins were also high in skin tumors from Bcl-x(L)-deficient mice that developed in response to either UVB or two-stage carcinogenesis protocols. Collectively, these studies demonstrate that Bcl-x(L) plays a role early in skin carcinogenesis through its anti-apoptotic functions to enhance survival of keratinocytes, including bulge region keratinocyte stem cells, following DNA damage.

Information processing in contamination fear: a covariation bias examination of fear and disgust.

The current study represents the first examination of covariation biases in contamination fear. Using an undergraduate sample we examined covariation bias for specific emotion outcomes (fear specific and disgust specific) associated with contamination stimuli in high contamination fear (HCF; n=32) and low contamination fear (LCF; n=30) individuals. Following random stimulus-outcome presentation participants provided estimations on the proportion of each presented stimulus-expression pairing. Analyses revealed a specific bias for the over-estimation of fear and disgust contingencies among the HCF group, but not the LCF group. The current study also revealed a specific covariation bias among HCF, not LCF, participants to over-estimate the contingency between contamination stimuli and fear outcomes, not disgust outcomes. Further, results indicate that HCF individuals significantly under-estimate the covariation among contamination stimuli and safety outcomes compared to LCF participants. These findings are discussed in terms of theoretical implications for information processing biases in anxiety disorders.

Can a policy-induced reduction in alcohol consumption improve health outcomes and stimulate the UK economy?: A potential 'double dividend'.

INTRODUCTION AND AIMS: The health benefits of reducing excessive alcohol consumption are well-documented and widely accepted, but policies directed to this end are often regarded as damaging to the economy. Previous UK alcohol impact studies typically focus on what are in effect the 'gross' impacts of a fall in alcohol consumption considered in isolation, so that estimated economic impacts are always negative. Here we investigate the 'net' impacts of a reduction in consumption accounting for the reallocation of household spending and the expenditure of any increase in government revenues. DESIGN AND METHODS: We employ a health-augmented, Input-Output modelling framework. We simulate the impact of a reduction in alcohol consumption due to: a change in consumer tastes that generate a reallocation of household spending; an increase in alcohol duties accompanied by the use of increased revenues to stimulate government expenditure. RESULTS: We find evidence of a trade-off between employment and health benefits for the case of a tastes-induced switch from alcohol consumption, but this is less severe than past analyses would suggest (and does not apply to economic activity more generally). For the case of increased taxation on alcohol (and increased government spending) we find that there is in fact no trade-off between employment on the one hand and health on the other; employment and economic activity are stimulated while health outcomes improve. DISCUSSION AND CONCLUSIONS: There is a potential 'double-dividend' of improved health outcomes and increased economic activity as a consequence of a rise in alcohol duties.