Operationalizing a fisheries social-ecological system through a Bayesian belief network reveals hotspots for its adaptive capacity in the southern North sea.

Fisheries social-ecological systems (SES) in the North Sea region confront multifaceted challenges stemming from environmental changes, offshore wind farm expansion, and marine protected area establishment. In this paper, we demonstrate the utility of a Bayesian Belief Network (BN) approach in comprehensively capturing and assessing the intricate spatial dynamics within the German plaice-related fisheries SES. The BN integrates ecological, economic, and socio-cultural factors to generate high-resolution maps of profitability and adaptive capacity potential (ACP) as prospective management targets. Our analysis of future scenarios, delineating changes in spatial constraints, economics, and socio-cultural aspects, identifies factors that will exert significant influence on this fisheries SES in the near future. These include the loss of fishing grounds due to the installation of offshore wind farms and marine protected areas, as well as reduced plaice landings due to climate change. The identified ACP hotspots hold the potential to guide the development of localized management strategies and sustainable planning efforts by highlighting the consequences of management decisions. Our findings emphasize the need to consider detailed spatial dynamics of fisheries SES within marine spatial planning (MSP) and illustrate how this information may assist decision-makers and practitioners in area prioritization. We, therefore, propose adopting the concept of fisheries SES within broader integrated management approaches to foster sustainable development of inherently dynamic SES in a rapidly evolving marine environment.

Evaluation of pain-alleviating strategies during allergy shots (subcutaneous immunotherapy): a randomized controlled pilot study.

Summary: Background. Subcutaneous immunotherapy (SCIT) is a potential disease-modifying therapy effective for treatment of various allergic disorders. Pain and fear are common concerns of children, which can pose stress and result in negative experiences. The purpose of this study was to evaluate and compare the effectiveness of three marketed distraction devices and ethyl chloride spray (a routinely used topical anesthetic agent for painful procedures), the current clinical standard of care in reducing the perception of needle pain during SCIT administration in children. Methods. 40 children, aged 4-17 years, receiving SCIT with use of one of three alternative pain therapies or with standard practice were enrolled. Participants were randomly assigned to one of the pain-modifying interventions. The three interventional groups were ShotBlocker® (Bionix, Toledo, OH, USA), Buzzy® I (Pain Care Labs, Atlanta, GA, USA) (vibration only), and Buzzy® II (vibration with ice). Control group was ethyl chloride spray. The study consisted of two visits during SCIT administration process. Results. Of these 40 children, 12 received the ShotBlocker, 8 received the Buzzy I, 11 received the Buzzy II, and 9 received ethyl chloride spray (control group). Conclusions. There were no significant differences found between each of the distraction devices and between the control group. Type II error/false negative finding cannot be ruled out because of a small sample. Therefore, we cannot conclude that no true difference exists between each distraction device and the control group simply because of occurrence of a non-significant P-value in our study.

Allosteric modulators of the δ GABAA receptor subtype demonstrate a therapeutic effect in morphine-antinociceptive tolerance and withdrawal in mice.

The present study evaluated the effects of compounds targeting extrasynaptic δ subunit-containing γ-aminobutyric acid type A receptors (δ*-GABAARs) to interrogate the role of tonic inhibition in the development of antinociceptive tolerance caused by repeated morphine administration. We investigated the effect of subchronic or acute treatment with non-steroidal positive allosteric modulators (PAMs) of δ*-GABAARs, such as 2-261, on the morphine-antinociceptive tolerance. Mice were treated twice daily with morphine for 9 days and antinociception was measured using the hot water tail immersion test. Co-treatment with 2-261 and morphine prevented morphine-antinociceptive tolerance and acute administration of 2-261 on day 9 was sufficient to reverse the tolerance. Other compounds with activity at δ*-GABAARs also reversed morphine tolerance, whereas an enaminone that lacked activity at δ*-GABAARs did not. Acute administration of 2-261 did not cause an additive or synergistic antinociceptive effect when combined with an acute submaximal dose of morphine. We then used Cre/LoxP recombination to generate GABAA δ-subunit knockout mice to corroborate the pharmacological results. Observations of male δ-knockout mice demonstrated that the δ*-GABAARs was necessary for 2-261 modulation of both analgesic tolerance and somatic withdrawal symptoms produced by subchronic morphine. While female mice still benefited from the positive effects of 2-261, the δ-subunit was not necessary for these effects, highlighting a distinction of the different pathways that could have implications for some of the sex-related differences seen in human opioid-induced outcomes. Consequently, subtype-specific allosteric modulators of GABAARs may warrant further investigation as pharmacological targets to manage tolerance and withdrawal from opioids.

Evaluation of marine spatial planning requires fit for purpose monitoring strategies.

Marine spatial planning (MSP) has rapidly become the most widely used integrated, place-based management approach in the marine environment. Monitoring and evaluation of MSP is key to inform best practices, adaptive management and plan iteration. While standardised evaluation frameworks cannot be readily applied, accounting for evaluation essentials such as the definition of evaluation objectives, indicators and stakeholder engagement of stakeholders is a prerequisite for meaningful evaluation outcomes. By way of a literature review and eleven practical MSP case studies, we analysed present day trends in evaluation approaches and unravelled the adoption of evaluation essentials for three categories for monitoring and evaluation for plan making, plan outcomes, and policy implementation. We found that at a global scale the focus of MSP evaluation has shifted over the past decade from evaluating predominantly plan outcomes towards the evaluation of plan making. Independent of the scope of the evaluation, evaluation approaches varied greatly from formal and structured processes, building for instance on MSP goals and objectives, to informal processes based on stakeholder interviews. We noted a trend in the adoption of formalised approaches where MSP evaluations have increasingly become linked to MSP policy goals and objectives. However, the enhanced use of MSP objectives and indicators did not result in a more straightforward reporting of outcomes, e.g. such as the achievement of specific MSP objectives. Overall, we found weak linkages between defined MSP objectives, indicators and available monitoring data. While the apparent shift towards a focus on objectives is promising, we highlight the need of fit-for-purpose monitoring data to enable effective evaluation of those objectives. Hence, effective MSP and adaptive management processes require customised and concurrent monitoring and evaluation strategies and procedures. We argue that evaluation processes would also benefit from a better understanding of the general environmental, socio-economic and socio-cultural effects of MSP. Therefore, to understand better environmental effects of MSP, we praise that forthcoming MSP processes need to deepen the understanding and considerations of cause-effect pathways between human activities and changes of ecosystem state through the adoption of targeted cumulative effects assessments.

Socio-ecological vulnerability to tipping points: A review of empirical approaches and their use for marine management.

Sustainability in the provision of ecosystem services requires understanding of the vulnerability of social-ecological systems (SES) to tipping points (TPs). Assessing SES vulnerability to abrupt ecosystem state changes remains challenging, however, because frameworks do not operationally link ecological, socio-economic and cultural elements of the SES. We conducted a targeted literature review on empirical assessments of SES and TPs in the marine realm and their use in ecosystem-based management. Our results revealed a plurality of terminologies, definitions and concepts that hampers practical operationalisation of these concepts. Furthermore, we found a striking lack of socio-cultural aspects in SES vulnerability assessments, possibly because of a lack of involvement of stakeholders and interest groups. We propose guiding principles for assessing vulnerability to TPs that build on participative approaches and prioritise the connectivity between SES components by accounting for component linkages, cascading effects and feedback processes.

Single Portion Packaging and the Use of User Test Protocols to Determine Patient Accessibility.

In 2015, the UK National Health Service (NHS) established a taskforce to review single portion food and beverage packaging, which has been identified as a potential challenge to users in hospitals. Hence, a study was undertaken to determine the suitability and accessibility of the current single portion packs. The packaging was assessed using ISO 17480 (Guidelines for Accessible Packaging), Annex D. The standard determines a pass or fail of packaging opening asking a panel 20 older adults to open a pack. A pack is recorded as a failure if within the 20 people cohort, there is an example of pack being unable to be opened within the time limit (defined as 1 minute) or the overall satisfaction score ranks below 3 on a 5-point Likert scale. Ten standard single portion packaging items were randomly selected for testing. The packs were chosen to reflect a broad range of food and beverage and packaging types. The results showed that the standard provided useful assessment data, identifying that 70% of the packs were so poorly designed that they failed to pass the standard, with 50% of the packs having examples that were unopenable by the participants, whilst a further 20% rated poorly for satisfaction.

IL-27 amplifies cytokine responses to Gram-negative bacterial products and Salmonella typhimurium infection.

Cytokine responses from monocytes and macrophages exposed to bacteria are of particular importance in innate immunity. Focusing on the impact of the immunoregulatory cytokine interleukin (IL)-27 on control of innate immune system responses, we examined human immune responses to bacterial products and bacterial infection by E. coli and S. typhimurium. Since the effect of IL-27 treatment in human myeloid cells infected with bacteria is understudied, we treated human monocytes and macrophages with IL-27 and either LPS, flagellin, or bacteria, to investigate the effect on inflammatory signaling and cytokine responses. We determined that simultaneous stimulation with IL-27 and LPS derived from E. coli or S. typhimurium resulted in enhanced IL-12p40, TNF-α, and IL-6 expression compared to that by LPS alone. To elucidate if IL-27 manipulated the cellular response to infection with bacteria, we infected IL-27 treated human macrophages with S. typhimurium. While IL-27 did not affect susceptibility to S. typhimurium infection or S. typhimurium-induced cell death, IL-27 significantly enhanced proinflammatory cytokine production in infected cells. Taken together, we highlight a role for IL-27 in modulating innate immune responses to bacterial infection.

Ultra-hydrophilic stent platforms promote early vascular healing and minimise late tissue response: a potential alternative to second-generation drug-eluting stents.

AIMS: Simple surface modifications can enhance coronary stent performance. Ultra-hydrophilic surface (UHS) treatment of contemporary bare metal stents (BMS) was assessed in vivo to verify whether such stents can provide long-term efficacy comparable to second-generation drug-eluting stents (DES) while promoting healing comparably to BMS. METHODS AND RESULTS: UHS-treated BMS, untreated BMS and corresponding DES were tested for three commercial platforms. A thirty-day and a 90-day porcine coronary model were used to characterise late tissue response. Three-day porcine coronary and seven-day rabbit iliac models were used for early healing assessment. In porcine coronary arteries, hydrophilic treatment reduced intimal hyperplasia relative to the BMS and corresponding DES platforms (1.5-fold to threefold reduction in 30-day angiographic and histological stenosis; p<0.04). Endothelialisation was similar on UHS-treated BMS and untreated BMS, both in swine and rabbit models, and lower on DES. Elevation in thrombotic indices was infrequent (never observed with UHS, rare with BMS, most often with DES), but, when present, correlated with reduced endothelialisation (p<0.01). CONCLUSIONS: Ultra-hydrophilic surface treatment of contemporary stents conferred good healing while moderating neointimal and thrombotic responses. Such surfaces may offer safe alternatives to DES, particularly when rapid healing and short dual antiplatelet therapy (DAPT) are crucial.

Stent thrombogenicity early in high-risk interventional settings is driven by stent design and deployment and protected by polymer-drug coatings.

BACKGROUND: Stent thrombosis is a lethal complication of endovascular intervention. Concern has been raised about the inherent risk associated with specific stent designs and drug-eluting coatings, yet clinical and animal support is equivocal. METHODS AND RESULTS: We examined whether drug-eluting coatings are inherently thrombogenic and if the response to these materials was determined to a greater degree by stent design and deployment with custom-built stents. Drug/polymer coatings uniformly reduce rather than increase thrombogenicity relative to matched bare metal counterparts (0.65-fold; P=0.011). Thick-strutted (162 µm) stents were 1.5-fold more thrombogenic than otherwise identical thin-strutted (81 µm) devices in ex vivo flow loops (P<0.001), commensurate with 1.6-fold greater thrombus coverage 3 days after implantation in porcine coronary arteries (P=0.004). When bare metal stents were deployed in malapposed or overlapping configurations, thrombogenicity increased compared with apposed, length-matched controls (1.58-fold, P=0.001; and 2.32-fold, P<0.001). The thrombogenicity of polymer-coated stents with thin struts was lowest in all configurations and remained insensitive to incomplete deployment. Computational modeling-based predictions of stent-induced flow derangements correlated with spatial distribution of formed clots. CONCLUSIONS: Contrary to popular perception, drug/polymer coatings do not inherently increase acute stent clotting; they reduce thrombosis. However, strut dimensions and positioning relative to the vessel wall are critical factors in modulating stent thrombogenicity. Optimal stent geometries and surfaces, as demonstrated with thin stent struts, help reduce the potential for thrombosis despite complex stent configurations and variability in deployment.

Humour experience in schizophrenia: relationship with executive dysfunction and psychosocial impairment.

BACKGROUND: The ability to appreciate humour is essential to successful human interactions. In this study, we hypothesized that individuals with schizophrenia would have diminished ability to recognize and appreciate humour. The relationship between humour experience and clinical symptoms, cognitive and social functioning was examined. METHOD: Thirty patients with a DSM-IV diagnosis of schizophrenia were compared with 30 age-, gender-, IQ- and ethnicity-matched healthy controls. Humour recognition was measured by identification of humorous moments in four silent slapstick comedy film clips and calculated as d-prime (d') according to signal detection theory. Humour appreciation was measured by self-report mood state and funniness ratings. Patients were assessed for clinical symptoms, theory of mind ability, executive function [using the Wisconsin Card Sorting Test (WCST)] and social functioning [using the Life Skills Profile (LSP)]. RESULTS: Patient and control groups did not differ in the funniness ratings they attributed to the video clips. Patients with schizophrenia had a lower d' (humour) compared to the controls, after controlling for (1) the performance of a baseline recognition task with a non-humorous video clip and (2) severity of depressive symptoms. In patients, d' (humour) had significant negative correlation with delusion and depression scores, the perseverative error score of the WCST and the total scores of the LSP. CONCLUSIONS: Compared with controls, patients with schizophrenia were less sensitive at detecting humour but similarly able to appreciate humour. The degree of humour recognition difficulty may be associated with the extent of executive dysfunction and thus contribute to the psychosocial impairment in patients with schizophrenia.

Photolysis of a caged peptide reveals rapid action of N-ethylmaleimide sensitive factor before neurotransmitter release.

The time at which the N-ethylmaleimide-sensitive factor (NSF) acts during synaptic vesicle (SV) trafficking was identified by time-controlled perturbation of NSF function with a photoactivatable inhibitory peptide. Photolysis of this caged peptide in the squid giant presynaptic terminal caused an abrupt (0.2 s) slowing of the kinetics of the postsynaptic current (PSC) and a more gradual (2-3 s) reduction in PSC amplitude. Based on the rapid rate of these inhibitory effects relative to the speed of SV recycling, we conclude that NSF functions in reactions that immediately precede neurotransmitter release. Our results indicate the locus of SNARE protein recycling in presynaptic terminals and reveal NSF as a potential target for rapid regulation of transmitter release.

Differences in bone density, body composition, physical activity, and diet between child gymnasts and untrained children 7-8 years of age.

Strategies that enhance the acquisition of bone mass may be protective against osteoporosis. BMD was compared in 20 artistic gymnasts (10 boys; 10 girls) and 20 untrained children ages 7-8 years. Higher regional values of BMD were observed in female gymnasts than untrained girls. If retained to adulthood, this higher BMD may protect skeletal integrity in later life. Strategies that enhance the acquisition of bone mass in children may assist with the prevention of osteoporosis. This study explored the effects of regular high-impact and weight-bearing activity before the age of 7 years on total and regional bone mineral density (BMD). Twenty artistic gymnasts (10 boys and 10 girls) and 20 untrained children, 7-8 years of age, were recruited. The untrained children were matched to gymnasts by sex, height, weight, and age. Female gymnasts trained 8-10 h per week and had trained regularly for 3-4 years. Male gymnasts trained 4-6 h per week and had trained for 1-2 years. Measurements of bone mineral density were made using DXA for total body BMD (TBBMD); lumbar spine, both areal (aSBMD) and volumetric (vSBMD); total spine; pelvis; arms; and legs. Significant mean differences (8-10%) in aSBMD, vSBMD, arm BMD, and TBBMD were observed between female gymnasts and untrained girls (p < 0.05: aSBMD, vSBMD, and TBBMD body mass (BM); p < 0.01: arm BMD). A nonsignificant trend toward a higher TBBMD/BM and arm BMD was observed in male gymnasts compared with untrained boys. Trends toward a higher BMD within the pelvis, legs, and total spine were also observed in gymnasts. There were no differences in total and regional BMD between untrained boys and untrained girls. The results suggest that gymnastics training before the age of 7 years enhances the acquisition of bone mass at selected skeletal sites. The magnitude of this enhancement seems to be linked to the cumulative volume of such training. If retained during adolescence and young adulthood, a surfeit of bone acquired through high-impact and weight-bearing activity in early childhood may protect skeletal integrity in later life.

A systematic review of outcome measures reported for the therapeutic effectiveness of oral anticoagulation.

AIMS: To evaluate the evidence of therapeutic international normalised ratio (INR) control reporting and to provide recommendations for future reporting, particularly for research and audit purposes. METHODS: A systematic review of literature published over a five year period describing therapeutic INR control. Papers were identified from the Medline electronic database, and those that met the quality criteria were reviewed independently by an academic general practitioner and a consultant haematologist. RESULTS: Fifteen papers were identified that met the quality criteria for review. The sample size of studies ranged from 53 to 2545 (mean, 483.9) patients. Follow up ranged from three months to 13 years. Twelve studies reported results from secondary care only, one from primary care only, and two from both primary and secondary care. Seven of the 15 papers reported percentage time in range, five of 15 papers reported mean INR, six of 15 papers reported the proportion of tests in range, and five of 15 papers reported mean warfarin dose. Additional methods of presenting INR results were: dose changes each month, distribution of INR results, deviation of INR value from mean, percentage dose changes, time between visits, and median INR value. Six papers reported only one outcome measure, six reported two outcomes, two papers reported three outcomes, and one paper reported five outcomes. CONCLUSIONS: It is recommended that at least two outcome measures should be reported and measures should be selected so that both the INR determinations and dosing advice are monitored.

A randomised controlled trial of patient self management of oral anticoagulation treatment compared with primary care management.

BACKGROUND: The increase in numbers of patients receiving warfarin treatment has led to the development of alternative models of service delivery for oral anticoagulant monitoring. Patient self management for oral anticoagulation is a model new to the UK. This randomised trial was the first to compare routine primary care management of oral anticoagulation with patient self management. AIM: To test whether patient self management is as safe, in terms of clinical effectiveness, as primary care management within the UK, as assessed by therapeutic international normalised ratio (INR) control. METHOD: Patients receiving warfarin from six general practices who satisfied study entry criteria were eligible to enter the study. Eligible patients were randomised to either intervention (patient self management) or control (routine primary care management) for six months. The intervention comprised two training sessions of one to two hours duration. Patients were allowed to undertake patient self management on successful completion of training. INR testing was undertaken using a Coaguchek device and regular internal/external quality control tests were performed. Patients were advised to perform INR tests every two weeks, or weekly if a dose adjustment was made. Dosage adjustment was undertaken using a simple dosing algorithm. RESULTS: Seventy eight of 206 (38%) patients were eligible for inclusion and, of these, 35 (45%) declined involvement or withdrew from the study. Altogether, 23 intervention and 26 control patients entered the study. There were no significant differences in INR control (per cent time in range: intervention, 74%; control, 77%). There were no serious adverse events in the intervention group, with one fatal retroperitoneal haemorrhage in the control group. Costs of patient self management were significantly greater than for routine care (pound 90 v pound 425/patient/year). CONCLUSION: These are the first UK data to demonstrate that patient self management is as safe as primary care management for a selected population. Further studies are needed to elucidate whether this model of care is suitable for a larger population.

Measuring zinc in living cells. A new generation of sensitive and selective fluorescent probes.

New fluorescent indicators with nanomolar to micromolar affinities for Zn(2+) have been synthesized in wavelengths from UV to the far red. The UV light-excited indicators are ratiometric. The visible wavelength indicators are non-ratiometric and exhibit large and pH-independent fluorescence increases with increasing zinc concentrations, with little to no sensitivity to physiologically relevant Ca(2+) concentrations. Experiments in neuronal and non-neuronal cell cultures show the new indicators to retain their sensitivity to and selectivity for zinc after conversion to cell-permeable forms.

Direct, real-time assessment of dopamine release autoinhibition in the rat caudate-putamen.

Inhibition of endogenous dopamine release by photo-released dopamine (i.e., autoinhibition) was characterized in the rat caudate-putamen using combined caged-dopamine photolysis and fast-scan cyclic voltammetry. Coronal brain slices (400 microm thick) were perfused with caged-dopamine (150-200 microM in artificial cerebrospinal fluid). Ultraviolet illumination of increasing duration (25-250 ms, approximately 100 microm beam diameter) was focused at the tip of the recording electrode to uncage increasing amounts of exogenous dopamine at the recording sites (0.5-5 microM); a single biphasic electrical stimulus was delivered 0.1-10 s later to induce endogenous dopamine release. The concentrations of both endogenous and exogenous dopamine were determined using voltammetry, thus enabling determination of concentration-dependent inhibition of the endogenous release by the latter. While unaffected by control ultraviolet illumination, endogenous dopamine release was rapidly inhibited by photo-released dopamine in a concentration-dependent manner. Photo-application of 3-5 microM exogenous dopamine inhibited the endogenous release by 90-100% (electrical stimulus applied 1 s after photolysis initiation), an effect prevented by 2 microM sulpiride. The autoinhibition was dependent on the time between photolysis onset and electrical stimulation. Terminal dopamine autoreceptor stimulation led to robust inhibition of endogenous dopamine release with a latency of approximately 200 ms and effective duration of less than 5 s. The percent autoinhibition was a skewed, U-shaped function of photolysis/electrical stimulation intervals with the peak inhibition at 1 s. This study directly demonstrates that autoreceptor-mediated inhibition of terminal dopamine release in caudate-putamen is designed to provide a rapid, robust, yet short-lasting modulation of terminal dopamine release.

Does the Birmingham model of oral anticoagulation management in primary care work outside trial conditions?

The effectiveness of the Birmingham model of primary care oral anticoagulation management has previously been demonstrated within a randomised controlled trial. The aim of this study was to assess the effectiveness of the Birmingham model in routine care. All patients from 12 primary care centres attending either practice-based or hospital-based anticoagulation clinics were retrospectively followed up from October 1996 to March 1998. Outcome measures were therapeutic International Normalised Ratio (INR) control, haemorrhagic and thrombotic episodes, and recall frequency; 452 patients who had two or more INR results during the follow-up period were investigated. There were no significant differences between practice-based and hospital-based populations in terms of the percentage time in range, (69% and 64% respectively). The proportion of tests in range was significantly higher in the practice-based group (61% practice-based, 57% hospital-based; P = 0.015). There was no difference between the two populations in terms of mean follow-up time (36 days in each group). There were no significant differences between groups for the number of clinical outcomes per patient. This study confirmed that, within these practices, oral anticoagulation management is safe and effective using the Birmingham model.

Differential effect of IL-4 and IL-13 on CD44 expression in the Burkitt's lymphoma B cell line BL30/B95-8 and in Epstein-Barr virus (EBV) transformed human B cells: loss of IL-13 receptors on Burkitt's lymphoma B cells.

IL-4 and IL-13, cytokines with similar biological effects may influence growth and progression of B-cell tumors through regulation of key cell surface molecules important in intercellular communications. In this study, we demonstrate that IL-4 and IL-13 exhibited differential effects on CD23 and CD44 expression and binding to hyaluronan in BL30/B95-8, a Burkitt's lymphoma (BL), and MK3.31, an Epstein-Barr virus transformed normal human B cell line (B-LCL). Studies conducted to understand the molecular mechanisms underlying this differential effect show that IL-4 induced phosphorylation of JAK1, JAK3, and STAT6 in BL30/B95-8 cells and of JAK3 and STAT6 in MK 3.31 cells. In contrast, IL-13 failed to induce the phosphorylation of JAK kinases or STAT6 proteins in these cell lines. The inability of BL30/B95-8 cells to respond to IL-13 was attributed to the loss of expression of IL-13R subunits alpha1 and alpha2, a finding confirmed for a number of other BL cell lines examined.

Caged Q-rhodamine dextran: a new photoactivated fluorescent tracer.

An amine-reactive caged rhodamine was synthesized and conjugated to aminodextran. The resulting tracer was injected into a single cell zebrafish embryo, and a portion of the tracer was photolyzed in a single cell after development. The resulting fluorescent cell was imaged by fluorescence microscopy through a single round of cell division.

Behavioral characterization of Co 134444 (3alpha-hydroxy-21-(1'-imidazolyl)-3beta-methoxymethyl-5alpha- pregnan-20-one), a novel sedative-hypnotic neuroactive steroid.

RATIONALE: Neuroactive steroids have been shown to exhibit a wide range of behavioral activities that are similar but not identical to those of benzodiazepines. These activities include anticonvulsant, anxiolytic and sedative-hypnotic effects. OBJECTIVE: The purpose of the present study was to characterize Co 134444 (3alpha-hydroxy-21-(1'-imidazolyl)-3 -methoxymethyl-5alpha-pregnan-20-one), a novel sedative-hypnotic neuroactive steroid, in a variety of behavioral procedures. METHODS: Anticonvulsant effects were determined by the ability to protect against pentylenetetrazol- and maximal electroshock-induced seizures in mice and rats. Anxiolytic-like effects were determined using a punished drinking procedure in rats. Ataxic effects were determined using a horizontal wire procedure in mice and a rotorod procedure in mice and rats. The discriminative stimulus effects were evaluated in rats trained to discriminate pregnanolone from vehicle. RESULTS: Co 134444 exhibited oral anticonvulsant activity against pentylenetetrazol and maximal electroshock with ED50s of 9.8 and 20.6 mg/kg, respectively, in mice and 23.6 and 25.3 mg/kg, respectively, in rats. Anxiolytic-like efficacy was observed at a dose as low as 3.0 mg/kg, PO, in rats. Ataxic effects were observed with rapid onset and short duration. TD50s were 17.4 and 21.2 mg/kg orally in mice in the horizontal wire and rotorod procedures, respectively, and 39.0 mg/kg in rats using the rotorod. Co 134444 completely substituted for pregnanolone as a discriminative stimulus with little effect on response rate. CONCLUSIONS: Co 134444 exhibits a wide variety of behavioral effects; however, its rapid onset and short duration are consistent with its potential use as a sedative-hypnotic drug.