Ectopic ACTH Syndrome in a Child With Abdominal Ewing Sarcoma: A Rare Paraneoplastic Phenomenon.

Ectopic adrenocorticotropic hormone syndrome is a paraneoplastic phenomenon rarely seen in pediatrics and rarely described in Ewing sarcoma. We report a 15-year-old boy with abdominal Ewing sarcoma and clinical and laboratory findings of ectopic adrenocorticotropic hormone syndrome that promptly resolved with treatment of the tumor.

The safety of achieved iron stores and their effect on IV iron and ESA use: post-hoc results from a randomized trial of ferric citrate as a phosphate binder in dialysis
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Iron stores assuring optimal efficacy/safety for erythropoiesis are unknown in the dialysis population. Using multicenter trial data, we related safety profiles, erythropoiesis-stimulating agent (ESA), and intravenous iron dosing to achieved iron stores in 441 subjects randomized 2 : 1 to ferric citrate or active control as their phosphate binder over 52 weeks. Intravenous iron was given at each site's discretion if ferritin ≤ 1,000 ng/mL and transferrin saturation ≤ 30%. Multivariable time-dependent Cox regression jointly related the primary safety outcome (composite of cardiac, infection, gastrointestinal, and hepatobiliary serious adverse events) to moving averages of ferritin and transferrin saturation over the preceding 90 days with covariate adjustment. Multivariable generalized estimating equations related elevated ESA and intravenous iron doses to trailing 90-day averages of ferritin and transferrin saturation with covariate adjustment. The adjusted hazard ratio for the safety composite per 10% increase in transferrin saturation was 0.84 (95% confidence interval 0.68 - 1.02, p = 0.08) and 1.09 (0.86 - 1.35, p = 0.48) per 400 ng/mL increase in ferritin. The adjusted hazard ratio for the safety composite was 0.50 (0.29 - 0.88, p = 0.016) for the highest transferrin saturation tertile vs. the lowest. Adjusted odds ratios for higher intravenous iron dose were lower in the highest (0.23 [0.16 - 0.35], p < 0.001) and middle transferrin saturation tertile (0.42 [0.31 - 0.57], p < 0.001) vs. lowest. Incidence of elevated ESA dose was lower in the highest transferrin saturation tertile (p = 0.01). Ferritin did not predict clinical events or ESA dose. Transferrin saturation may be a better marker than serum ferritin to judge optimal iron stores in dialysis patients. Transferrin saturations > 34% are safe and provide maximal efficacy.
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Asynchronous GABA Release Is a Key Determinant of Tonic Inhibition and Controls Neuronal Excitability: A Study in the Synapsin II-/- Mouse.

Idiopathic epilepsies have frequently been linked to mutations in voltage-gated channels (channelopathies); recently, mutations in several genes encoding presynaptic proteins have been shown to cause epilepsy in humans and mice, indicating that epilepsy can also be considered a synaptopathy. However, the functional mechanisms by which presynaptic dysfunctions lead to hyperexcitability and seizures are not well understood. We show that deletion of synapsin II (Syn II), a presynaptic protein contributing to epilepsy predisposition in humans, leads to a loss of tonic inhibition in mouse hippocampal slices due to a dramatic decrease in presynaptic asynchronous GABA release. We also show that the asynchronous GABA release reduces postsynaptic cell firing, and the parallel impairment of asynchronous GABA release and tonic inhibition results in an increased excitability at both single-neuron and network levels. Restoring tonic inhibition with THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol; gaboxadol), a selective agonist of δ subunit-containing GABAA receptors, fully rescues the SynII(-/-) epileptic phenotype both ex vivo and in vivo. The results demonstrate a causal relationship between the dynamics of GABA release and the generation of tonic inhibition, and identify a novel mechanism of epileptogenesis generated by dysfunctions in the dynamics of release that can be effectively targeted by novel antiepileptic strategies.

Ferric Citrate Reduces Intravenous Iron and Erythropoiesis-Stimulating Agent Use in ESRD.

Ferric citrate (FC) is a phosphate binder with shown efficacy and additional effects on iron stores and use of intravenous (iv) iron and erythropoiesis-stimulating agents (ESAs). We provide detailed analyses of changes in iron/hematologic parameters and iv iron/ESA use at time points throughout the active control period of a phase 3 international randomized clinical trial. In all, 441 subjects were randomized (292 to FC and 149 to sevelamer carbonate and/or calcium acetate [active control (AC)]) and followed for 52 weeks. Subjects on FC had increased ferritin and transferrin saturation (TSAT) levels compared with subjects on AC by week 12 (change in ferritin, 114.1±29.35 ng/ml; P<0.001; change in TSAT, 8.62%±1.57%; P<0.001). Change in TSAT plateaued at this point, whereas change in ferritin increased through week 24, remaining relatively stable thereafter. Subjects on FC needed less iv iron compared with subjects on AC over 52 weeks (median [interquartile range] dose=12.9 [1.0-28.9] versus 26.8 [13.4-47.6] mg/wk; P<0.001), and the percentage of subjects not requiring iv iron was higher with FC (P<0.001). Cumulative ESA over 52 weeks was lower with FC than AC (median [interquartile range] dose=5303 [2023-9695] versus 6954 [2664-12,375] units/wk; P=0.04). Overall, 90.3% of subjects on FC and 89.3% of subjects on AC experienced adverse events. In conclusion, treatment with FC as a phosphate binder results in increased iron parameters apparent after 12 weeks and reduces iv iron and ESA use while maintaining hemoglobin over 52 weeks, with a safety profile similar to that of available binders.

Interplay between synaptic endocannabinoid signaling and metaplasticity in neuronal circuit function and dysfunction.

Synaptic neuromodulation acts across different functional domains to regulate cognitive processing and behavior. Recent challenges are related to elucidating the molecular and cellular mechanisms through which neuromodulatory pathways act on multiple time scales to signal state-dependent contingencies at the synaptic level or to stabilise synaptic connections during behavior. Here, we present a framework with the synaptic neuromodulators endocannabinoids (eCBs) as key players in dynamic synaptic changes. Modulation of various molecular components of the eCB pathway yields interconnected functional activation states of eCB signaling (prior, tonic, and persistent), which may contribute to metaplastic control of synaptic and behavioral functions in health and disease. The emerging picture supports aberrant metaplasticity as a contributor to cognitive dysfunction associated with several pathological states in which eCB signaling, or other neuromodulatory pathways, are deregulated.

A Prospective Clinical Study to EvaluAte the AbiliTy of the CloudCath System to Detect Peritonitis During In-Home Peritoneal Dialysis (CATCH).

Introduction: Peritonitis is the leading complication of peritoneal dialysis (PD). Patients are instructed to seek care promptly for signs (cloudy effluent) or symptoms (abdominal pain), and earlier treatment improves outcomes. The CloudCath Peritoneal Dialysis Drain Set Monitoring (CloudCath) system monitors turbidity in dialysis effluent and sends notifications of changes signaling possible peritonitis. Methods: We conducted this single-arm, open-label, multicenter study of CloudCath system use during PD. We deactivated system notifications to participants and investigators, who followed standard-of-care for peritonitis signs and symptoms. Effectiveness endpoints measured time between CloudCath system notifications and peritonitis events using International Society of Peritoneal Dialysis (ISPD) criteria. Results: Two hundred forty-three participants used the CloudCath system for 178.8 patient-years. Of 71 potential peritonitis events, 51 events (0.29 per patient-year) met ISPD white blood cell (WBC) count criteria. The system triggered notifications for 41 of 51 events (80.4%), with a median lead time of 2.6 days (10%-90% range, -1.0 to 15.7; P < 0.0001). Excluding 6 peritonitis events that occurred when the system was not in use, the system triggered notifications for 41 of 45 events (91.1%), with a median lead time of 3.0 days (10%-90% range, -0.5 to 18.8; P < 0.0001). Of the 0.78 notifications per patient-year, the majority were peritonitis events or nonperitonitis events such as exit site and tunnel infections or catheter/cycler issues. Conclusion: The CloudCath system detected peritonitis events during PD several days earlier than the current standard-of-care and has the capacity to send notifications that could expedite peritonitis diagnosis and treatment.

Ryanodine receptor blockade reduces amyloid-ß load and memory impairments in Tg2576 mouse model of Alzheimer disease.

In Alzheimer disease (AD), the perturbation of the endoplasmic reticulum (ER) calcium (Ca²âº) homeostasis has been linked to presenilins, the catalytic core in γ-secretase complexes cleaving the amyloid precursor protein (APP), thereby generating amyloid-ß (Aß) peptides. Here we investigate whether APP contributes to ER Ca²âº homeostasis and whether ER Ca²âº could in turn influence Aß production. We show that overexpression of wild-type human APP (APP(695)), or APP harboring the Swedish double mutation (APP(swe)) triggers increased ryanodine receptor (RyR) expression and enhances RyR-mediated ER Ca²âº release in SH-SY5Y neuroblastoma cells and in APP(swe)-expressing (Tg2576) mice. Interestingly, dantrolene-induced lowering of RyR-mediated Ca²âº release leads to the reduction of both intracellular and extracellular Aß load in neuroblastoma cells as well as in primary cultured neurons derived from Tg2576 mice. This Aß reduction can be accounted for by decreased Thr-668-dependent APP phosphorylation and ß- and γ-secretases activities. Importantly, dantrolene diminishes Aß load, reduces Aß-related histological lesions, and slows down learning and memory deficits in Tg2576 mice. Overall, our data document a key role of RyR in Aß production and learning and memory performances, and delineate RyR-mediated control of Ca²âº homeostasis as a physiological paradigm that could be targeted for innovative therapeutic approaches.

Renal artery stenosis: prevalence of, risk factors for, and management of in-stent stenosis.

Atherosclerotic renal artery stenosis is common and is associated with hypertension and chronic kidney disease. More frequent use of percutaneous renal artery stent placement for the treatment of renal artery stenosis during the past 2 decades has increased the number of patients with implanted stents. In-stent stenosis is a serious problem, occurring more frequently than earlier reports suggest and potentially resulting in late complications. Currently, there are no guidelines covering the approach to restenosis after renal artery stent placement. This article reviews data on the prevalence of and risk factors for the development of in-stent stenosis and the clinical manifestations, evaluation, and treatment of in-stent stenosis and suggests a strategy for the management of patients after percutaneous renal artery stent placement.

Non-small cell lung cancer evaluated with quantitative contrast-enhanced CT and PET-CT: net enhancement and standardized uptake values are related to tumour size and histology.

BACKGROUND: Personalized cancer therapy remains a challenge. In this context, we attempted to identify correlations between tumour angiogenesis, tumour metabolism and tumour cell type. To this aim, we used single=phase multidetector computed tomography (MDCT) and hybrid positron emission tomography-computed tomography (PET/CT) to determine whether net enhancement and standardized uptake value (SUVmax) were correlated with tumour size and cytology in patients affected by non-small cell lung cancer (NSCLC). MATERIAL AND METHODS: Our study included 38 patients (30 men, 8 women, mean age 70) with a NSCLC measuring between 3 cm and 7 cm, using a 16-slice multidetector CT (Brilliance Philips) and with PET-CT (Biograph 16 Siemens Medical Solutions). The following lesion parameters were evaluated: maximum diameter, medium density before contrast injection (CTpre), medium density after contrast injection (CTpost average), density in the most enhanced part of the lesion after contrast (CTpost max), net enhancement, SUVmax, age, and cytology. Correlation coefficient and p-value were computed for each pair of variables. In addition, correlations were computed for each pair of variables, and for all combinations of tumour types. We focused on subsets of data with more than 10 observations, and with correlation r>0.500 and p<0.05. RESULTS: A weak correlation (r=0.32; p=0.048) was found between SUVmax and tumour size; the correlation was stronger for masses larger than 31 mm (r=0.4515; p=0.0268). No other correlations were found among the variables examined. CONCLUSIONS: Our data may have prognostic significance, and could lead to more appropriate surgical treatment and better treatment outcome.

Assessing accuracy of estimated dry weight in dialysis patients post transplantation: the kidney knows best.

INTRODUCTION: Estimated dry weight is used to guide fluid removal during outpatient hemodialysis sessions. Errors in estimated dry weight can result in intradialytic hypotension and interdialytic fluid overload. The goal of this study was to assess the accuracy of estimated dry weight by comparing it to the 2-week post-transplant weight in two cohorts of hemodialysis patients. METHODS: This observational, multi-center, retrospective cohort study included maintenance hemodialysis patients who underwent kidney transplantation at two medical centers in Massachusetts. The relationship between estimated dry weight pre-transplant and weight at week 2 post-transplant in patients with good allograft function (serum creatinine ≤ 1.5 mg/dL) was analyzed. Estimated dry weight was considered accurate if it was within ± 2% of the week 2 post-transplant weight. RESULTS: Fifty seven patients with good allograft function were identified: mean age 54 ± 14 years, 32 (58%) from deceased donors, 22 (38.6%) females. 38 were Caucasian (66.7%), 11 Hispanic (19.3%), 3 black (5.3%), and 5 others (8.8%). 2-week mean post transplantation serum creatinine was 1.2 ± 0.2 mg/dL. Mean (SD) estimated dry weight was 71.4 ± 15.9. Before transplantation, only 14 (24.6%) patients were within ± 2% of the 2-week post-transplant weight; 23 (40.3%) were above and 20 (35.1%) were below. CONCLUSIONS: Our point of view, based on the assumption that the weight of patients with good allograft function at 2 weeks post-transplant approaches their accurate dry weight, is that a majority of maintenance hemodialysis patients (75.4%) are hypervolemic or hypovolemic prior to renal transplantation. This highlights the importance of finding novel tools to achieve euvolemia in patients undertaking dialysis. Timely feedback regarding achieved weight 2 weeks post-transplant to treating nephrologists and dialysis centers may be a starting point for assessing accuracy of dry weight.

Stress Biomarkers Do Not Correlate With Risk Factors for Kidney Injury After Cardiac Surgery.

BACKGROUND: The urinary cell cycle arrest biomarkers (UBs) insulin-like growth factor-binding protein-7 and tissue inhibitor of metalloproteinases-2 provide early detection of kidney stress, and elevations may predict cardiac surgery-associated acute kidney injury (CS-AKI). We sought to determine whether known clinical risk factors for CS-AKI correlated with increased UB values. METHODS: UBs were measured over a 12-month period the morning after on-pump cardiac surgery. Patients with a preoperative serum creatinine level greater than 2.0 mg/dL or patients undergoing dialysis were excluded. Known clinical AKI risk factors in patients with elevated UB (>0.3 (ng/mL)2/1000), that is known to correlate with kidney stress, were compared with patients with low scores (≤0.3 (ng/mL)2/1000) by using logistic regression; the analysis was repeated with UB as a continuous variable. RESULTS: A total of 412 patients met inclusion criteria. Unadjusted results demonstrated a clinically similar CS-AKI risk profile in patients with either elevated or low UB values. The Pearson correlation between preoperative estimated glomerular filtration rate and UB was low (r = 0.16). Clinical risk factors for CS-AKI were not associated with elevated UB values in the logistic regression model, thus producing an area under the receiver operating characteristic curve of 0.63. Linear regression analysis also found few associations between CS-AKI clinical risk factors and UB when measured as a continuous variable, (R2) = 0.15. CONCLUSIONS: Traditional CS-AKI clinical risk factors do not differ between patients with normal or elevated UB values. This UB test may identify patients at increased risk for AKI who otherwise would appear to be at low risk by traditional metrics.

Using urinary biomarkers to reduce acute kidney injury following cardiac surgery.

BACKGROUND: Prediction of acute kidney injury (AKI) following cardiac surgery is unreliable through the use of serum creatinine or urinary output alone. Cell cycle arrest urinary biomarkers insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP2) provide early detection of kidney stress and possibly AKI. We sought to determine whether therapeutic interventions driven by elevated urinary biomarkers (UB) reduces post-cardiac surgery stage 2/3 AKI. METHODS: A quality improvement initiative based on UB was undertaken in all adult on-pump cardiac surgical patients with a preoperative serum creatinine level ≤2.0 mg/dL. A UB score the morning after cardiac surgery that was considered positive for kidney stress (≥0.3 [ng/mL]2/1000) triggered activation of a multidisciplinary acute kidney response team (AKRT) with implementation of a predefined staged protocol, including targeted goal-directed fluid management, liberalized transfusion thresholds, continued invasive hemodynamic monitoring and its optimization in the intensive care unit, and avoidance of nephrotoxins. We compared the incidence of stage 2/3 AKI before (pre-UB) versus after (post-UB) implementation of the Kidney Disease: Improving Global Outcomes quality improvement initiative. Standardized, protocolized, evidence-based care pathways were used pre-UB. RESULTS: The incidence of stage 2/3 AKI was compared in 435 pre-UB patients and 412 post-UB patients. Fifty-five percent of the post-UB patients had a moderate or high UB score (≥0.3 [ng/mL]2/1000). Ten patients (2.30%) had stage 2/3 AKI pre-UB, compared with 1 patient (0.24%) post-UB, a relative reduction of 89% (P = .01). The total and postoperative lengths of stay, cost, mortality, and readmissions were similar in the 2 groups. The negative predictive value for AKI of UB <0.3 [ng/mL]2/1000 was 100%. CONCLUSIONS: The routine measurement of UB and subsequent activation of an AKRT are useful post-cardiac surgery therapeutic adjuncts. They are associated with early detection of kidney stress, allowing for targeted proactive intervention, and a significant decrease in postoperative stage 2/3 AKI without increases in cost or length of stay.

Evaluation of renal artery stenosis in dialysis patients.

Atherosclerotic renal artery stenosis (RAS), recognized as a contributor to chronic kidney disease (CKD), may be present in a substantial fraction of dialysis patients. It is generally unknown what proportion of end-stage renal disease patients on dialysis could recover kidney function if RAS were treated. Patients with CKD are often inadequately screened for RAS because of technical limitations of various screening modalities. Multiple small case series and studies have evaluated the role of revascularization for renal salvage in dialysis patients with RAS; these studies are reviewed. Large prospective, randomized multicenter trials of intervention for RAS exclude patients with advanced CKD. The risks of intervention must be weighed against the potential for renal recovery, even when predictors of success are not known with certainty.

Prediction of cardiovascular outcomes with machine learning techniques: application to the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) study.

BACKGROUND: Data derived from the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) study were analyzed in an effort to employ machine learning methods to predict the composite endpoint described in the original study. METHODS: We identified 573 CORAL subjects with complete baseline data and the presence or absence of a composite endpoint for the study. These data were subjected to several models including a generalized linear (logistic-linear) model, support vector machine, decision tree, feed-forward neural network, and random forest, in an effort to attempt to predict the composite endpoint. The subjects were arbitrarily divided into training and testing subsets according to an 80%:20% distribution with various seeds. Prediction models were optimized within the CARET package of R. RESULTS: The best performance of the different machine learning techniques was that of the random forest method which yielded a receiver operator curve (ROC) area of 68.1%±4.2% (mean ± SD) on the testing subset with ten different seed values used to separate training and testing subsets. The four most important variables in the random forest method were SBP, serum creatinine, glycosylated hemoglobin, and DBP. Each of these variables was also important in at least some of the other methods. The treatment assignment group was not consistently an important determinant in any of the models. CONCLUSION: Prediction of a composite cardiovascular outcome was difficult in the CORAL population, even when employing machine learning methods. Assignment to either the stenting or best medical therapy group did not serve as an important predictor of composite outcome. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT00081731.

Large Scale Phenotyping Provides Insight into the Diversity of Vegetative and Reproductive Organs in a Wide Collection of Wild and Domesticated Peppers (Capsicum spp.).

In the past years, the diversity of Capsicum has been mainly investigated through genetics and genomics approaches, fewer efforts have been made in the field of plant phenomics. Assessment of crop traits with high-throughput methodologies could enhance the knowledge of the plant phenome, giving at the same time a key contribution to the understanding of the function of many genes. In this study, a wide germplasm collection of 307 accessions retrieved from 48 world regions, and belonging to nine Capsicum species was characterized for 54 plant, leaf, flower and fruit traits. Conventional descriptors and semi-automated tools based on image analysis and colour coordinate detection were used. Significant differences were found among accessions, between species and between sweet and spicy cultivated types, revealing a large diversity. The results highlighted how the domestication process and the continued selection have increased the variability of fruit shape and colour. Hierarchical clustering based on conventional and fruit morphological descriptors reflected the separation of species on the basis of their phylogenetic relationships. These observations suggested that the flow between distinct gene pools could have contributed to determine the similarity of the species on the basis of morphological plant and fruit parameters. The approach used represents the first high-throughput phenotyping effort in Capsicum spp. aimed at broadening the knowledge of the diversity of domesticated and wild peppers. The data could help to select best the candidates for breeding and provide new insight into the understanding of the genetic base of the fruit shape of pepper.

Adherence rates to ferric citrate as compared to active control in patients with end stage kidney disease on dialysis.

INTRODUCTION: Oral phosphate binders are the main stay of treatment of hyperphosphatemia. Adherence rates to ferric citrate, a recently approved phosphate binder, are unknown. METHODS: We conducted a post-hoc analysis to evaluate whether adherence rates were different for ferric citrate vs. active control in 412 subjects with end stage kidney disease (ESKD) who were randomized to ferric citrate vs. active control (sevelamer carbonate and/or calcium acetate). Adherence was defined as percent of actual number of pills taken to total number of pills prescribed. FINDINGS: There were no significant differences in baseline characteristics including gender, race/ethnicity, and age between the ferric citrate and active control groups. Baseline phosphorus, calcium, and parathyroid hormone levels were similar. Mean (SD) adherence was 81.4% (17.4) and 81.7% (15.9) in the ferric citrate and active control groups, respectively (P = 0.88). Adherence remained similar between both groups after adjusting for gender, race/ethnicity, age, cardiovascular disease (CVD), and diabetic nephropathy (mean [95% CI]: 81.4% [78.2, 84.6] and 81.5% [77.7, 85.2] for ferric citrate and active control, respectively). Gender, race/ethnicity, age, and diagnosis of diabetic nephropathy did not influence adherence to the prescribed phosphate binder. Subjects with CVD had lower adherence rates to phosphate binder; this was significant only in the active control group. DISCUSSION: Adherence rates to the phosphate binder, ferric citrate, were similar to adherence rates to active control. Similar adherence rates to ferric citrate are notable since tolerance to active control was an entry criteria and the study was open label. Gender, race/ethnicity, nor age influenced adherence.

Recognition and Management of Resistant Hypertension.

Despite improvements in hypertension awareness and treatment, 30%-60% of hypertensive patients do not achieve BP targets and subsequently remain at risk for target organ damage. This therapeutic gap is particularly important to nephrologists, who frequently encounter treatment-resistant hypertension in patients with CKD. Data are limited on how best to treat patients with CKD and resistant hypertension, because patients with CKD have historically been excluded from hypertension treatment trials. First, we propose a consistent definition of resistant hypertension as BP levels confirmed by both in-office and out-of-office measurements that exceed appropriate targets while the patient is receiving treatment with at least three antihypertensive medications, including a diuretic, at dosages optimized to provide maximum benefit in the absence of intolerable side effects. Second, we recommend that each patient undergo a standardized, stepwise evaluation to assess adherence to dietary and lifestyle modifications and antihypertensive medications to identify and reduce barriers and discontinue use of substances that may exacerbate hypertension. Patients in whom there is high clinical suspicion should be evaluated for potential secondary causes of hypertension. Evidence-based management of resistant hypertension is discussed with special considerations of the differences in approach to patients with and without CKD, including the specific roles of diuretics and mineralocorticoid receptor antagonists and the current place of emerging therapies, such as renal denervation and baroreceptor stimulation. We endorse use of such a systematic approach to improve recognition and care for this vulnerable patient group that is at high risk for future kidney and cardiovascular events.

Reduced attention and increased impulsivity in mice lacking NPY Y2 receptors: relation to anxiolytic-like phenotype.

Neuropeptide (NPY) Y2 receptors play an important role in some anxiety-related and stress-related behaviours in mice. Changes in the level of anxiety can affect some cognitive functions such as memory, attention and inhibitory response control. We investigated the effects of NPY Y2 receptor deletion (Y2(-/-)) in mice on visual attention and response control using the five-choice serial reaction time (5-CSRT) task in which accuracy of detection of a brief visual stimulus across five spatial locations may serve as a valid behavioural index of attentional functioning. Anticipatory and perseverative responses provide a measure of inhibitory response control. During training, the Y2(-/-) mice had lower accuracy (% correct), and made more anticipatory responses. At stimulus durations of 2 and 4s the Y2(-/-) were as accurate as the Y2(+/+) mice but still more impulsive than Y(+/+). At stimulus durations of 0.25 and 0.5s both groups performed worse but the Y2(-/-) mice made significantly fewer correct responses than the Y2(+/+) controls. The anxiolytic drug diazepam at 2mg/kg IP greatly increased the anticipatory responding of Y2(-/-) mice compared to Y2(+/+). The anxiogenic inverse benzodiazepine agonist, FG 7142, at 10mg/kg IP reduced the anticipatory responding of Y2(-/-) but not Y2(+/+) mice. These data suggest that NPY Y2 receptors make an important contribution to mechanisms controlling attentional functioning and "impulsivity". They also show that "impulsivity" of NPY Y2(-/-) mice may depend on their level of anxiety. These findings may help in understanding the pathophysiology of stress disorders and depression.