Game-based training of flexibility and attention improves task-switch performance: near and far transfer of cognitive training in an EEG study.

There is a demand for ways to enhance cognitive flexibility, as it can be a limiting factor for performance in daily life. Video game training has been linked to advantages in cognitive functioning, raising the question if training with video games can promote cognitive flexibility. In the current study, we investigated if game-based computerized cognitive training (GCCT) could enhance cognitive flexibility in a healthy young adult sample (N = 72), as measured by task-switch performance. Three GCCT schedules were contrasted, which targeted: (1) cognitive flexibility and task switching, (2) attention and working memory, or (3) an active control involving basic math games, in twenty 45-min sessions across 4-6 weeks. Performance on an alternating-runs task-switch paradigm during pretest and posttest sessions indicated greater overall reaction time improvements after both flexibility and attention training as compared to control, although not related to local switch cost. Flexibility training enhanced performance in the presence of distractor-related interference. In contrast, attention training was beneficial when low task difficulty undermined sustained selective attention. Furthermore, flexibility training improved response selection as indicated by a larger N2 amplitude after training as compared to control, and more efficient conflict monitoring as indicated by reduced Nc/CRN and larger Pe amplitude after training. These results provide tentative support for the efficacy of GCCT and suggest that an ideal training might include both task switching and attention components, with maximal task diversity both within and between training games.

A systematic surveillance programme for infectious salmon anaemia virus supports its absence in the Pacific Northwest of the United States.

In response to reported findings of infectious salmon anaemia virus (ISAV) in British Columbia (BC), Canada, in 2011, U.S. national, state and tribal fisheries managers and fish health specialists developed and implemented a collaborative ISAV surveillance plan for the Pacific Northwest region of the United States. Accordingly, over a 3-1/2-year period, 4,962 salmonids were sampled and successfully tested by real-time reverse-transcription PCR. The sample set included multiple tissues from free-ranging Pacific salmonids from coastal regions of Alaska and Washington and farmed Atlantic salmon (Salmo salar L.) from Washington, all representing fish exposed to marine environments. The survey design targeted physiologically compromised or moribund animals more vulnerable to infection as well as species considered susceptible to ISAV. Samples were handled with a documented chain of custody and testing protocols, and criteria for interpretation of test results were defined in advance. All 4,962 completed tests were negative for ISAV RNA. Results of this surveillance effort provide sound evidence to support the absence of ISAV in represented populations of free-ranging and marine-farmed salmonids on the northwest coast of the United States.

Molecular testing of adult Pacific salmon and trout (Oncorhynchus spp.) for several RNA viruses demonstrates widespread distribution of piscine orthoreovirus in Alaska and Washington.

This research was initiated in conjunction with a systematic, multiagency surveillance effort in the United States (U.S.) in response to reported findings of infectious salmon anaemia virus (ISAV) RNA in British Columbia, Canada. In the systematic surveillance study reported in a companion paper, tissues from various salmonids taken from Washington and Alaska were surveyed for ISAV RNA using the U.S.-approved diagnostic method, and samples were released for use in this present study only after testing negative. Here, we tested a subset of these samples for ISAV RNA with three additional published molecular assays, as well as for RNA from salmonid alphavirus (SAV), piscine myocarditis virus (PMCV) and piscine orthoreovirus (PRV). All samples (n = 2,252; 121 stock cohorts) tested negative for RNA from ISAV, PMCV, and SAV. In contrast, there were 25 stock cohorts from Washington and Alaska that had one or more individuals test positive for PRV RNA; prevalence within stocks varied and ranged from 2% to 73%. The overall prevalence of PRV RNA-positive individuals across the study was 3.4% (77 of 2,252 fish tested). Findings of PRV RNA were most common in coho (Oncorhynchus kisutch Walbaum) and Chinook (O. tshawytscha Walbaum) salmon.

Anatomical and gene expression mapping of the ventral pallium in a three-dimensional model of developing human brain.

Combining gene expression data with morphological information has revolutionized developmental neuroanatomy in the last decade. Visualization and interpretation of complex images have been crucial to these advances in our understanding of mechanisms underlying early brain development, as most developmental processes are spatially oriented, in topologically invariant patterns that become overtly distorted during brain morphogenesis. It has also become clear that more powerful methodologies are needed to accommodate the increasing volume of data available and the increasingly sophisticated analyses that are required, for example analyzing anatomy and multiple gene expression patterns at individual developmental stages, or identifying and analyzing homologous structures through time and/or between species. Three-dimensional models have long been recognized as a valuable way of providing a visual interpretation and overview of complex morphological data. We have used a recently developed method, optical projection tomography, to generate digital three-dimensional models of early human brain development. These models can be used both as frameworks, onto which normal or experimental gene expression data can be mapped, and as objects, within which topological morphological relationships can be investigated in silico. Gene expression patterns and selected morphological structures or boundaries can then be visualized individually or in different combinations in order to study their respective morphogenetic significance. Here, we review briefly the optical projection tomography method, placing it in the context of other methods used to generate developmental three dimensional models, and show the definition of some CNS anatomical domains within a Carnegie stage 19 human model. We also map the telencephalic EMX1 and PAX6 gene expression patterns to this model, corroborating for the first time the existence of a ventral pallium primordium in the telencephalon of human embryos, a distinct claustroamygdaloid histogenetic area comparable to the recently defined mouse primordium given that name [Puelles L, Kuwana E, Puelles E, Bulfone A, Shimamura K, Keleher J, Smiga S, Rubenstein JLR (2000) Pallial and subpallial derivatives in the embryonic chick and mouse telencephalon, traced by the expression of the genes Dlx-2, Emx-1, Nkx-2.1, Pax-6, and Tbr-1. J Comp Neurol 424:409-438; Puelles L, Martínez S, Martínez-de-la-Torre M, Rubenstein JLR (2004) Gene maps and related histogenetic domains in the forebrain and midbrain. In: The rat nervous system, 3rd ed (Paxinos G, ed), pp 3-25. San Diego: Academic Press].

Structure-activity studies for a novel series of bicyclic substituted hexahydrobenz[e]isoindole alpha1A adrenoceptor antagonists as potential agents for the symptomatic treatment of benign prostatic hyperplasia.

In search of a uroselective alpha1A subtype selective antagonist, a novel series of 6-OMe hexahydrobenz[e]isoindoles attached to a bicyclic heterocyclic moiety via a two-carbon linker was synthesized. It was found that in contrast to the previously described series of tricyclic heterocycles,(1) this bicyclic series has very specific requirements for the heterocyclic attachments. The most important structural features contributing to the alpha1A/alpha1B selectivity of these compounds were identified. In vitro functional assays for the alpha1 adrenoceptor subtypes were used to further characterize the most selective compounds, and in vivo models of vascular vs prostatic tone were used to assess uroselectivity. Compound 48 showed the highest degree of selectivity in the radioligand binding assays (56-fold), in the in vitro functional tests (80-fold), and for in vivo prostate selectivity (960-fold).

Automated external defibrillators and sudden cardiac arrest.

In April 1998, R.R., aged 72 (a man with no prior history of cardiac disease), was leaving his house with two friends to play golf when he suddenly collapsed. One friend initiated CPR, and the other called 911 on his cellular phone. A Chatham police squad arrived within three minutes; the police "first responder" applied a portable automated external defibrillator (AED) to the unresponsive patient. The AED instructed the first responder to push the shock button. Pulse and blood pressure were immediately restored, and the patient was brought to the Overlook Hospital Emergency Room. The patient subsequently awakened, had a cardiac catheterization revealing severe three-vessel coronary artery disease, and then underwent successful coronary artery bypass surgery. Two and a half years later he remained asymptomatic and was seen in the office of his cardiologist for a routine semiannual exam. Later that same day he was scheduled to play golf with the same two friends who had previously saved his life.

Prophylactic and therapeutic effects of a humanized monoclonal antibody against the IL-2 receptor (DACLIZUMAB) on collagen-induced arthritis (CIA) in rhesus monkeys.

CIA in the rhesus monkey is an autoimmune-based polyarthritis with inflammation and erosion of synovial joints that shares various features with human rheumatoid arthritis (RA). The close phylogenetic relationship between man and rhesus monkey makes the model very suitable for preclinical safety and efficacy testing of new therapeutics with exclusive reactivity in primates. In this study we have investigated the prophylactic and therapeutic effects of a humanized monoclonal antibody (Daclizumab) against the alpha-chain of the IL-2 receptor (CD25). When Daclizumab treatment was started well after immunization but before the expected onset of CIA a significant reduction of joint-inflammation and joint-erosion was observed. A therapeutic treatment, initiated as soon as the first clinical signs of CIA were observed, proved also effective since joint-degradation was abrogated. The results of this study indicate that Daclizumab has clinical potential for the treatment of RA during periods of active inflammation and suppression of the destruction of the joint tissues.

Structure-activity studies for a novel series of tricyclic substituted hexahydrobenz[e]isoindole alpha(1A) adrenoceptor antagonists as potential agents for the symptomatic treatment of benign prostatic hyperplasia (BPH).

In search of a uroselective agent that exhibits a high level of selectivity for the alpha(1A) receptor, a novel series of tricyclic hexahydrobenz[e]isoindoles was synthesized. A generic pharmacophoric model was developed requiring the presence of a basic amine core and a fused heterocyclic side chain separated by an alkyl chain. It was shown that the 6-OMe substitution with R, R stereochemistry of the ring junction of the benz[e]isoindole and a two-carbon spacer chain were optimal. In contrast to the highly specific requirements for the benz[e]isoindole portion and linker chain, a wide variety of tricyclic fused heterocyclic attachments were tolerated with retention of potency and selectivity. In vitro functional assays for the alpha(1) adrenoceptor subtypes were used to further characterize these compounds, and in vivo models of vascular vs prostatic tone were used to assess uroselectivity.

Mass spectrometric profiling of glucosamine, glucosamine polymers and their catecholamine adducts. Model reactions and cuticular hydrolysates of Toxorhynchites amboinensis (Culicidae) pupae.

Glucosamine (Gln), glucosamine polymers, and their catecholamine adducts were characterized using positive ion electrospray mass spectrometry (ESMS) and tandem mass spectrometry (ESMS-MS). N-acetyldopamine (NADA), a catecholamine found in many insect cuticles, was oxidized using mushroom tyrosinase, and the resulting quinone derivatives were reacted with Gln, (Gln)3, and polymeric glucosamine (chitosan). Adducts of glucosamine and its trisaccharide with NADA were readily identified as [M + H]+ ions in ESMS spectra, and ESMS-MS of selected ions confirmed the condensation of 1-3 NADA residues with Gln. In addition to Gln modification by the quinone derivatives of NADA, other spectra were consistent with the formation of adducts with N-acetylnoradrenaline and moieties formed by intramolecular cyclization following oxidation. The primary amine of glucosamine was involved in initial adduct formation, but the sites for subsequent additions of oxidized NADA to glucosamine, presumably via hydroxyl groups, could not be identified by ESMS alone. The ESMS spectra of chitosan films infused into the spectrometer following solubilization in acidic methanol/water produced spectra similar to that of (Gln)3 up to m/z 502. Ions of gradually decreasing intensity consistent with (Gln)x, where x = 4-8, were observed. Modification of chitosan films following incubation with NADA plus tyrosinase rendered the films insoluble in dilute acid, simulating the cross-linking process proposed to occur during insect cuticle sclerotization. Acid hydrolysates of the pupal stage of the mosquito Toxorhynchites amboinensis, using only two pupal exuviae for the hydrolyses, were infused into the mass spectrometer without preliminary chromatography. Eight amino acids, glucosamine, N-acetylglucosamine, catecholamines, and a variety of polymers incorporating these compound classes were identified.

Mass spectrometric analysis of catechol-histidine adducts from insect cuticle.

Adducts of catechols and histidine, which are produced by reactions of 1,2-quinones and p-quinone methides with histidyl residues in proteins incorporated into the insect exoskeleton, were characterized using electrospray ionization mass spectrometry (ESMS), tandem electrospray mass spectrometry (ESMS-MS, collision-induced dissociation), and ion trap mass spectrometry (ITMS). Compounds examined included adducts obtained from acid hydrolysates of Manduca sexta (tobacco hornworm) pupal cuticle exuviae and products obtained from model reactions under defined conditions. The ESMS and ITMS spectra of 6-(N-3')-histidyldopamine [6-(N-3')-His-DA, pi isomer] isolated from M. sexta cuticle were dominated by a [M + H]+ ion at m/z 308, rather than the expected m/z 307. High-resolution fast atom bombardment MS yielded an empirical formula of C14H18N3O5, which was consistent with this compound being 6-(N-1')-histidyl-2-(3, 4-dihydroxyphenyl)ethanol [6-(N-1')-His-DOPET] instead of a DA adduct. Similar results were obtained when histidyl-catechol compounds linked at C-7 of the catechol were examined; the (N-1') isomer was confirmed as a DA adduct, and the (N-3') isomer identified as an (N-1')-DOPET derivative. Direct MS analysis of unfractionated cuticle hydrolysate revealed intense parent and product ions characteristic of 6- and 7-linked adducts of histidine and DOPET. Mass spectrometric analysis of model adducts synthesized by electrochemical oxidative coupling of N-acetyldopamine (NADA) quinone and N-acetylhistidine (NAcH) identified the point of attachment in the two isomers. A prominent product ion corresponding to loss of CO2 from [M + H]+ of 2-NAcH-NADA confirmed this as being the (N-3') isomer. Loss of (H2O + CO) from 6-NAcH-NADA suggested that this adduct was the (N-1') isomer. The results support the hypothesis that insect cuticle sclerotization involves the formation of C-N cross-links between histidine residues in cuticular proteins, and both ring and side-chain carbons of three catechols: NADA, N-beta-alanyldopamine, and DOPET.

The Medicare home health benefit implications of recent payment changes.

The interim payment system (IPS) for Medicare home health services, enacted in the Balanced Budget Act of 1997, was intended to slow the growth of home health expenses until HCFA could design a new prospective system. Instead, the IPS has acted like a per-case payment system without case-mix adjustment. Its impact on agencies, along with other policy pressures, has been first to slow and then to reverse the dramatic expansion of the home health sector. In this paper, we identify the impetus for payment changes in the recent history of the Medicare home health benefit. We then present emerging evidence about the effects of IPS and other recent policies on home health. Finally, we draw several lessons from this experience for the impending prospective payment system.

"Don't know" responses in surveys: is what I know what you want to know and do I want you to know it?

Responses to survey questions are assumed to be based on what respondents can actually draw from memory. For example, if respondents report engaging in some behavior a certain number of times, we assume that a substantive answer reflects what they really know. Conversely, when respondents say that they "don't know" (DK) the answer, it is believed that their response reflects a lack of memory relevant to the question. However, survey responding is now understood to be a highly complex process. In this article, we propose a framework to account for the kind of reports made by respondents to a survey. The framework holds that respondent reports are based on three factors: what the respondent actually knows (the person's "cognitive state"); whether the respondent believes that the potential answer meets the requirements of the question (an "adequacy judgement"); and whether the respondent chooses to provide this answer (the person's "communicative intent"). Subsequently, the article examines how relevant findings in the literature support the framework, and then evaluates the assumptions made about cognitive states in light of the results of two experiments. The literature and research presented demonstrate that survey responding can be accounted for by a framework that assumes responding is based on certain key cognitive processes.

Nitroaromatic amino acids as inhibitors of neuronal nitric oxide synthase.

Nitric oxide (NO.) is an important biomodulator of many physiological processes. The inhibition of inappropriate production of NO. by the isoforms of nitric oxide synthase (NOS) has been proposed as a therapeutic approach for the treatment of stroke, inflammation, and other processes. In this study, certain 2-nitroaryl-substituted amino acid analogues were discovered to inhibit NOS. Analogues bearing a 5-methyl substituent on the aromatic ring demonstrated maximal inhibitory potency. For two selected inhibitors, investigation of the kinetics of the enzyme showed the inhibition to be competitive with l-arginine. Additionally, functional NOS inhibition in tissue preparations was demonstrated.

Actions of A-131701, a novel, selective antagonist for alpha-1A compared with alpha-1B adrenoceptors on intraurethral and blood pressure responses in conscious dogs and a pharmacodynamic assessment of in vivo prostatic selectivity.

A-131701 (3-[2-((3aR,9bR)-cis-6-methoxy-2,3,3a,4,5,9b, hexahydro-[1H]-benz[e]isoindol-2-yl)ethyl]pyrido [3',4': 4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione) is a novel compound previously shown to be selective for alpha-1a sites compared with alpha-1b adrenoceptors in radioligand binding studies and isolated tissue bioassays and to block canine urethral pressure (IUP) responses to exogenous alpha-1 adrenergic agonists to a greater extent than blood pressure responses. In conscious dogs in which IUP and mean arterial blood pressure (MABP) responses were measured periodically up to 24 hr, A-131701 blocked phenylephrine (PHE)-induced increases in IUP to a greater extent than MABP responses, and the blockade of the IUP effects of PHE was significantly different from control for up to 12 hr after doses greater than 0.3 mg/kg p.o., whereas blood pressure effects were of a lesser extent and duration. In addition to the weak antagonism of PHE-induced blood pressure responses, A-131701 also exhibited minimal effects on basal blood pressure in the dog, unlike terazosin, doxazosin or tamsulosin. Pharmacokinetic analysis of plasma samples from dogs indicated that A-131701 had a half-life of 0.4 to 0.8 hr and a bioavailability of 30 to 50% in dogs. Somewhat longer half-lives were observed in rat and monkey, with bioavailability values in the 25 to 30% range. Evidence of nonlinearity of pharmacokinetics was obtained in dogs and monkeys. Pharmacodynamic analysis revealed differences between A-131701 and nonselective alpha-1 adrenoceptor antagonists in selectivity for prostatic versus vascular alpha-1 adrenoceptors based on either extent or duration of blockade, which were either similar to or superior to compounds such as tamsulosin or REC 15/2739. These data demonstrate that A-131701 selectively blocks canine prostatic alpha-1 adrenoceptors for prolonged periods compared with MABP responses in vivo. Therefore, A-131701 should have clinical utility in the pharmacotherapy of benign prostatic hyperplasia.

Bispecific humanized anti-IL-2 receptor alpha beta antibodies inhibitory for both IL-2- and IL-15-mediated proliferation.

Humanized anti-Tac (HAT) and Mik beta1 (HuMik beta 1) Abs directed at IL-2R alpha and IL-2R beta, respectively, inhibit IL-2 binding and biological activity and together act synergistically in vitro. The Abs have been used successfully in primate models of allograft rejection, graft-vs-host disease, and autoimmunity. We produced bifunctional humanized anti-IL-2R alpha beta Abs (BF-IgG) to combine the specificity of the two Abs into one entity by fusing HAT-producing NSO cells and HuMik beta 1-producing Sp2/0 cells. BF-IgG was purified using protein G-Sepharose affinity chromatography, followed by IL-2R alpha and IL-2R beta affinity chromatography and hydrophobic interaction chromatography. BF-IgG exhibited both anti-IL-2R alpha and anti-IL-2R beta specificities in binding assays. While the Ab binds the IL-2R with intermediate affinity (Kd = 2.82 nM), it does not inhibit IL-15 binding to its high affinity IL-15R. In Kit225/K6 (IL-2R alpha beta gamma+) cells, BF-IgG was 10-fold more potent than a HAT/HuMik beta 1 equimolar mixture in blocking IL-2-induced proliferation and, unexpectedly, was at least 65-fold more active than the mixture in blocking IL-15-induced proliferation. This dual inhibitory activity may be due to cross-linking of the IL-2R alpha and IL-2R beta, thus blocking IL-2 binding and possibly impeding the association of IL-2R beta with IL-15R. BF-IgG has potent immunosuppressant activities against both IL-2- and IL-15-mediated responses, and this antagonist could be more efficacious than HAT and/or HuMik beta 1 for the treatment of autoimmunity and the prevention of allograft rejection.