GABAB receptor allosteric modulators exhibit pathway-dependent and species-selective activity.

Positive modulation of the GABAB receptor (GABABR) represents a potentially useful therapeutic approach for the treatment of nicotine addiction. The positive allosteric modulators (PAMs) of GABABR GS39783 and BHF177 enhance GABA-stimulated [35S]GTP γS-binding, and have shown efficacy in a rodent nicotine self-administration procedure reflecting aspects of nicotine dependence. Interestingly, the structural related analog, NVP998, had no effect on nicotine self-administration in rats despite demonstrating similar pharmacokinetic properties. Extensive in vitro characterization of GS39783, BHF177, and NVP998 activity on GABABR-regulated signaling events, including modulation of cAMP, intracellular calcium levels, and ERK activation, revealed that these structurally related molecules display distinct pathway-specific signaling activities that correlate with the dissimilarities observed in rodent models and may be predictive of in vivo efficacy. Furthermore, these GABABR allosteric modulators exhibit species-dependent activity. Collectively, these data will be useful in guiding the development of GABABR allosteric modulators that display optimal in vivo efficacy in a preclinical model of nicotine dependence, and will identify those that have the potential to lead to novel antismoking therapies

Methylphenidate Treatment in Children with Borderline IQ and Mental Retardation: Analysis of Three Aggregated Studies

Objective: To determine response of low-IQ children with attention deficit hyperactivity disorder (ADHD) symptoms to methylphenidate (MPH). Methods: An aggregated analysis was conducted in 90 children with low IQ who received the same dose regimen of MPH in three independent, placebo-controlled studies. Active drug and placebo were given from 2 to 4 weeks each. Outcome measures included teacher and parent ratings on standardized behavior scales (mean n = 84), performance on computer-controlled cognitive-motor tests (n = 62), and measures of cardiovascular response (n = 85). Results: Both teachers and parents rated the children consistently as being improved on subscales assessing attention, overactivity, and conduct problems. Some 44% of the subjects showed at least a 30% reduction compared with placebo on teacher ratings. MPH improved accuracy on several cognitive tests, response speed was increased on some, and seat activity declined for one of three tests; heart rate was mildly increased (3.9 beats/minute) with MPH. Analyses of IQ and mental age as moderator variables suggested that lower functional level (especially lower IQ) may be associated with a less favorable response to MPH. Conclusions: Children with low IQ and ADHD clearly respond to MPH, but their rate of beneficial response appears to be well under that of normal-IQ children and more varied. Different attentional mechanisms may moderate response to psychostimulants

Comparing research investment to United Kingdom institutions and published outputs for tuberculosis, HIV and malaria: A systematic analysis across 1997-2013

Background: The "Unfinished Agenda" of infectious diseases is of great importance to policymakers and research funding agencies that require ongoing research evidence on their effective management. Journal publications help effectively share and disseminate research results to inform policy and practice. We assess research investments to United Kingdom institutions in HIV, tuberculosis and malaria, and analyse these by numbers of publications and citations and by disease and type of science. Methods: Information on infection-related research investments awarded to United Kingdom institutions across 1997-2010 were sourced from funding agencies and individually categorised by disease and type of science. Publications were sourced from the Scopus database via keyword searches and filtered to include only publications relating to human disease and containing a United Kingdom-based first and/or last author. Data were matched by disease and type of science categories. Investment (United Kingdom pounds) and publications were compared to generate an 'investment per publication' metric; similarly, an 'investment per citation' metric was also developed as a measure of the usefulness of research. Results: Total research investment for all three diseases was £1.4 billion, and was greatest for HIV (£651.4 million), followed by malaria (£518.7 million) and tuberculosis (£239.1 million). There were 17,271 included publications, with 9,322 for HIV, 4,451 for malaria, and 3,498 for tuberculosis. HIV publications received the most citations (254,949), followed by malaria (148,559) and tuberculosis (100,244). According to UK pound per publication, tuberculosis (£50,691) appeared the most productive for investment, compared to HIV (£61,971) and malaria (£94,483). By type of science, public health research was most productive for HIV (£27,296) and tuberculosis (£22,273), while phase I-III trials were most productive for malaria (£60,491). According to UK pound per citation, tuberculosis (£1,797) was the most productive area for investment, compared to HIV (£2,265) and malaria (£2,834). Public health research was the most productive type of science for HIV (£2,265) and tuberculosis (£1,797), whereas phase I-III trials were most productive for malaria (£1,713). Conclusions: When comparing total publications and citations with research investment to United Kingdom institutions, tuberculosis research appears to perform best in terms of efficiency. There were more public health-related publications and citations for HIV and tuberculosis than other types of science. These findings demonstrate the diversity of research funding and outputs, and provide new evidence to inform research investment strategies for policymakers, funders, academic institutions, and healthcare organizations.Infectious Disease Research Networ

Using genetic algorithms to generate test sequences for complex timed systems

The generation of test data for state based specifications is a computationally expensive process. This problem is magnified if we consider that time con- straints have to be taken into account to govern the transitions of the studied system. The main goal of this paper is to introduce a complete methodology, sup- ported by tools, that addresses this issue by represent- ing the test data generation problem as an optimisa- tion problem. We use heuristics to generate test cases. In order to assess the suitability of our approach we consider two different case studies: a communication protocol and the scientific application BIPS3D. We give details concerning how the test case generation problem can be presented as a search problem and automated. Genetic algorithms (GAs) and random search are used to generate test data and evaluate the approach. GAs outperform random search and seem to scale well as the problem size increases. It is worth to mention that we use a very simple fitness function that can be eas- ily adapted to be used with other evolutionary search techniques

Enhancing continuous online microdialysis using dexamethasone: measurement of dynamic neurometabolic changes during spreading depolarization

Microdialysis is well established in chemical neuroscience as a mainstay technology for real time intracranial chemical monitoring in both animal models and human patients. Evidence shows that microdialysis can be enhanced by mitigating the penetration injury caused during the insertion of microdialysis probes into brain tissue. Herein, we show that retrodialysis of dexamethasone in the rat cortex enhances the microdialysis detection of K(+) and glucose transients induced by spreading depolarization. Without dexamethasone, quantification of glucose transients was unreliable by 5 days after probe insertion. With dexamethasone, robust K(+) and glucose transients were readily quantified at 2 h, 5 days, and 10 days after probe insertion. The amplitudes of the K(+) transients declined day-to-day following probe insertion, and the amplitudes of the glucose transients exhibited a decreasing trend that did not reach statistical significance. Immunohistochemistry and fluorescence microscopy confirm that dexamethasone is highly effective at preserving a healthy probe-brain interface for at least 10 days even though retrodialysis of dexamethasone ceased after 5 days

Higher resolution total velocity Vt and Va finite-volume formulations on cell-centred structured and unstructured grids

Novel cell-centred finite-volume formulations are presented for incompressible and immiscible two-phase flow with both gravity and capillary pressure effects on structured and unstructured grids. The Darcy-flux is approximated by a control-volume distributed multipoint flux approximation (CVD-MPFA) coupled with a higher resolution approximation for convective transport. The CVD-MPFA method is used for Darcy-flux approximation involving pressure, gravity, and capillary pressure flux operators. Two IMPES formulations for coupling the pressure equation with fluid transport are presented. The first is based on the classical total velocity Vt fractional flow (Buckley Leverett) formulation, and the second is based on a more recent Va formulation. The CVD-MPFA method is employed for both Vt and Va formulations. The advantages of both coupled formulations are contrasted. The methods are tested on a range of structured and unstructured quadrilateral and triangular grids. The tests show that the resulting methods are found to be comparable for a number of classical cases, including channel flow problems. However, when gravity is present, flow regimes are identified where the Va formulation becomes locally unstable, in contrast to the total velocity formulation. The test cases also show the advantages of the higher resolution method compared to standard first-order single-point upstream weighting

The return trip effect: Why the return trip often seems to take less time

Three studies confirm the existence of the return trip effect: The return trip often seems shorter than the initial trip, even though the distance traveled and the actual time spent traveling are identical. A pretest shows that people indeed experience a return trip effect regularly, and the effect was found on a bus trip (Study 1), a bicycle trip (Study 2), and when participants watched a video of someone else traveling (Study 3). The return trip effect also existed when another, equidistant route was taken on the return trip, showing that it is not familiarity with the route that causes this effect. Rather, it seems that a violation of expectations causes this effect

Cavity QED with a Bose-Einstein condensate

Cavity quantum electrodynamics (cavity QED) describes the coherent interaction between matter and an electromagnetic field confined within a resonator structure, and is providing a useful platform for developing concepts in quantum information processing. By using high-quality resonators, a strong coupling regime can be reached experimentally in which atoms coherently exchange a photon with a single light-field mode many times before dissipation sets in. This has led to fundamental studies with both microwave and optical resonators. To meet the challenges posed by quantum state engineering and quantum information processing, recent experiments have focused on laser cooling and trapping of atoms inside an optical cavity. However, the tremendous degree of control over atomic gases achieved with Bose-Einstein condensation has so far not been used for cavity QED. Here we achieve the strong coupling of a Bose-Einstein condensate to the quantized field of an ultrahigh-finesse optical cavity and present a measurement of its eigenenergy spectrum. This is a conceptually new regime of cavity QED, in which all atoms occupy a single mode of a matter-wave field and couple identically to the light field, sharing a single excitation. This opens possibilities ranging from quantum communication to a wealth of new phenomena that can be expected in the many-body physics of quantum gases with cavity-mediated interactions.Comment: 6 pages, 4 figures; version accepted for publication in Nature; updated Fig. 4; changed atom numbers due to new calibratio

Early Trends in Cystatin C and Outcomes in Patients with Cirrhosis and Acute Kidney Injury

Background. Acute kidney injury (AKI) is a common and severe complication in patients with cirrhosis. Progression of AKI to a higher stage associates with increased mortality. Intervening early in AKI when renal dysfunction is worsening may improve outcomes. However, serum creatinine correlates poorly with glomerular filtration in patients with cirrhosis and fluctuations may mask progression early in the course of AKI. Cystatin C, a low-molecular-weight cysteine proteinase inhibitor, is a potentially more accurate marker of glomerular filtration. Methods. We conducted a prospective multicenter study in patients with cirrhosis comparing changes in cystatin and creatinine immediately following onset of AKI as predictors of a composite endpoint of dialysis or mortality. Results. Of 106 patients, 37 (35%) met the endpoint. Cystatin demonstrated less variability between samples than creatinine. Patients were stratified into four groups reflecting changes in creatinine and cystatin: both unchanged or decreased 38 (36%) (Scr−/CysC−); only cystatin increased 25 (24%) (Scr−/CysC+); only creatinine increased 15 (14%) (Scr+/CysC−); and both increased 28 (26%) (Scr+/CysC+). With Scr−/CysC− as the reference, in both instances where cystatin rose, Scr−/CysC+ and Scr+/CysC+, the primary outcome was significantly more frequent in multivariate analysis, and , respectively. However, when only creatinine rose, outcomes were similar to the reference group. Conclusions. Changes in cystatin levels early in AKI are more closely associated with eventual dialysis or mortality than creatinine and may allow more rapid identification of patients at risk for adverse outcomes