Anticipatory activation in the amygdala and anterior cingulate in generalized anxiety disorder and prediction of treatment response

OBJECTIVE: The anticipation of adverse outcomes, or worry, is a cardinal symptom of generalized anxiety disorder. Prior work with healthy subjects has shown that anticipating aversive events recruits a network of brain regions, including the amygdala and anterior cingulate cortex. This study tested whether patients with generalized anxiety disorder have alterations in anticipatory amygdala function and whether anticipatory activity in the anterior cingulate cortex predicts treatment response. METHOD: Functional magnetic resonance imaging (fMRI) was employed with 14 generalized anxiety disorder patients and 12 healthy comparison subjects matched for age, sex, and education. The event-related fMRI paradigm was composed of one warning cue that preceded aversive pictures and a second cue that preceded neutral pictures. Following the fMRI session, patients received 8 weeks of treatment with extended-release venlafaxine. RESULTS: Patients with generalized anxiety disorder showed greater anticipatory activity than healthy comparison subjects in the bilateral dorsal amygdala preceding both aversive and neutral pictures. Building on prior reports of pretreatment anterior cingulate cortex activity predicting treatment response, anticipatory activity in that area was associated with clinical outcome 8 weeks later following treatment with venlafaxine. Higher levels of pretreatment anterior cingulate cortex activity in anticipation of both aversive and neutral pictures were associated with greater reductions in anxiety and worry symptoms. CONCLUSIONS: These findings of heightened and indiscriminate amygdala responses to anticipatory signals in generalized anxiety disorder and of anterior cingulate cortex associations with treatment response provide neurobiological support for the role of anticipatory processes in the pathophysiology of generalized anxiety disorder.

Predicting outcomes following cognitive behavior therapy in child anxiety disorders: the influence of genetic, demographic and clinical information

Background. Within a therapeutic gene by environment (GxE) framework, we recently demonstrated that variation in the Serotonin Transporter Promoter Polymorphism; 5HTTLPR and marker rs6330 in Nerve Growth Factor gene; NGF is associated with poorer outcomes following cognitive behaviour therapy (CBT) for child anxiety disorders. The aim of this study was to explore one potential means of extending the translational reach of G×E data in a way that may be clinically informative. We describe a ‘risk-index’ approach combining genetic, demographic and clinical data and test its ability to predict diagnostic outcome following CBT in anxious children. Method. DNA and clinical data were collected from 384 children with a primary anxiety disorder undergoing CBT. We tested our risk model in five cross-validation training sets. Results. In predicting treatment outcome, six variables had a minimum mean beta value of 0.5: 5HTTLPR, NGF rs6330, gender, primary anxiety severity, comorbid mood disorder and comorbid externalising disorder. A risk index (range 0-8) constructed from these variables had moderate predictive ability (AUC = .62-.69) in this study. Children scoring high on this index (5-8) were approximately three times as likely to retain their primary anxiety disorder at follow-up as compared to those children scoring 2 or less. Conclusion. Significant genetic, demographic and clinical predictors of outcome following CBT for anxiety-disordered children were identified. Combining these predictors within a risk-index could be used to identify which children are less likely to be diagnosis free following CBT alone or thus require longer or enhanced treatment. The ‘risk-index’ approach represents one means of harnessing the translational potential of G×E data.

Characterisation of blends based on hydroxyethylcellulose and maleic acid-alt-methyl vinyl ether

Hydrophilic polymeric films based on blends of hydroxyethylcellulose and maleic acid-co-methyl vinyl ether were produced by casting from aqueous solutions. The physicochemical properties of the blends have been assessed using Fourier transform infrared spectroscopy, thermal gravimetric analysis, differential scanning calorimetry, dielectric spectroscopy, etc. The pristine films exhibit complete miscibility due to the formation of intermacromolecular hydrogen bonding. The thermal treatment of the blend films leads to cross-linking via intermacromolecular esterification and anhydride formation. The cross-linked materials are able to swell in water and their swelling degree can be easily controlled by temperature and thermal treatment time. The formation of the crosslinks is apparent in the dynamic properties of the blends as observed through the mechanical relaxation and dielectric relaxation spectra. The dielectric characteristics of the material are influenced by the effects of change in the local structure of the blend on the ionic conduction processes and the rate of dipolar relaxation. Separation of these processes is attempted using the dielectric modulus method. Significant deviations from a simple additive rule of mixing on the activation energy are observed consistent with hydrogen bonding and crosslinking of the matrix. This paper indicates a method for the creation of films with good mechanical and physical characteristics by exposing the blends to a relatively mild thermal treatment.

Effect of time and mode of depuration on tissue copper concentrations of the earthworms Eisenia andrei, Lumbricus rubellus and Lumbricus terrestris

Eisenia andrei, Lumbricus rubellus and Lumbricus terrestris were exposed to 250, 250 and 350 mg kg(-1) Cu respectively in Cu(NO3)(2(aq)) amended soil for 28 d. Earthworms were then depurated for 24 to 72 h, digested and analysed for Cu and Ti or, subsequent to depuration were dissected to remove any remaining soil particles from the alimentary canal and then digested and analysed. This latter treatment proved impossible for E. andrei due to its small size. Regardless of depuration time, soil particles were retained in the alimentary canal of L. rubellus and L. terrestris. Tissue concentration determinations indicate that E. andrei should be depurated for 24 h, L. rubellus for 48 h and L. terrestris should be dissected. Ti was bioaccumulated and therefore could not be used as an inert tracer to determine mass of retained soil. Calculations indicate that after 28 d earthworms were still absorbing Cu from soil. (C) 2006 Elsevier Ltd. All rights reserved.

Assessment of the effect of time and temperature on the availability of residual phosphate in a glasshouse study of four soils using the Olsen method

The Olsen method is an indicator of plant-available phosphorus (P). The effect of time and temperature on residual phosphate in soils was measured using the Olsen method in a pot experiment. Four soils were investigated: two from Pakistan and one each from England (calcareous) and Colombia (acidic). Two levels of residual phosphate were developed in each soil after addition of phosphate by incubation at either 10degreesC or 45degreesC. The amount of phosphate added was based on the P maximum of each soil, calculated using the Langmuir equation. Rvegrass was used as the test crop. The pooled data for the four soils incubated at 10degreesC showed good correlation between Olsen P and dry matter yield or P uptake (r(2) = 0.85 and 0.77, respectively), whereas at 45 degreesC, each soil had its own relationship and pooled data did not show correlation of Olsen P with dry matter yield or P uptake. When the data at both temperatures were pooled, Olsen P was a good indicator of yield and uptake for the English soil. For the Pakistani soils, Olsen P after 45 degreesC treatment was an underestimate relative to the 10 degreesC data and for the Colombian soil it was an overestimate. The reasons for these differences need to be explored further before high temperature incubation can be used to simulate long-term changes in the field.

Results from the Covered Catchment Experiment at Gårdsjön, Sweden, after ten years of clean precipitation treatment

The Covered Catchment Experiment at Gordsjon is a large scale forest ecosystem manipulation, where acid precipitation was intercepted by a 7000 m(2) plastic roof and replaced by 'clean precipitation' sprinkled below the roof for ten years between 1991 and 2001. The treatment resulted in a strong positive response of runoff quality. The runoff sulphate, inorganic aluminium and base cations decreased, while there was a strong increase in runoff ANC and a moderate increase in pH. The runoff continued to improve over the whole duration of the experiment. The achieved quality was, however, after ten years still considerably worse than estimated pre-industrial runoff at the site. Stable isotopes of sulphur were analysed to study the soil sulphur cycling. At the initial years of the experiment, the desorption of SO4 from the mineral soil appeared to control the runoff SO4 concentration. However, as the experiment proceeded, there was growing evidence that net mineralisation of soil organic sulphur in the humus layer was an additional source of SO4 in runoff. This might provide a challenge to current acidification models. The experiment convincingly demonstrated on a catchment scale, that reduction in acid deposition causes an immediate improvement of surface water quality even at heavily acidified sites. The improvement of the runoff appeared to be largely a result of cation exchange processes in the soil due to decreasing concentrations of the soil solution, while any potential change in soil base saturation seemed to be less important for the runoff chemistry over the short time period of one decade. These findings should be considered when interpreting and extrapolating regional trends in surface water chemistry to the terrestrial parts of ecosystems.

Modelling monsoons: understanding and predicting current and future behaviour

The global monsoon system is so varied and complex that understanding and predicting its diverse behaviour remains a challenge that will occupy modellers for many years to come. Despite the difficult task ahead, an improved monsoon modelling capability has been realized through the inclusion of more detailed physics of the climate system and higher resolution in our numerical models. Perhaps the most crucial improvement to date has been the development of coupled ocean-atmosphere models. From subseasonal to interdecadal time scales, only through the inclusion of air-sea interaction can the proper phasing and teleconnections of convection be attained with respect to sea surface temperature variations. Even then, the response to slow variations in remote forcings (e.g., El Niño—Southern Oscillation) does not result in a robust solution, as there are a host of competing modes of variability that must be represented, including those that appear to be chaotic. Understanding the links between monsoons and land surface processes is not as mature as that explored regarding air-sea interactions. A land surface forcing signal appears to dominate the onset of wet season rainfall over the North American monsoon region, though the relative role of ocean versus land forcing remains a topic of investigation in all the monsoon systems. Also, improved forecasts have been made during periods in which additional sounding observations are available for data assimilation. Thus, there is untapped predictability that can only be attained through the development of a more comprehensive observing system for all monsoon regions. Additionally, improved parameterizations - for example, of convection, cloud, radiation, and boundary layer schemes as well as land surface processes - are essential to realize the full potential of monsoon predictability. A more comprehensive assessment is needed of the impact of black carbon aerosols, which may modulate that of other anthropogenic greenhouse gases. Dynamical considerations require ever increased horizontal resolution (probably to 0.5 degree or higher) in order to resolve many monsoon features including, but not limited to, the Mei-Yu/Baiu sudden onset and withdrawal, low-level jet orientation and variability, and orographic forced rainfall. Under anthropogenic climate change many competing factors complicate making robust projections of monsoon changes. Absent aerosol effects, increased land-sea temperature contrast suggests strengthened monsoon circulation due to climate change. However, increased aerosol emissions will reflect more solar radiation back to space, which may temper or even reduce the strength of monsoon circulations compared to the present day. Precipitation may behave independently from the circulation under warming conditions in which an increased atmospheric moisture loading, based purely on thermodynamic considerations, could result in increased monsoon rainfall under climate change. The challenge to improve model parameterizations and include more complex processes and feedbacks pushes computing resources to their limit, thus requiring continuous upgrades of computational infrastructure to ensure progress in understanding and predicting current and future behaviour of monsoons.

Sequential designs for phase III clinical trials incorporating treatment selection

Most statistical methodology for phase III clinical trials focuses on the comparison of a single experimental treatment with a control. An increasing desire to reduce the time before regulatory approval of a new drug is sought has led to development of two-stage or sequential designs for trials that combine the definitive analysis associated with phase III with the treatment selection element of a phase II study. In this paper we consider a trial in which the most promising of a number of experimental treatments is selected at the first interim analysis. This considerably reduces the computational load associated with the construction of stopping boundaries compared to the approach proposed by Follman, Proschan and Geller (Biometrics 1994; 50: 325-336). The computational requirement does not exceed that for the sequential comparison of a single experimental treatment with a control. Existing methods are extended in two ways. First, the use of the efficient score as a test statistic makes the analysis of binary, normal or failure-time data, as well as adjustment for covariates or stratification straightforward. Second, the question of trial power is also considered, enabling the determination of sample size required to give specified power. Copyright © 2003 John Wiley & Sons, Ltd.

An adaptive group sequential design for phase II/III clinical trials that select a single treatment from several

There is increasing interest in combining Phases II and III of clinical development into a single trial in which one of a small number of competing experimental treatments is ultimately selected and where a valid comparison is made between this treatment and the control treatment. Such a trial usually proceeds in stages, with the least promising experimental treatments dropped as soon as possible. In this paper we present a highly flexible design that uses adaptive group sequential methodology to monitor an order statistic. By using this approach, it is possible to design a trial which can have any number of stages, begins with any number of experimental treatments, and permits any number of these to continue at any stage. The test statistic used is based upon efficient scores, so the method can be easily applied to binary, ordinal, failure time, or normally distributed outcomes. The method is illustrated with an example, and simulations are conducted to investigate its type I error rate and power under a range of scenarios.

Predicting the functional response of a farmland bird

1. Mechanistic models may be able to predict how changes in agricultural practice influence farmland bird populations. A key component of these models is the link between food and competitor densities and the rate at which birds consume food, i.e. the functional response. 2. This paper tests whether the functional response of a farmland bird, the rook Corvus frugilegus, can be predicted from three parameters: searching speed, food detection distance and handling time. It is often difficult to measure the functional response of farmland birds directly, but it may be possible to measure behavioural parameters more quickly. 3. We performed experiments in which rooks fed on a range of artificial food densities in two grass sward heights. Food detection distance was greater in the shorter sward, but sward height did not influence searching speed or handling time. The functional response could be accurately predicted in both sward heights. 4. We show that the functional response of a farmland bird can be predicted from parameters that can be measured more quickly than the alternative of measuring the functional response directly. This implies that the functional responses of other farmland birds may be predicted using a minimum of information.

Reducing fouling during UHT treatment of goat's milk

Whole fresh goat's milk was heat treated at 135 degrees C for 4 s using a miniature UHT plant. The temperature of the milk in the preheating and sterilizer sections, and the milk flow rate were monitored to evaluate the overall heat transfer coefficient (OHTC). The decrease in OHTC was used to estimate the extent of fouling. Goat's milk fouled very quickly and run times of the UHT plant were short. The use of sodium hexametaphosphate, trisodium citrate and cation exchange resins to reduce ionic calcium prior to UHT processing, increased the pH and alcohol stability of the milk and markedly increased the run time of the UHT plant.

Predicting the thermal inactivation of bacteria in a solid matrix: simulation studies on the relative effects of microbial thermal resistance parameters and process conditions

A combined mathematical model for predicting heat penetration and microbial inactivation in a solid body heated by conduction was tested experimentally by inoculating agar cylinders with Salmonella typhimurium or Enterococcus faecium and heating in a water bath. Regions of growth where bacteria had survived after heating were measured by image analysis and compared with model predictions. Visualisation of the regions of growth was improved by incorporating chromogenic metabolic indicators into the agar. Preliminary tests established that the model performed satisfactorily with both test organisms and with cylinders of different diameter. The model was then used in simulation studies in which the parameters D, z, inoculum size, cylinder diameter and heating temperature were systematically varied. These simulations showed that the biological variables D, z and inoculum size had a relatively small effect on the time needed to eliminate bacteria at the cylinder axis in comparison with the physical variables heating temperature and cylinder diameter, which had a much greater relative effect. (c) 2005 Elsevier B.V All rights reserved.

New mathematical modeling approach for predicting microbial inactivation by high hydrostatic pressure

A new primary model based on a thermodynamically consistent first-order kinetic approach was constructed to describe non-log-linear inactivation kinetics of pressure-treated bacteria. The model assumes a first-order process in which the specific inactivation rate changes inversely with the square root of time. The model gave reasonable fits to experimental data over six to seven orders of magnitude. It was also tested on 138 published data sets and provided good fits in about 70% of cases in which the shape of the curve followed the typical convex upward form. In the remainder of published examples, curves contained additional shoulder regions or extended tail regions. Curves with shoulders could be accommodated by including an additional time delay parameter and curves with tails shoulders could be accommodated by omitting points in the tail beyond the point at which survival levels remained more or less constant. The model parameters varied regularly with pressure, which may reflect a genuine mechanistic basis for the model. This property also allowed the calculation of (a) parameters analogous to the decimal reduction time D and z, the temperature increase needed to change the D value by a factor of 10, in thermal processing, and hence the processing conditions needed to attain a desired level of inactivation; and (b) the apparent thermodynamic volumes of activation associated with the lethal events. The hypothesis that inactivation rates changed as a function of the square root of time would be consistent with a diffusion-limited process.

Effect of a cellulase treatment on extraction of antioxidant phenols from black currant (Ribes nigrum L.) pomace

The effect of a commercial cellulase preparation on phenol liberation and extraction from black currant pomace was studied. The enzyme used, which was from Trichoderma spp., was an effective "cellulase-hemicellulase" blend with low P-glucosidase activity and various side activities. Enzyme treatment significantly increased plant cell wall polysaccharide degradation as well as increasing the availability of phenols for subsequent methanolic extraction. The release of anthocyanins and other phenols was dependent on reaction parameters, including enzyme dosage, temperature, and time. At 50 degrees C, anthocyanin yields following extraction increased by 44% after 3 h and by 60% after 1.5 h for the lower and higher enzyme/substrate ratio (E/S), respectively. Phenolic acids were more easily released in the hydrolytic mixture (supernatant) and, although a short hydrolysis time was adequate to release hydroxybenzoic acids (HBA), hydroxycinnamic acids (HCA) required longer times. The highest E/S value of 0.16 gave a significant increase of flavonol yields in all samples. The antioxidant capacity of extracts, assessed by scavenging of 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) radical cation, the oxygen radical absorbance capacity, and the ferric reducing antioxidant potential depended on the concentration and composition of the phenols present.

Differences in cell morphology, lipid and apo B secretory capacity in caco-2 cells following long term treatment with saturated and monounsaturated fatty acids

The suitability of the caco-2 cell line as a model for studying the long term impact of dietary fatty acids on intestinal lipid handling and chylomicron production was examined. Chronic supplementation of caco-2 cells with palmitic acid (PA) resulted in a lower triacylglycerol secretion than oleic acid (OA). This was coupled with a detrimental effect of PA, but not OA, on transepithelial electrical resistance (TER) measurements, suggesting a loss of structural integrity across the cell monolayer. Addition of OA reversed the adverse effects of PA and stearic acid on TER and increased the ability of cells to synthesise and accumulate lipid, but did not normalise the secretion of lipids by caco-2 cells. Increasing amounts of OA and decreasing amounts of PA in the incubation media markedly improved the ability of cells to synthesise apolipoprotein B and secrete lipids. Real time RT-PCR revealed a down regulation of genes involved in lipoprotein synthesis following PA than OA. Electron microscopy showed adverse effects of PA on cellular morphology consistent with immature enterocytes such as stunted microvilli and poor tight junction formation. In conclusion, previously reported differences in lipoprotein secretion by caco-2 cells supplemented with saturated fatty acids (SFA) and OA may partly reflect early cytotoxic effects of SFA on cellular integrity and function. (C) 2007 Elsevier B.V. All rights reserved.