Showing papers by "University of Aberdeen published in 2005"

Principal Component Analysis

Abstract: When large multivariate datasets are analyzed, it is often desirable to reduce their dimensionality. Principal component analysis is one technique for doing this. It replaces the p original variables by a smaller number, q, of derived variables, the principal components, which are linear combinations of the original variables. Often, it is possible to retain most of the variability in the original variables with q very much smaller than p. Despite its apparent simplicity, principal component analysis has a number of subtleties, and it has many uses and extensions. A number of choices associated with the technique are briefly discussed, namely, covariance or correlation, how many components, and different normalization constraints, as well as confusion with factor analysis. Various uses and extensions are outlined. Keywords: dimension reduction; factor analysis; multivariate analysis; variance maximization

The short-form version of the Depression Anxiety Stress Scales (DASS-21): Construct validity and normative data in a large non-clinical sample

Abstract: Objectives. To test the construct validity of the short-form version of the Depression anxiety and stress scale (DASS-21), and in particular, to assess whether stress as indexed by this measure is synonymous with negative affectivity (NA) or whether it represents a related, but distinct, construct. To provide normative data for the general adult population. Design. Cross-sectional, correlational and confirmatory factor analysis (CFA). Methods. The DASS-21 was administered to a non-clinical sample, broadly representative of the general adult UK population (N=1,794). Competing models of the latent structure of the DASS-21 were evaluated using CFA. Results. The model with optimal fit (RCFI = 0.94) had a quadripartite structure, and consisted of a general factor of psychological distress plus orthogonal specific factors of depression, anxiety, and stress. This model was a significantly better fit than a competing model that tested the possibility that the Stress scale simply measures NA. Conclusions. The DASS-21 subscales can validly be used to measure the dimensions of depression, anxiety, and stress. However, each of these subscales also taps a more general dimension of psychological distress or NA. The utility of the measure is enhanced by the provision of normative data based on a large sample.

Causes and consequences of animal dispersal strategies: relating individual behaviour to spatial dynamics.

Abstract: Knowledge of the ecological and evolutionary causes of dispersal can be crucial in understanding the behaviour of spatially structured populations, and predicting how species respond to environmental change. Despite the focus of much theoretical research, simplistic assumptions regarding the dispersal process are still made. Dispersal is usually regarded as an unconditional process although in many cases fitness gains of dispersal are dependent on environmental factors and individual state. Condition-dependent dispersal strategies will often be superior to unconditional, fixed strategies. In addition, dispersal is often collapsed into a single parameter, despite it being a process composed of three interdependent stages: emigration, inter-patch movement and immigration, each of which may display different condition dependencies. Empirical studies have investigated correlates of these stages, emigration in particular, providing evidence for the prevalence of conditional dispersal strategies. Ill-defined use of the term ‘dispersal’, for movement across many different spatial scales, further hinders making general conclusions and relating movement correlates to consequences at the population level. Logistical difficulties preclude a detailed study of dispersal for many species, however incorporating unrealistic dispersal assumptions in spatial population models may yield inaccurate and costly predictions. Further studies are necessary to explore the importance of incorporating specific condition-dependent dispersal strategies for evolutionary and population dynamic predictions.

Effectiveness and efficiency of guideline dissemination and implementation strategies

Abstract: Objectives: A systematic review of the effectiveness and costs of different guideline development, dissemination, and implementation strategies wasundertaken. The resource implications of these strategies was estimated, and a framework for deciding when it is efficient to develop and introduce clinical guidelines was developed.

Contributions of nitrification and denitrification to N2O emissions from soils at different water-filled pore space.

Abstract: A combination of stable isotope and acetylene (0.01% v/v) inhibition techniques were used for the first time to determine N2O production during denitrification, autotrophic nitrification and heterotrophic nitrification in a fertilised (200 kg N ha−1) silt loam soil at contrasting (20–70%) water-filled pore space (WFPS). 15N-N2O emissions from 14NH415NO3 replicates were attributed to denitrification and 15N-N2O from 15NH415NO3 minus that from 14NH415NO3 replicates was attributed to nitrification and heterotrophic nitrification in the presence of acetylene, as there was no dissimilatory nitrate reduction to ammonium or immobilisation and remineralisation of 15N-NO3−. All of the N2O emitted at 70% WFPS (31.6 mg N2O-N m−2 over 24 days; 1.12 μg N2O-N g dry soil−1; 0.16% of N applied) was produced during denitrification, but at 35–60% WFPS nitrification was the main process producing N2O, accounting for 81% of 15N-N2O emitted at 60% WFPS, and 7.9 μg 15N-N2O m−2 (0.28 ng 15N-N2O g dry soil−1) was estimated to be emitted over 7 days during heterotrophic nitrification in the 50% WFPS treatment and accounted for 20% of 15N-N2O from this treatment. Denitrification was the predominant N2O-producing process at 20% WFPS (2.6 μg 15N-N2O m−2 over 7 days; 0.09 ng 15N-N2O g dry soil−1; 85% of 15N-N2O from this treatment) and may have been due to the occurrence of aerobic denitrification at this WFPS. Our results demonstrate the usefulness of a combined stable isotope and acetylene approach to quantify N2O emissions from different processes and to show that several processes may contribute to N2O emission from agricultural soils depending on soil WFPS.

UNITE: a database providing web-based methods for the molecular identification of ectomycorrhizal fungi

Abstract: Identification of ectomycorrhizal (ECM) fungi is often achieved through comparisons of ribosomal DNA internal transcribed spacer (ITS) sequences with accessioned sequences deposited in public databases. A major problem encountered is that annotation of the sequences in these databases is not always complete or trustworthy. In order to overcome this deficiency, we report on UNITE, an open-access database. • UNITE comprises well annotated fungal ITS sequences from well defined herbarium specimens that include full herbarium reference identification data, collector/source and ecological data. At present UNITE contains 758 ITS sequences from 455 species and 67 genera of ECM fungi. • UNITE can be searched by taxon name, via sequence similarity using blastn, and via phylogenetic sequence identification using galaxie. Following implementation, galaxie performs a phylogenetic analysis of the query sequence after alignment either to pre-existing generic alignments, or to matches retrieved from a blast search on the UNITE data. It should be noted that the current version of UNITE is dedicated to the reliable identification of ECM fungi. • The UNITE database is accessible through the URL http://unite.zbi.ee

Controlling Cell Behavior Electrically: Current Views and Future Potential

Abstract: Direct-current (DC) electric fields are present in all developing and regenerating animal tissues, yet their existence and potential impact on tissue repair and development are largely ignored. This is primarily due to ignorance of the phenomenon by most researchers, some technically poor early studies of the effects of applied fields on cells, and widespread misunderstanding of the fundamental concepts that underlie bioelectricity. This review aims to resolve these issues by describing: 1) the historical context of bioelectricity, 2) the fundamental principles of physics and physiology responsible for DC electric fields within cells and tissues, 3) the cellular mechanisms for the effects of small electric fields on cell behavior, and 4) the clinical potential for electric field treatment of damaged tissues such as epithelia and the nervous system.

Action planning and coping planning for long-term lifestyle change: Theory and assessment

Abstract: Planning is regarded as highly valuable in the process of health behaviour change. It bridges the gap between behavioural intentions and health behaviour. To further develop this concept, a distinction is made between action planning and coping planning. The latter refers to the mental simulation of overcoming anticipated barriers to action. Action planning and coping planning for physical exercise were examined in a longitudinal study with 352 cardiac patients. They were approached during rehabilitation treatment and followed up at two and four months after discharge. Both planning cognitions were psychometrically identified, and it was found that they operated differently in the behavioural change process. Action plans were more influential early in the rehabilitation process, whereas coping plans were more instrumental later on. Participants with higher levels of coping planning after discharge were more likely to report higher levels of exercise four months after discharge. It is suggested to include both kinds of planning in interventions at different stages in health behaviour change.

Variation in Arsenic Speciation and Concentration in Paddy Rice Related to Dietary Exposure

Abstract: Ingestion of drinking water is not the only elevated source of arsenic to the diet in the Bengal Delta. Even at background levels, the arsenic in rice contributes considerably to arsenic ingestion in subsistence rice diets. We set out to survey As speciation in different rice varieties from different parts of the globe to understand the contribution of rice to arsenic exposure. Pot experiments were utilized to ascertain whether growing rice on As contaminated soil affected speciation and whether genetic variation accounted for uptake and speciation. USA long grain rice had the highest mean arsenic level in the grain at 0.26 microg As g(-1) (n = 7), and the highest grain arsenic value of the survey at 0.40 microg As g(-1). The mean arsenic level of Bangladeshi rice was 0.13 microg As g(-1) (n = 15). The main As species detected in the rice extract were AsIII, DMAV, and AsV. In European, Bangladeshi, and Indian rice 64 +/- 1% (n = 7), 80 +/- 3% (n = 11), and 81 +/- 4% (n = 15), respectively, of the recovered arsenic was found to be inorganic. In contrast, DMAV was the predominant species in rice from the USA, with only 42 +/- 5% (n = 12) of the arsenic being inorganic. Pot experiments show that the proportions of DMAV in the grain are significantly dependent on rice cultivar (p = 0.026) and that plant nutrient status is effected by arsenic exposure.

Similar response of labile and resistant soil organic matter pools to changes in temperature

Abstract: Our understanding of the relationship between the decomposition of soil organic matter (SOM) and soil temperature affects our predictions of the impact of climate change on soil-stored carbon. One current opinion is that the decomposition of soil labile carbon is sensitive to temperature variation whereas resistant components are insensitive. The resistant carbon or organic matter in mineral soil is then assumed to be unresponsive to global warming. But the global pattern and magnitude of the predicted future soil carbon stock will mainly rely on the temperature sensitivity of these resistant carbon pools. To investigate this sensitivity, we have incubated soils under changing temperature. Here we report that SOM decomposition or soil basal respiration rate was significantly affected by changes in SOM components associated with soil depth, sampling method and incubation time. We find, however, that the temperature sensitivity for SOM decomposition was not affected, suggesting that the temperature sensitivity for resistant organic matter pools does not differ significantly from that of labile pools, and that both types of SOM will therefore respond similarly to global warming.

Pharmacological actions of cannabinoids.

Abstract: Mammalian tissues express at least two types of cannabinoid receptor, CB1 and CB2, both G protein coupled. CB1 receptors are expressed predominantly at nerve terminals where they mediate inhibition of transmitter release. CB2 receptors

Laparoscopic surgery for inguinal hernia repair: systematic review of effectiveness and economic evaluation.

Abstract: Objectives To determine whether laparoscopic methods are more effective and cost-effective than open mesh methods of inguinal hernia repair, and then whether laparoscopic transabdominal preperitoneal (TAPP) repair is more effective and cost-effective than laparoscopic totally extraperitoneal (TEP). Data sources Electronic databases. Conference proceedings. Manufacturers' submissions to the National Institute for Clinical Excellence (NICE) were reviewed. Review methods Selected studies were rigorously assessed. Dichotomous outcome data were combined using the relative risk method and continuous outcomes were combined using the Mantel-Haenszel weighted mean difference method. Time to return to usual activities was described using hazard ratios derived from individual patient data reanalysis. A review of economic evaluations undertaken by NICE in 2001 was updated and an economic evaluation was performed. The estimation of cost-effectiveness focused on the comparison of laparoscopic repair with open flat mesh. A Markov model incorporating the data from the systematic review was used to estimate cost-effectiveness for a time horizon up to 25 years. Results Thirty-seven randomised control trials (RCTs) and quasi-RCTs met the inclusion criteria on effectiveness. Fourteen studies were included in the review of economic evaluations. Laparoscopic repair was associated with a faster return to usual activities and less persisting pain and numbness. There also appeared to be fewer cases of wound/superficial infection and haematoma. However, operation times are longer and there appears to be a higher rate of serious complications in respect of visceral (especially bladder) injuries. Mesh infection is very uncommon with similar rates noted between the surgical approaches. There is no apparent difference in the rate of hernia recurrence. Laparoscopic repair was more costly to the health service than open repair, with an estimated extra cost from studies conducted in the UK of about 300-350 pounds per patient. The point estimates of cost provided by the economic model also suggest that the laparoscopic techniques are more costly (approximately 100-200 pounds more per patient after 5 years). From the review of economic evaluations, the estimates of incremental cost per additional day at usual activities were between 86 pounds and 130 pounds. Where productivity costs were included, they eliminated the cost differential between laparoscopic and open repair. Additional analysis incorporating new trial evidence suggested that TEP was associated with significantly more recurrences than open mesh but these data did not greatly influence cost-effectiveness. Conclusions For the management of unilateral hernias, the base-case analysis and most of the sensitivity analysis suggest that open flat mesh is the least costly option but provides less quality adjusted life years (QALYs) than TEP or TAPP. TEP is likely to dominate TAPP (on average TEP is estimated to be less costly and more effective). It is likely that, for management of symptomatic bilateral hernias, laparoscopic repair would be more cost-effective as differences in operation time (a key cost driver) may be reduced and differences in convalescence time are more marked (hence QALYs will increase) for laparoscopic compared with open mesh repair. When possible repair of contralateral occult hernias is taken into account, TEP repair is most likely to be considered cost-effective at threshold values for the cost per additional QALY above 20,000 pounds. The increased adoption of laparoscopic techniques may allow patients to return to usual activities faster. This may, for some people, reduce any loss of income. For the NHS, increased use of laparoscopic repair would lead to an increased requirement for training and the risk of serious complications may be higher. Chronic pain should now be addressed prospectively using standard definitions and allowing assessment of the degree of pain. More evidence is required on the loss of utility caused by persisting pain and numbness, as well as serious complications resulting from minor surgery. Prospective population-based registries of new surgical procedures may be the best way to address this, as a complement to randomised trials assessing effectiveness. Further research relating to whether the balance of advantages and disadvantages changes when hernias are recurrent or bilateral is also required as current data are limited. Methodologically sound RCTs are needed to consider the relative merits and risks of TAPP and TEP. Further methodological research is required into the complexity of laparoscopic groin hernia repair and the improvement of performance that accompanies experience.

Candida orthopsilosis and Candida metapsilosis spp. nov. to replace Candida parapsilosis groups II and III

Abstract: Although Candida albicans remains the most common Candida species encountered as a cause of human infections, other Candida species have been increasingly associated with disseminated disease since the 1990s. C. parapsilosis is the second most common yeast species isolated from the blood in Latin American countries and Asia (20, 23), and it is also found commonly in European surveys (19, 23). The species is particularly associated with bloodstream infections in neonates and also with catheter-associated candidemia and intravenous hyperalimentation (12). Early work with restriction fragment polymorphisms showed that C. parapsilosis isolates were more genotypically heterogeneous than those of other Candida species (24). C. parapsilosis isolates can be divided into three groups distinguished on the basis of randomly amplified polymorphic DNA (RAPD) (16), multilocus enzyme electrophoresis (17), internal transcribed spacer (ITS) sequences of DNA encoding ribosomes (17), DNA relatedness (21), morphotyping (4), mitochondrial DNA sequence differences (18), DNA topoisomerase II gene sequences (11), and an oligonucleotide probe used for fingerprinting C. parapsilosis strains (7). In several of these studies, the authors stated that the extent of the differences between the subgroups of C. parapsilosis was sufficient to merit their designation as distinct species (4, 11, 17, 21). Kurtzman and Robnett (14, 15) considered the six nucleotide differences in the rRNA D1/D2 domain between the C. parapsilosis type strain and a group II isolate to be sufficient to justify regarding the latter as a new species. As part of our ongoing research into multilocus sequence typing (MLST) of strains within pathogenic Candida species (3, 26, 27), we attempted to find genes with polymorphic loci that could differentiate a panel of C. parapsilosis isolates from diverse anatomic and geographic sources. Several of the genes we studied yielded PCR products only with isolates belonging to group I according to their RAPD profiles and ITS1 sequences (17). When isolates from C. parapsilosis groups I, II, and III gave products that could be sequenced, the sequences differed at a level characteristic for separate species. We describe here the MLST sequence diversity within these groups and formally designate C. parapsilosis groups II and III as the new species C. orthopsilosis and C. metapsilosis on the grounds that the level of genotypic differences between these taxa is too great for them to retain any longer their status as subgroups of a form species.

Biomarker evidence for green and purple sulphur bacteria in a stratified Palaeoproterozoic sea

Abstract: Rising oxygen levels in the Earth's early atmosphere marked the end of a 2.5-billion-year period dominated by oceans with low levels of oxygen. But geochemical evidence suggests that for the following billion years the oceans remained largely devoid of oxygen. The discovery of molecular fossils (hydrocarbon biomarkers) in 1.6-billion-year-old sedimentary rocks from a marine basin in northern Australia now offers insights into the marine ecosystem at the time. The biomarkers record an anoxic and sulphidic world hostile to to many forms of life but supporting blooms of sulphide-breathing green and purple bacteria. The disappearance of iron formations from the geological record ∼1.8 billion years (Gyr) ago was the consequence of rising oxygen levels in the atmosphere starting 2.45–2.32 Gyr ago1,2,3. It marks the end of a 2.5-Gyr period dominated by anoxic and iron-rich deep oceans. However, despite rising oxygen levels and a concomitant increase in marine sulphate concentration, related to enhanced sulphide oxidation during continental weathering4, the chemistry of the oceans in the following mid-Proterozoic interval (∼1.8–0.8 Gyr ago) probably did not yet resemble our oxygen-rich modern oceans. Recent data5,6,7,8 indicate that marine oxygen and sulphate concentrations may have remained well below current levels during this period, with one model indicating that anoxic and sulphidic marine basins were widespread, and perhaps even globally distributed4. Here we present hydrocarbon biomarkers (molecular fossils) from a 1.64-Gyr-old basin in northern Australia, revealing the ecological structure of mid-Proterozoic marine communities. The biomarkers signify a marine basin with anoxic, sulphidic, sulphate-poor and permanently stratified deep waters, hostile to eukaryotic algae. Phototrophic purple sulphur bacteria (Chromatiaceae) were detected in the geological record based on the new carotenoid biomarker okenane, and they seem to have co-existed with communities of green sulphur bacteria (Chlorobiaceae). Collectively, the biomarkers support mounting evidence for a long-lasting Proterozoic world in which oxygen levels remained well below modern levels.

Bacterial diversity promotes community stability and functional resilience after perturbation

Abstract: Summary The relationships between bacterial community diver- sity and stability were investigated by perturbing soils, with naturally differing levels of diversity, to equivalent toxicity using copper sulfate and benzene. Benzene amendment led to large decreases in total bacterial numbers and biomass in both soils. Benzene amendment of an organo-mineral/improved pasture soil altered total soil bacterial community structure but, unlike amendment of the mineral/arable soil, maintained genetic diversity, based on polymerase chain reaction-denaturing gradient gel electrophore- sis (PCR-DGGE ) analysis targeting DNA and RNA, until week 9 of the perturbation experiment. Assuming equivalent toxicity, the genetic diversity of the natu- rally more diverse soil was more resistant to benzene perturbation than the less diverse soil. The broad scale function (mineralization of 14 C-labelled wheat shoot) of both benzene- and copper-treated soil com- munities was unaffected. However, narrow niche func- tion (mineralization of 14 C-labelled 2,4-dichlorophenol) was impaired for both benzene-polluted soils. The organo-mineral soil recovered this function by the end of the experiment but the mineral soil did not, sug- gesting greater resilience in the more diverse soil. Despite a large reduction in bacterial numbers and biomass in the copper-treated soils, only small differ- ences in bacterial community diversity were observed by week 9 in the copper-polluted soils. The overall community structure was little altered and functional- ity, measured by mineralization rates, remained unchanged. This suggested a non-selective pressure and a degree of genetic and functional resistance to copper perturbation, despite a significant reduction in bacterial numbers and biomass. However, initial shifts in physiological profiles of both copper-polluted soils were observed but rapidly returned to those of the controls. This apparent functional recovery, accompanied by an increase in culturability, possibly reflects adaptation by the surviving communities to perturbation. The findings indicate that, although soil communities may be robust, relationships between diversity and stability need to be considered in devel- oping a predictive understanding of response to envi- ronmental perturbations.

Granulocytes govern the transcriptional response, morphology and proliferation of Candida albicans in human blood.

Abstract: Survival in blood and escape from blood vessels into tissues are essential steps for the yeast Candida albicans to cause systemic infections. To elucidate the influence of blood components on fungal growth, morphology and transcript profile during bloodstream infections, we exposed C. albicans to blood, blood fractions enriched in erythrocytes, polymorphonuclear or mononuclear leukocytes, blood depleted of neutrophils and plasma. C. albicans cells exposed to erythrocytes, mononuclear cells, plasma or blood lacking neutrophils were physiologically active and rapidly switched to filamentous growth. In contrast, the presence of neutrophils arrested C. albicans growth, enhanced the fungal response to overcome nitrogen and carbohydrate starvation, and induced the expression of a large number of genes involved in the oxidative stress response. In particular, SOD5, encoding a glycosylphosphatidylinositol (GPI)-anchored superoxide dismutase localized on the cell surface of C. albicans, was strongly expressed in yeast cells that were associated with neutrophils. Mutants lacking key genes involved in oxidative stress, morphology or virulence had significantly reduced survival rates in blood and the neutrophil fraction, but remained viable for at least 1 h of incubation when exposed to erythrocytes, mononuclear cells, plasma or blood lacking neutrophils. These data suggest that C. albicans genes expressed in blood were predominantly induced in response to neutrophils, and that neutrophils play a key role during C. albicans bloodstream infections. However, C. albicans is equipped with several genes and transcriptional programmes, which may help the fungus to counteract the attack of neutrophils, to escape from the bloodstream and to cause systemic infections.

Whole body vibration exercise: are vibrations good for you?

Abstract: Whole body vibration has been recently proposed as an exercise intervention because of its potential for increasing force generating capacity in the lower limbs. Its recent popularity is due to the combined effects on the neuromuscular and neuroendocrine systems. Preliminary results seem to recommend vibration exercise as a therapeutic approach for sarcopenia and possibly osteoporosis. This review analyses state of the art whole body vibration exercise techniques, suggesting reasons why vibration may be an effective stimulus for human muscles and providing the rationale for future studies.

Diet as a risk factor for atopy and asthma.

Abstract: It has been hypothesized that decreasing antioxidant (fruit and vegetables), increased n-6 polyunsaturated fatty acid (PUFA; (margarine, vegetable oil), and decreased n-3 PUFA (oily fish) intakes have contributed to the recent increases in asthma and atopic disease. Epidemiologic studies in adults and children have reported beneficial associations between dietary antioxidants and lipids and parameters of asthma and atopic disease. The associations with n-6 and n-3 PUFA appear to be very complex and might differ between asthma and atopic dermatitis. Dietary antioxidants are probably exerting antioxidant and nonantioxidant immunomodulatory effects. Dietary lipids exert numerous complex effects on proinflammatory and immunologic pathways. It has also been suggested that atopic dermatitis is associated with an enzyme defect in lipid metabolism. In spite of this, the results of interventional supplementation studies in established disease have been disappointing, and there is now increasing interest in the possibility that dietary antioxidant and lipid intakes might be important in determining expression of disease during pregnancy and early childhood and that dietary interventions should be targeted at these groups. It also seems likely that there is individual variation in the responses of individuals to lipid, and probably antioxidant, supplementation. Further research to determine whether dietary intervention can reduce the risk of asthma and atopic disease is justified.

Carbon-isotope stratigraphy recorded by the Cenomanian–Turonian Oceanic Anoxic Event: correlation and implications based on three key localities

Abstract: We present new, detailed carbon-isotope records for bulk carbonate, total organic carbon (TOC) and phytane from three key sections spanning the Cenomanian–Turonian boundary interval (Eastbourne, England; Gubbio, Italy; Tarfaya, Morocco), with the purpose of establishing a common chemostratigraphic framework for Oceanic Anoxic Event (OAE) 2. Isotope curves from all localities are characterized by a positive carbon-isotope excursion of c . 4‰ for TOC and phytane and c . 2.5‰ for carbonate, although diagenetic overprinting appears to have obliterated the primary carbonate carbon-isotope signal in at least part of the Tarfaya section. Stratigraphically, peak δ 13 C values for all components are followed by intervals of high, near-constant δ 13 C in the form of an isotopic plateau. Recognition of an unambiguous return to background δ 13 C values above the plateau is, however, contentious in all sections, hence no firm chemostratigraphic marker for the end-point of the positive isotopic excursion can be established. The stratigraphically consistent first appearance of the calcareous nannofossil Quadrum gartneri at or near the Cenomanian–Turonian boundary as established by ammonite stratigraphy, in conjunction with the end of the δ 13 C maximum characteristic of the isotopic plateau, provides a potentially powerful tool for delimiting the stratigraphic extent and duration of OAE 2. This Oceanic Anoxic Event is demonstrated to be largely, if not wholly, confined to the latest part of the Cenomanian stage.

Allosteric Modulation of the Cannabinoid CB1 Receptor

Abstract: We investigated the pharmacology of three novel compounds, Org 27569 (5-chloro-3-ethyl-1H-indole-2-carboxylic acid [2-(4-piperidin-1-yl-phenyl)-ethyl]-amide), Org 27759 (3-ethyl-5-fluoro-1H-indole-2-carboxylic acid [2-94-dimethylamino-phenyl)-ethyl]-amide), and Org 29647 (5-chloro-3-ethyl-1H-indole-2-carboxylic acid (1-benzyl-pyrrolidin-3-yl)-amide, 2-enedioic acid salt), at the cannabinoid CB1 receptor. In equilibrium binding assays, the Org compounds significantly increased the binding of the CB1 receptor agonist [3H]CP 55,940 [(1R,3R,4R)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl)cyclohexan-1-ol], indicative of a positively cooperative allosteric effect. The same compounds caused a significant, but incomplete, decrease in the specific binding of the CB1 receptor inverse agonist [3H]SR 141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride], indicative of a limited negative binding cooperativity. Analysis of the data according to an allosteric ternary complex model revealed that the estimated affinity of each Org compound was not significantly different when the radioligand was [3H]CP 55,940 or [3H]SR 141716A. However, the estimated cooperatively factor for the interaction between modulator and radioligand was greater than 1 when determined against [3H]CP 55,940 and less than 1 when determined against [3H]SR 141716A. [3H]CP 55,940 dissociation kinetic studies also validated the allosteric nature of the Org compounds, because they all significantly decreased radioligand dissociation. These data suggest that the Org compounds bind allosterically to the CB1 receptor and elicit a conformational change that increases agonist affinity for the orthosteric binding site. In contrast to the binding assays, however, the Org compounds behaved as insurmountable antagonists of receptor function; in the reporter gene assay, the guanosine 5′-O-(3-[35S]thio)triphosphate binding assay and the mouse vas deferens assay they elicited a significant reduction in the Emax value for CB1 receptor agonists. The data presented clearly demonstrate, for the first time, that the cannabinoid CB1 receptor contains an allosteric binding site that can be recognized by synthetic small molecule ligands.

Characteristics of fetal anticonvulsant syndrome associated autistic disorder

Abstract: The aim of this study was to evaluate the clinical features and frequency of autistic disorder or Asperger syndrome (AS; according to Diagnostic and Statistical Manual of Mental Disorders, 4th edition [DSM-IV] criteria) in children exposed to anticonvulsant medication in utero. During a 20-year study period, 626 children were born in Aberdeen to mothers taking antiepileptic drugs (AEDs). The study examined long-term effects of prenatal exposure to AEDs in 260 children (122 males, 138 females). Of these, 26 (16 males) were reported by parents to have social or behavioural difficulties. Eleven children (6 males, 5 females) fulfilled the DSM-IV criteria for autistic disorder and one (female) fulfilled the DSM-IV criteria for AS. These children comprised 4.6% of the exposed children studied, and 1.9% of all exposed children born during the study period. Mean age of these children at diagnosis was 5 years 4 months (SD 2y 11mo) and 9 years 10 months (SD 3y 10mo) at the time of this study. Other children from the group of 26 had difficulties in areas of speech and language development and social communication but did not meet the criteria for an autism spectrum disorder (ASD). Sodium valproate was the drug most commonly associated with autistic disorder, five of 56 (8.9%) of the study children exposed to sodium valproate alone had either autistic disorder or AS. It was concluded that prenatal exposure to anticonvulsant medication is a risk factor for the development of an ASD. Fetal anticonvulsant syndrome associated autistic disorder is characterized by an even sex ratio, absence of regression or skill loss, and language delay in the absence of global delay.

The influence of surgical operations on components of the human immune system

Abstract: Surgical operations have been shown to cause a variety of immunological disturbances in man both in vivo and in vitro. With few exceptions the overall picture is one of a generalized state of immunodepression in the postoperative period. The implications of these observations are that host defences may be compromised by surgical procedures, thus providing a 'fertile soil' for bacterial invasion and tumour cell metastasis at the very time when risks from invading pathogens and viable tumour cells are maximal. We have studied the effects of surgical operations on the immune system in 35 patients with benign disease. Surgical procedures were classified as either minor (n = 15) or major (n = 20). A panel of monoclonal antibodies was used to identify peripheral blood lymphocyte subpopulations and analysis was performed using flow cytometry. Simultaneous estimations of plasma alpha-1 proteinase inhibitor (alpha-1-PI), alpha-2-macroglobulin (alpha-2-M), alpha-2-pregnancy-associated glycoprotein (alpha-2-PAG) and plasma suppressive activity (PSA) on stimulated allogeneic lymphocytes were performed before operation and on postoperative days 1, 3, 7, 17 and 21. Circulating numbers of all lymphocyte subpopulations fell significantly following surgery, except for B lymphocytes which did not change. The magnitude, and duration of the reduction in cell numbers and the subpopulation affected was significantly related to the degree of surgical trauma, and returned to pre-operative values by postoperative day 7. Changes in alpha-1-PI, alpha-2-M, alpha-2-PAG and PSA were also significantly related to the degree of surgical trauma, and these plasma changes persisted longer than the cellular disturbances. Surgical operations induce a reversible depression of cellular immunity which precedes plasma suppressive activity in its return to pre-operative levels. Immunostimulating agents such as interferon and the interleukins deserve evaluation as prophylactic agents pre-operatively.

Long‐term non‐pharmacological weight loss interventions for adults with prediabetes

Abstract: Most persons with prediabetes (impaired glucose tolerance or impaired fasting glucose) are overweight, and obesity worsens the metabolic and physiologic abnormalities associated with this condition. Prediabetes is an important risk factor for the development of type 2 diabetes. The objective of this review was to assess the effectiveness of dietary, physical activity, and behavioural weight loss, and weight control interventions for adults with prediabetes.

Testing for suspected impairments and dissociations in single-case studies in neuropsychology: evaluation of alternatives using monte carlo simulations and revised tests for dissociations.

Abstract: In neuropsychological single-case studies, a patient is compared with a small control sample. Methods of testing for a deficit on Task X, or a significant difference between Tasks X and Y, either treat the control sample statistics as parameters (using z and z(D)) or use modified t tests. Monte Carlo simulations demonstrated that if z is used to test for a deficit, the Type I error rate is high for small control samples, whereas control of the error rate is essentially perfect for a modified t test. Simulations on tests for differences revealed that error rates were very high for z(D). A new method of testing for a difference (the revised standardized difference test) achieved good control of the error rate, even with very small sample sizes. A computer program that implements this new test (and applies criteria to test for classical and strong dissociations) is made available.

Identification and Bioactivities of IFN-γ in Rainbow Trout Oncorhynchus mykiss: The First Th1-Type Cytokine Characterized Functionally in Fish

Abstract: IFN-gamma is one of the key cytokines in defining Th1 immune responses. In this study, an IFN-gamma homologue has been identified in rainbow trout Oncorhynchus mykiss, and its biological activities have been characterized. The trout IFN-gamma cDNA is 1034 bp in length and translates into a 180-aa protein. The first intron of the trout IFN-gamma gene contains highly polymorphic GACA minisatellites and 44-bp DNA repeats, giving rise to at least six alleles. IFN-gamma is structurally conserved among vertebrates, and a signature motif has been identified. A nuclear localization sequence known to be crucial for IFN-gamma biological activities is also present in the C-terminal region of the trout IFN-gamma. The IFN-gamma expression was induced in head kidney leukocytes by stimulation with PHA or poly(I:C) and in kidney and spleen of fish injected with poly(I:C). rIFN-gamma produced in Escherichia coli significantly stimulated gene expression of IFN-gamma-inducible protein 10 (gammaIP-10), MHC class II beta-chain, and STAT1, and enhanced respiratory burst activity in macrophages. Deletion of 29-aa residues from the C terminus containing the nuclear localization sequence motif resulted in loss of activity with respect to induction of gammaIP-10 in RTS-11 cells. Moreover, IFN-gamma-induced gammaIP-10 expression was completely abolished by the protein kinase C inhibitor staurosporine, and partially reduced by U0126, a specific inhibitor for ERKs. Taken together, the present study has demonstrated for the first time a functional IFN-gamma homologue in a fish species, strongly suggesting a conserved Th1 immune response is most likely present in lower vertebrates.