Modulating the rate and rhythmicity of perceptual rivalry alternations with the mixed 5-HT2A and 5-HT1A agonist psilocybin

Binocular rivalry occurs when different images are presented simultaneously to corresponding points within the left and right eyes. Under these conditions, the observer's perception will alternate between the two perceptual alternatives. Motivated by the reported link between the rate of perceptual alternations, symptoms of psychosis and an incidental observation that the rhythmicity of perceptual alternations during binocular rivalry was greatly increased 10 h after the consumption of LSD, this study aimed to investigate the pharmacology underlying binocular rivalry and to explore the connection between the timing of perceptual switching and psychosis. Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine, PY) was chosen for the study because, like LSD, it is known to act as an agonist at serotonin (5-HT)(1A) and 5-HT2A receptors and to produce an altered state sometimes marked by psychosis-like symptoms. A total of 12 healthy human volunteers were tested under placebo, low-dose ( 115 mg/kg) and high-dose ( 250 mg/kg) PY conditions. In line with predictions, under both low- and high-dose conditions, the results show that at 90 min postadministration ( the peak of drug action), rate and rhythmicity of perceptual alternations were significantly reduced from placebo levels. Following the 90 min testing period, the perceptual switch rate successively increased, with some individuals showing increases well beyond pretest levels at the final testing, 360 min postadministration. However, as some subjects had still not returned to pretest levels by this time, the mean phase duration at 360 min was not found to differ significantly from placebo. Reflecting the drug-induced changes in rivalry phase durations, subjects showed clear changes in psychological state as indexed by the 5D-ASC ( altered states of consciousness) rating scales. This study suggests the involvement of serotonergic pathways in binocular rivalry and supports the previously proposed role of a brainstem oscillator in perceptual rivalry alternations and symptoms of psychosis.

Levels of physical activity for colon cancer prevention compared with generic public health recommendations: Population prevalence and sociodemographic correlates

Background: The proportion of Australian adults achieving physical activity levels believed to be sufficient for colon cancer prevention was estimated, and sociodemographic correlates (age, gender, educational attainment, occupation, marital status, and children in household) of meeting these levels of activity were analyzed. Methods: Data from the 2000 National Physical Activity Survey were used to estimate the prevalence of participation in physical activity in relation to three criteria: generic public health recommendations, weekly amount of at least moderate-intensity physical activity currently believed to reduce risk of colon cancer, and weekly amount of vigorous-intensity physical activity believed to reduce risk of colon cancer. Results: Overall, 46% of adults met the generic public health criterion, 26% met the colon cancer criterion based on participation in at least moderate-intensity physical activity, and 10% met the colon cancer criterion based on vigorous-intensity physical activity. Women were less likely than men to meet the colon cancer criteria. Younger and more educated persons were more likely to meet all three criteria. The most pronounced differences between gender, age, and educational attainment groups were found for meeting the amount of vigorous-intensity physical activity believed to reduce risk of colon cancer. Conclusions: The population prevalence for meeting proposed physical activity criteria for colon cancer prevention is low and much lower than that related to the more generic public health recommendations. If further epidemiologic studies confirm that high volumes and intensities of activity are required, the public health challenges for colon cancer will be significant.

The use and implications of ribosomal DNA sequencing for the discrimination of digenean species

In just over a decade, the use of molecular approaches for the recognition of parasites has become commonplace. For trematodes, the internal transcribed spacer region of ribosomal DNA (ITS rDNA) has become the default region of choice. Here, we review the findings of 63 studies that report ITS rDNA sequence data for about 155 digenean species from 19 families, and then review the levels of variation that have been reported and how the variation has been interpreted. Overall, complete ITS sequences (or ITS1 or ITS2 regions alone) usually distinguish trematode species clearly, including combinations for which morphology gives ambiguous results. Closely related species may have few base differences and in at least one convincing case the ITS2 sequences of two good species are identical. In some cases, the ITS1 region gives greater resolution than the ITS2 because of the presence of variable repeat units that are generally lacking in the ITS2. Intraspecific variation is usually low and frequently apparently absent. Information on geographical variation of digeneans is limited but at least some of the reported variation probably reflects the presence of multiple species. Despite the accepted dogma that concerted evolution makes the individual representative of the entire species, a significant number of studies have reported at least some intraspecific variation. The significance of such variation is difficult to assess a posteriori, but it seems likely that identification and sequencing errors account for some of it and failure to recognise separate species may also be significant. Some reported variation clearly requires further analysis. The use of a yardstick to determine when separate species should be recognised is flawed. Instead, we argue that consistent genetic differences that are associated with consistent morphological or biological traits should be considered the marker for separate species. We propose a generalised approach to the use of rDNA to distinguish trematode species.

A Site Description of the CARICOMP Mangrove, Seagrass and Coral Reef Sites in Bocas del Toro, Panama

Bocas del Toro is located in the western region of the Republic of Panama. It is part of a province of approximately 8917 km(2) with an estimated 68% of its area covered by tropical rainforest. The area receives 2870 mm/year of rainfall. The dry and rainy seasons are not clearly defined. There are two periods each of low and high rainfall, March and September-October, and July and December, respectively. Mangrove forests, seagrass meadows and coral reefs are vast, covering large areas in the shallow waters surrounding the islands of the archipelago and along the mainland coast. The CARICOMP sites were established in 1998-99 and are periodically monitored following Level I protocol. Herein we describe the sites in a regional context and present the baseline data for each site. This paper fulfills the requirements of the formal site description for CARICOMP monitoring sites.

Global assessment of coral bleaching and required rates of adaptation under climate change

Elevated ocean temperatures can cause coral bleaching, the loss of colour from reef-building corals because of a breakdown of the symbiosis with the dinoflagellate Symbiodinium. Recent studies have warned that global climate change could increase the frequency of coral bleaching and threaten the long-term viability of coral reefs. These assertions are based on projecting the coarse output from atmosphere-ocean general circulation models (GCMs) to the local conditions around representative coral reefs. Here, we conduct the first comprehensive global assessment of coral bleaching under climate change by adapting the NOAA Coral Reef Watch bleaching prediction method to the output of a low- and high-climate sensitivity GCM. First, we develop and test algorithms for predicting mass coral bleaching with GCM-resolution sea surface temperatures for thousands of coral reefs, using a global coral reef map and 1985-2002 bleaching prediction data. We then use the algorithms to determine the frequency of coral bleaching and required thermal adaptation by corals and their endosymbionts under two different emissions scenarios. The results indicate that bleaching could become an annual or biannual event for the vast majority of the world's coral reefs in the next 30-50 years without an increase in thermal tolerance of 0.2-1.0 degrees C per decade. The geographic variability in required thermal adaptation found in each model and emissions scenario suggests that coral reefs in some regions, like Micronesia and western Polynesia, may be particularly vulnerable to climate change. Advances in modelling and monitoring will refine the forecast for individual reefs, but this assessment concludes that the global prognosis is unlikely to change without an accelerated effort to stabilize atmospheric greenhouse gas concentrations.

A phase I biological and pharmacologic study of the heparanase inhibitor PI-88 in patients with advanced solid tumors

Purpose: PI-88 is a mixture of highly sulfated oligosaccharides that inhibits heparanase, an extracellular matrix endoglycosidase, and the binding of angiogenic growth factors to heparan sulfate. This agent showed potent inhibition of placental blood vessel angiogenesis as well as growth inhibition in multiple xenograft models, thus forming the basis for this study. Experimental Design: This study evaluated the toxicity and pharmacokinetics of PI-88 (80-315 mg) when administered s.c. daily for 4 consecutive days bimonthly (part 1) or weekly (part 2). Results: Forty-two patients [median age, 53 years (range, 19-78 years); median performance status, 1] with a range of advanced solid tumors received a total of 232 courses. The maximum tolerated dose was 250 mg/d. Dose-limiting toxicity consisted of thrombocytopenia and pulmonary embolism. Other toxicity was generally mild and included prolongation of the activated partial thromboplastin time and injection site echymosis. The pharmacokinetics were linear with dose. Intrapatient variability was low and interpatient variability was moderate. Both AUC and C-max correlated with the percent increase in activated partial thromboplastin time, showing that this pharmacodynamic end point can be used as a surrogate for drug exposure, No association between PI-88 administration and vascular endothelial growth factor or basic fibroblast growth factor levels was observed. One patient with melanoma had a partial response, which was maintained for >50 months, and 9 patients had stable disease for >= 6 months. Conclusion: The recommended dose of PI-88 administered for 4 consecutive days bimonthly or weekly is 250 mg/d. PI-88 was generally well tolerated. Evidence of efficacy in melanoma supports further evaluation of PI-88 in phase II trials.

Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data

Background Our aim was to calculate the global burden of disease and risk factors for 2001, to examine regional trends from 1990 to 2001, and to provide a starting point for the analysis of the Disease Control Priorities Project (DCPP). Methods We calculated mortality, incidence, prevalence, and disability adjusted life years (DALYs) for 136 diseases and injuries, for seven income/geographic country groups. To assess trends, we re-estimated all-cause mortality for 1990 with the same methods as for 2001. We estimated mortality and disease burden attributable to 19 risk factors. Findings About 56 million people died in 2001. Of these, 10.6 million were children, 99% of whom lived in low-and-middle-income countries. More than half of child deaths in 2001 were attributable to acute respiratory infections, measles, diarrhoea, malaria, and HIV/AIDS. The ten leading diseases for global disease burden were perinatal conditions, lower respiratory infections, ischaemic heart disease, cerebrovascular disease, HIV/AIDS, diarrhoeal diseases, unipolar major depression, malaria, chronic obstructive pulmonary disease, and tuberculosis. There was a 20% reduction in global disease burden per head due to communicable, maternal, perinatal, and nutritional conditions between 1990 and 2001. Almost half the disease burden in low-and-middle-income countries is now from non-communicable diseases (disease burden per head in Sub-Saharan Africa and the low-and-middle-income countries of Europe and Central Asia increased between 1990 and 2001). Undernutrition remains the leading risk factor for health loss. An estimated 45% of global mortality and 36% of global disease burden are attributable to the joint hazardous effects of the 19 risk factors studied. Uncertainty in all-cause mortality estimates ranged from around 1% in high-income countries to 15-20% in Sub-Saharan Africa. Uncertainty was larger for mortality from specific diseases, and for incidence and prevalence of non-fatal outcomes. Interpretation Despite uncertainties about mortality and burden of disease estimates, our findings suggest that substantial gains in health have been achieved in most populations, countered by the HIV/AIDS epidemic in Sub-Saharan Africa and setbacks in adult mortality in countries of the former Soviet Union. our results on major disease, injury, and risk factor causes of loss of health, together with information on the cost-effectiveness of interventions, can assist in accelerating progress towards better health and reducing the persistent differentials in health between poor and rich countries.

Novel approach to tailoring molecular weight distribution and structure with a difunctional RAFT agent

This work has demonstrated that for the first time a single RAFT agent (i. e., difunctional) can be used in conjunction with a radical initiator to obtain a desired M-n and PDI with controlled rates of polymerization. Simulations were used not only to verify the model but also to provide us with a predictive tool to generate other MWDs. It was also shown that all the MWDs prepared in this work could be translated to higher molecular weights through chain extension experiments with little or no compromise in the control of end group functionality. The ratio of monofunctional to difunctional SdC(CH2Ph)S- end groups, XPX and XP (where X) S=C(CH2Ph) S-), can be controlled by simply changing the concentration of initiator, AIBN. Importantly, the amount of dead polymer is extremely low and fulfils the criterion as suggested by Szwarc (Nature 1956) that to meet living requirements nonfunctional polymeric species formed by side reactions in the process should be undetectable by analytical techniques. In addition, this novel methodology will allow the synthesis of AB, ABA, and statistical multiblock copolymers with predetermined ratios to be produced in a one-pot reaction.

Prevalence, severity, and heritability of Stephanofilaria lesions on cattle in central and southern Queensland, Australia

Observations of cattle in central and southern Queensland are collated to de. ne the prevalence and area of Stephanofilaria lesions associated with infestations of the buffalo fly, Haematobia irritans exigua. The observations were made on herds that were being used for other purposes. In a survey of similar to 1500 animals at Belmont in central Queensland in 1982, 98% of cows and 70% of calves had lesions. Most lesions were on the neck and dewlap and 10% were raw and weeping at the time of sampling. The total area of lesions per animal was strongly related to cattle breed and age. Old Bos taurus animals had the greatest area of lesions, whereas young Bos indicus had the least. Heritability estimates were low, averaging 0.01 for calves and 0.18 for cows. A smaller survey of cows and steers at Craighoyle in central Queensland in 1986 showed a higher numbers of lesions and positive correlations between the total lesion area and animal size. The lesion area increased with tick survival, suggesting that tick-resistant animals are also resistant to Stephanofilaria infection. Steers had smaller areas of lesions than cows, as found previously with cattle ticks. Long-term monitoring observations in central and southern Queensland between 1981 and 1986 showed that the total area of lesions was seasonal with a peak in late summer, consistent with the seasonal incidence of buffalo fly. Animals segregated into Low and High lesion herds maintained their differences over time. The lesions penetrated the dermis of the cattle hides and rendered the affected area unusable, but few lesions occurred on valuable parts of the hide so such economic effects are likely to be insignificant. One animal nearly died of a haemorrhage from a lesion on the dewlap and had to be treated. The results can inform policy on buffalo fly control, and biosecurity preparations in relation to the potential establishment of the OldWorld screw-worm fly, Chrysomyia bezziana, in Australia, which will be facilitated by the lesions. The results emphasise the significant animal welfare and biosecurity risks posed by the lesions in northern Australia.

The inhibitory effects of free nitrous acid on the energy generation and growth processes of an enriched Nitrobacter culture

The inhibitory effects of nitrite (NO2-)/free nitrous acid (HNO2-FNA) on the metabolism of Nitrobacter were investigated using a method allowing the decoupling of the growth and energy generation processes. A lab-scale sequencing batch reactor was operated for the enrichment of a Nitrobacter culture. Fluorescent in situ hybridization (FISH) analysis showed that 73% of the bacterial population was Nitrobacter. Batch tests were carried out to assess the oxygen and nitrite consumption rates of the enriched culture at low and high nitrite levels, in the presence or absence of inorganic carbon. It was observed that in the absence of CO2, the Nitrobacter culture was able to oxidize nitrite at a rate that is 76% of that in the presence of CO2, with an oxygen consumption rate that is 85% of that measured in the presence of CO2. This enabled the impacts of nitrite/FNA on the catabolic and anabolic processes of Nitrobacter to be assessed separately. FNA rather than nitrite was likely the actual inhibitor to the Nitrobacter metabolism. It was revealed that FNA of up to 0.05 mg HNO2-N center dot L-1 (3.4 mu M), which was the highest FNA concentration used in this study, did not have any inhibitory effect on the catabolic processes of Nitrobacter. However, FNA initiated its inhibition to the anabolic processes of Nitrobacter at approximately 0.011 mg HNO2-N center dot L-1 (0.8 mu M), and completely stopped biomass synthesis at a concentration of approximately 0.023 mg HNO2-N center dot L-1 (1.6 mu M). The inhibitory effect could be described by an empirical inhibitory model proposed in this paper, but the underlying mechanisms remain to be revealed.

Risk stratification of patients with chronic kidney disease: Results of screening strategies incorporating clinical risk scoring and dobutamine stress echocardiography

Background Cardiac disease is the principal cause of death in patients with chronic kidney disease (CKD). Ischemia at dobutamine stress echocardiography (DSE) is associated with adverse events in these patients. We sought the efficacy of combining clinical risk evaluation with DSE. Methods We allocated 244 patients with CKD (mean age 54 years, 140 men, 169 dialysis-dependent at baseline) into low- and high-risk groups based on two disease-specific scores and the Framingham risk model. All underwent DSE and were further stratified according to DSE results. Patients were followed over 20 +/- 14 months for events (death, myocardial infarction, acute coronary syndrome). Results There were 49 deaths and 32 cardiac events. Using the different clinical scores, allocation of high risk varied from 34% to 79% of patients, and 39% to 50% of high-risk patients had an abnormal DSE. In the high-risk groups, depending on the clinical score chosen, 25% to 44% with an abnormal DSE had a cardiac event, compared with 8% to 22% with a.normal DSE. Cardiac events occurred in 2.0%, 3.1 %, and 9.7% of the low-risk patients, using the two disease-specific and Framingham scores, respectively, and DSE results did not add to risk evaluation in this subgroup. Independent DSE predictors of cardiac events were a lower resting diastolic blood pressure, angina during the test, and the combination of ischemia with resting left ventricular dysfunction. Conclusion In CKD patients, high-risk findings by DSE can predict outcome. A stepwise strategy of combining clinical risk scores with DSE for CAD screening in CKD reduces the number of tests required and identifies a high-risk subgroup among whom DSE results more effectively stratify high and low risk.

The fraction of ischaemic heart disease and stroke attributable to smoking in the WHO Pacific and South-East Asian regions

Background: Tobacco will soon be the biggest cause of death worldwide, with the greatest burden being borne by low and middle-income countries where 8/10 smokers now live. Objective: This study aimed to quantify the direct burden of smoking for cardiovascular diseases (CVD) by calculating the population attributable fractions (PAF) for fatal ischaemic heart disease (IHD) and stroke (haemorrhagic and ischaemic) for all 38 countries in the World Health Organization Western Pacific and South East Asian regions. Design and subjects: Sex-specific prevalence of smoking was obtained from existing data. Estimates of the hazard ratio (HR) for IHD and stroke with smoking as an independent risk factor were obtained from the,600 000 adult subjects in the Asia Pacific Cohort Studies Collaboration (APCSC). HR estimates and prevalence were then used to calculate sex-specific PAF for IHD and stroke by country. Results: The prevalence of smoking in the 33 countries, for which relevant data could be obtained, ranged from 28-82% in males and from 1-65% in females. The fraction of IHD attributable to smoking ranged from 13-33% in males and from < 1-28% in females. The percentage of haemorrhagic stroke attributable to smoking ranged from 4-12% in males and from < 1-9% in females. Corresponding figures for ischaemic stroke were 11-27% in males and < 1-22% in females. Conclusions: Up to 30% of some cardiovascular fatalities can be attributed to smoking. This is likely an underestimate of the current burden of smoking on CVD, given that the smoking epidemic has developed further since many of the studies were conducted.

Uncertainty and the influence of group norms in the attitude-behaviour relationship

Two studies were conducted to examine the impact of subjective uncertainty on conformity to group norms in the attitude-behaviour context. In both studies, subjective uncertainty was manipulated using a deliberative mindset manipulation (McGregor, Zanna, Holmes, & Spencer, 2001). In Study 1 (N = 106), participants were exposed to either an attitude-congruent or an attitude-incongruent in-group norm. In Study 2(N = 83), participants were exposed to either a congruent, incongruent, or an ambiguous in-group norm. Ranges of attitude-behaviour outcomes, including attitude-intention consistency and change in attitude-certainty, were assessed. In both studies, levels of group-normative behaviour varied as a function of uncertainty condition. In Study 1, conformity to group norms, as evidenced by variations in the level of attitude-intention consistency, was observed only in the high uncertainty condition. In Study 2, exposure to an ambiguous norm had different effects for those in the low and die high uncertainty conditions. In the low uncertainty condition, greatest conformity was observed in the attitude-congruent norm condition compared with an attitude-congruent or ambiguous norm. In contrast, individuals in the high uncertainty condition displayed greatest conformity when exposed to either an attitude-congruent or an ambiguous in-group norm. The implications of these results for the role of subjective uncertainty in social influence processes are discussed. © 2007 The British Psychological Society.

Innovation, ownership and profitability

There is lots of evidence that innovating firms are persistently more profitable than non-innovators, but little agreement on why this is the case. It may be because innovators are somehow able to protect their new products from the competition which normally erodes profits, or because innovating firms have superior capabilities and are able to introduce multiple innovations over time. And very little is known about the relationship between innovation, external ownership and profitability, despite the fact that foreign-owned firms are frequently highly innovative and very profitable. This paper considers the relationship between innovation, ownership and profitability for a panel of manufacturing plants in Ireland and Northern Ireland. We consider the link between innovation and profits separately for innovators and non-innovators, and for indigenous innovators and non-innovators and externally-owned plants. We also consider the determinants of innovation over the distribution of plant-level profitability, and find that the determinants of profitability – including innovation and external ownership – are quite different for low and high-profitability plants. We find support for the view that innovators and non-innovators have different profitability determinants, and that externally-owned plants have their profitability determined in a quite different way from indigenous enterprises. For indigenous non-innovators only the sector matters. Profitability in these enterprises is dictated largely by the industry they are in, with plants having virtually no means of differentiating their profitability from the norms of the industry. By contrast, indigenously-owned innovators are able to differentiate their profit performance from industry norms to some extent. Absolute size matters (negatively) and they get a strong boost from product innovation, but having a high market share does not matter for the profitability of indigenously-owned innovators. Externally-owned plants have a quite different set of profitability determinants from both of these groups. What matters for these plants is not the boost they get from innovating (there is none) but instead their position in the domestic market – a high market share boosts profitability. In policy terms our results suggest both optimistic and cautionary messages. On the positive side our results suggest that efforts to promote innovation activity among indigenously-owned plants are likely to have significant longer term benefits through their capability effects. For the development agencies in Ireland this is a reassuring result. On the more negative side, the lack of any relationship in our models between the innovation activities of externally-owned plants and their (profitability) performance raises potential concerns. This finding may reflect the lack of linkages between externally-owned plants and their Irish resource base, in turn raising some worrying issues about the ‘embeddedness’ of much FDI into Ireland and therefore its ‘stickiness’ in the face of Ireland’s increasing high relative cost base.