Relationships of tacrolimus pharmacokinetic measures and adverse outcomes in stable adult liver transplant recipients

Alternative measures to trough concentrations [non-trough concentrations and limited area under the concentration-time curve (AUC)] have been shown to better predict tacrolimus AUC. The aim of this study was to determine if these are also better predictors of adverse outcomes in long term liver transplant recipients. The associations between tacrolimus trough concentrations (C-0), non-trough concentrations (C-1, C-2, C-4, C-6/8), and AUC(0-12) and the occurrence of hypertension, hyperkalaemia, hyperglycaemia and nephrotoxicity were assessed in 34 clinically stable liver transplant patients. The most common adverse outcome was hypertension, prevalence of 36%. Hyperkalaemia and hyperglycaemia had a prevalence of 21% and 13%, respectively. A sequential population pharmacokinetic/pharmacodynamic approach was implemented. No significant association between predicted C-0, C-1, C-2, C-4, C-6/8 or AUC(0-12) and adverse effects could be found. Tacrolimus concentrations and AUC measures were in the same range in patients with and without adverse effects. Measures reported to provide benefit, preventing graft rejection and minimizing acute adverse effects in the early post-transplant period, were not able to predict adverse effects in stable adult liver recipients whose trough concentrations were maintained in the notional target range.

The effects of equine skin preparation on transdermal drug penetration in vitro

An increasing number of formulations are applied to equine skin, yet variable penetration can affect efficacy, or the incidence of adverse effects, or both. To investigate the effects of common methods of skin preparation on transdermal drug penetration in vitro, we clipped, harvested, and froze skin samples from 5 Thoroughbred geldings. Thawed samples were prepared as follows: control (no preparation); cleaned with aqueous chlorhexidine (Aq-C, 0.1% w/v); cleaned with alcoholic chlorhexidine (Al-C, 0.5% w/v); shaved (Sh); or tape-stripped (Ta) with the use of adhesive tape. The samples were then placed in diffusion cells, and 2 g of methylsalicylate (MeSa) gel (Dencorub) was applied to the stratum corneum side. The penetration of MeSa and its analyte, salicylate (Sa), through the skin samples was measured over 10 h. Compared with control skin, significantly more MeSa penetrated through skin prepared with Al-C or Sh (P < 0.01) or with Aq-C or Ta (P < 0.05), and significantly more Sa was recovered in the receptor phase from skin prepared with Aq-C, Al-C, or Sh (P < 0.05) or with Ta (P < 0.01). A significantly higher rate of penetration and shorter lag time were also noted for MeSa with all the prepared skin samples, compared with the control samples. The results show that clinical techniques routinely used to clean or prepare skin can significantly affect the rate and extent of penetration of a topically applied drug. This may result in greater systemic availability of active drug, which could lead to enhanced efficacy and, possibly, a higher incidence of adverse effects.

Effects of metformin on BRIN-BD11 beta-cell insulin secretory desensitization induced by prolonged exposure to sulphonylureas

Aims: Prolonged exposure of pancreatic beta-cells in vitro to the sulphonylureas tolbutamide and glibenclamide induces subsequent desensitization of insulinotropic pathways. Clinically, the insulin-sensitizing biguanide drug metformin is often administered alongside sulphonylurea as antidiabetic therapy. The present study examines the functional effects of metformin (200 µM) on tolbutamide- and glibenclamide-induced desensitisation. Methods: Acute and prolonged (18 h) effects of exposure to tolbutamide and glibenclamide alone, or in the presence of metformin, were examined in insulin-secreting BRIN-BD11 cells. Results: In acute 20 min incubations at 1.1 mM glucose, metformin increased (1.2-1.7-fold; p <0.001) the insulin-releasing actions of tolbutamide and glibenclamide. At 16.7 mM glucose, metformin significantly enhanced glibenclamide-induced insulin release at all concentrations (50-400 µM) examined, but tolbutamide-stimulated insulin secretion was only augmented at higher concentrations (300-400 µM). Exposure for 18 h to 100 µM tolbutamide or glibenclamide significantly impaired insulin release in response to glucose and a broad range of insulin secretagogues. Concomitant culture with metformin (200 µM) prevented or partially reversed many of the adverse effects on K channel dependent and independent insulinotropic pathways. Beneficial effects of metformin were also observed in cells exposed to glibenclamide for 18 h with significant improvements in the insulin secretory responsiveness to alanine, GLP-1 and sulphonylureas. The decrease of viable cell numbers observed with glibenclamide was reversed by co-culture with metformin, but cellular insulin content was depressed. Conclusions: The results suggest that metformin can prevent the aspects of sulphonylurea-induced beta-cell desensitization. © 2010 Blackwell Publishing Ltd.

Interpreting adverse signals in diabetes drug development programs

Detection and interpretation of adverse signals during preclinical and clinical stages of drug development inform the benefit-risk assessment that determines suitability for use in real-world situations. This review considers some recent signals associated with diabetes therapies, illustrating the difficulties in ascribing causality and evaluating absolute risk, predictability, prevention, and containment. Individual clinical trials are necessarily restricted for patient selection, number, and duration; they can introduce allocation and ascertainment bias and they often rely on biomarkers to estimate long-term clinical outcomes. In diabetes, the risk perspective is inevitably confounded by emergent comorbid conditions and potential interactions that limit therapeutic choice, hence the need for new therapies and better use of existing therapies to address the consequences of protracted glucotoxicity. However, for some therapies, the adverse effects may take several years to emerge, and it is evident that faint initial signals under trial conditions cannot be expected to foretell all eventualities. Thus, as information and experience accumulate with time, it should be accepted that benefit-risk deliberations will be refined, and adjustments to prescribing indications may become appropriate. © 2013 by the American Diabetes Association.

A comparison of the effects of ocular preservatives on mammalian and microbial ATP and glutathione levels

The aim of this study was to investigate the mechanism of action of the preservative sodium chlorite (NaClO2), and the relationship with intracellular glutathione depletion. A detailed comparison of the dose responses of two cultured ocular epithelial cell types and four species of microorganism was carried out, and comparisons were also made with the quaternary ammonium compound benzalkonium chloride (BAK), and the oxidant hydrogen peroxide (H2O2). The viability of mammalian and microbial cells was assessed in the same way, by the measurement of intracellular ATP using a bioluminescence method. Intracellular total glutathione was measured by reaction with 5,5'-dithiobis-2-nitrobenzoic acid in a glutathione reductase-dependent recycling assay. BAK and H2O2 caused complete toxicity to conjunctival and corneal epithelial cells at similar to25 ppm, in contrast to NaClO2 , where >100 ppm was required. The fungi Candida albicans and Alternaria alternata had a higher resistance to NaClO2 than the bacteria Staphyloccus aureus and Pseudomonas aeruginosa , but the bacteria were extremely resistant to H2O2 NaClO2 caused substantial depletion of intracellular glutathione in all cell types, at concentrations ranging from <10 ppm in Pseudomonas , 25-100 ppm in epithelial cells, to >500 ppm in fungal cells. The mechanisms of cytotoxicity of NaClO2 , H2O2 and BAK all appeared to differ. NaClO2 was found to have the best balance of high antibacterial toxicity with low ocular toxicity. The lower toxicity of NaClO2 to the ocular cells, compared with BAK and H2O2 , is in agreement with fewer reported adverse effects of application in the eye.

What one hand giveth the other taketh away:some unpredicted effects of enantiomers in psychopharmacology

It is well known that many medicines are a mixture of two enantiomers, or mirror-image molecules. Two enantiomers occur when a molecule has a single chiral centre and the two mirror images, called S or L (left handed) and R or D (right handed), are usually found in equal amounts in the parent (racemic) mixture. While for many compounds used in clinical practice the active moiety is found in one of the two enantiomers with the other being seen as an unnecessary and redundant component of the racemic mixture, the difference between enantiomers can mean a difference between therapeutic and adverse effects, as well as in beneficial pharmacological effect and potency. © 2010 The Author(s).

Disorienting Dilemmas: Their Effects on Learners, Impact on Performance, and Implications for Adult Educators

Disorienting dilemmas induced by adult educators have varied and often adverse effects on learners. Although this may lead to transformative learning, it can have both positive and negative impacts on their performance. Adult educators need to be wary in their efforts to foster and facilitate transformative learning.

Data compilation on the biological response to ocean acidification: environmental and experimental context of data sets and related literature

The exponential growth of studies on the biological response to ocean acidification over the last few decades has generated a large amount of data. To facilitate data comparison, a data compilation hosted at the data publisher PANGAEA was initiated in 2008 and is updated on a regular basis (doi:10.1594/PANGAEA.149999). By January 2015, a total of 581 data sets (over 4 000 000 data points) from 539 papers had been archived. Here we present the developments of this data compilation five years since its first description by Nisumaa et al. (2010). Most of study sites from which data archived are still in the Northern Hemisphere and the number of archived data from studies from the Southern Hemisphere and polar oceans are still relatively low. Data from 60 studies that investigated the response of a mix of organisms or natural communities were all added after 2010, indicating a welcomed shift from the study of individual organisms to communities and ecosystems. The initial imbalance of considerably more data archived on calcification and primary production than on other processes has improved. There is also a clear tendency towards more data archived from multifactorial studies after 2010. For easier and more effective access to ocean acidification data, the ocean acidification community is strongly encouraged to contribute to the data archiving effort, and help develop standard vocabularies describing the variables and define best practices for archiving ocean acidification data.

Self-titration by experienced e-cigarette users: blood nicotine delivery and subjective effects

Rationale Self-titration is well documented in the tobacco literature. The extent to which ecigarette users (vapers) self-titrate is unknown. Objective This study explored the effects of high and low nicotine strength liquid on puffing topography, nicotine delivery and subjective effects in experienced vapers. Methods Eleven experienced male vapers completed 60 minutes of ad libitum vaping under low (6 mg/mL) and high (24 mg/mL) nicotine liquid conditions in two separate sessions. Measurements included: puffing topography (puff number, puff duration, volume of liquid consumed); and changes in: plasma nicotine levels, craving, withdrawal symptoms, selfreported hit, satisfaction and adverse effects. Results Liquid consumption and puff number were higher, and puff duration longer, in the low nicotine strength condition (all ps < 0.01). The mean difference in nicotine boost from baseline in the low condition was 8.59 (7.52) ng/mL, 16.99 (11.72) ng/mL and 22.03 (16.19) ng/mL at 10, 30 and 60 minutes respectively. Corresponding values for the high condition were 33.77 (34.88) ng/mL, 35.48 (28.31) ng/mL and 43.57 (34.78) ng/mL (ps < 0.05). There were no statistically significant differences between conditions in self-reported craving, withdrawal symptoms, satisfaction, hit or adverse effects. Conclusions Vapers engaged in compensatory puffing with lower nicotine strength liquid, doubling their consumption. Whilst compensatory puffing was sufficient to reduce craving and withdrawal discomfort, self-titration was incomplete with significantly higher plasma nicotine levels in the high condition.

Microplastics in sediments: A review of techniques, occurrence and effects

Microplastics are omnipresent in the marine environment and sediments are hypothesized to be major sinks of these plastics. Here, over 100 articles spanning the last 50 year are reviewed with following objectives: (i) to evaluate current microplastic extraction techniques, (ii) to discuss the occurrence and worldwide distribution of microplastics in sediments, and (iii) to make a comprehensive assessment of the possible adverse effects of this type of pollution to marine organisms. Based on this review we propose future research needs and conclude that there is a clear need for a standardized techniques, unified reporting units and more realistic effect assessments.

Mineral and organic pollution in river Sabor (Northeastern Portugal): ecotoxicological effects on freshwater fauna

Aquatic ecosystems are final collectors of all kinds of pollution as an outcome of anthropogenic inputs, such us untreated industrial and municipal sewage and agricultural pollutants. There are several aquatic ecosystems that are threatened by mineral and organic pollution. In Northeastern Portugal, near Bragança, different watercourses are suffering negative impacts of human activities. It has been developed several studies in the monitoring of environmental impacts in these river basins, namely in Rio Fervença, affected by organic pollution, and in Portelo stream, affected, since 2009, by the collapse and continuous input of mining deposits. In this sense, the present study aimed to continue the monitoring study of ecological status of freshwater ecosystems of Northeastern Portugal, namely the following objectives: a) mineral pollution effects of mining deposits sudden incorporated into Portelo stream; b) organic pollution due to domestic and industrial inputs in River Fervença. Also, since fish are useful experimental models to evaluate toxicological mechanisms of contaminants, c) acute toxicity tests with Cu were conducted in laboratory conditions. During 2015/2016, it was made abiotic and biotic characterization of 16 sampling sites distributed by both Portelo and Fervença rivers, tributaries of main River Sabor (Douro Basin). Several physicochemical parameters were determined and Riparian Quality (QBR Index) and Channel Quality (GQC) Indexes were determined for habitat evaluation. Fish and invertebrate communities were sampled, according to protocols of Water Framework Directive (WFD). Several metrics were determined, with particular emphasis on the Biotic Index IBMWP and the Northern Portuguese Invertebrate Index (IPtIN). Acute toxicity tests were conducted with an Iberian fish species, common barbel (Luciobarbus bocagei) and some plasmatic electrolytes levels were evaluated, to assess their contribution to mitigate osmoregulatory adverse effects of Cu. Also, same electrolytes were measured after changing to clean water, in attempt to assess fish capacity to reverse this situation. Results obtained for both rivers showed a significant level of disturbance that affected decisively water, habitat and biological quality of aquatic ecosystems. Mineral and Organic Pollution in River Sabor (NE Portugal): Ecotoxicological Effects on Freshwater Fauna Due to this change of environmental conditions in Portelo stream (extreme pH values, high conductivity and presence of heavy metals), several biological metrics (e.g. taxonomic richness, abundance, diversity, evenness) confirmed, comparatively with reference sites, a substantial decrease on ecological integrity status. The same pattern was found for Fervença River; however other water parameters, namely the content of most limiting nutrients (e.g. N and P) seemed to have more influence in the composition and structure of macroinvertebrate and fish communities. In fact, despite the operation of the Sewage Treatment Plant of Bragança, Fervença River presented significant levels of disturbance that affected decisively the quality and ecological integrity of the aquatic ecosystem. The synergic effect of domestic and industrial pollution, intensive agriculture, regulation and degradation of aquatic and riparian habitats contributed to the decrease of ecological condition, namely in the downstream zones (after Bragança). The results for acute toxicity, showed that fish can change Na+ and K+ levels face to Cu exposition and, depending of Cu concentration tested, can also return to normal levels, providing some insights to that are believed to occurred in fish population, near the Portelo mines. The low ecological integrity status detected in the lotic ecosystems in NE Portugal as a result of mineral and organic pollution deserves the development of several measures for rehabilitation and improving of water quality. On the other hand, environmental education actions are needed to contribute to improvement of ecological integrity of the river and its conservation.

Quantification of air quality in space and time and its effects on health

The long-term adverse effects on health associated with air pollution exposure can be estimated using either cohort or spatio-temporal ecological designs. In a cohort study, the health status of a cohort of people are assessed periodically over a number of years, and then related to estimated ambient pollution concentrations in the cities in which they live. However, such cohort studies are expensive and time consuming to implement, due to the long-term follow up required for the cohort. Therefore, spatio-temporal ecological studies are also being used to estimate the long-term health effects of air pollution as they are easy to implement due to the routine availability of the required data. Spatio-temporal ecological studies estimate the health impact of air pollution by utilising geographical and temporal contrasts in air pollution and disease risk across $n$ contiguous small-areas, such as census tracts or electoral wards, for multiple time periods. The disease data are counts of the numbers of disease cases occurring in each areal unit and time period, and thus Poisson log-linear models are typically used for the analysis. The linear predictor includes pollutant concentrations and known confounders such as socio-economic deprivation. However, as the disease data typically contain residual spatial or spatio-temporal autocorrelation after the covariate effects have been accounted for, these known covariates are augmented by a set of random effects. One key problem in these studies is estimating spatially representative pollution concentrations in each areal which are typically estimated by applying Kriging to data from a sparse monitoring network, or by computing averages over modelled concentrations (grid level) from an atmospheric dispersion model. The aim of this thesis is to investigate the health effects of long-term exposure to Nitrogen Dioxide (NO2) and Particular matter (PM10) in mainland Scotland, UK. In order to have an initial impression about the air pollution health effects in mainland Scotland, chapter 3 presents a standard epidemiological study using a benchmark method. The remaining main chapters (4, 5, 6) cover the main methodological focus in this thesis which has been threefold: (i) how to better estimate pollution by developing a multivariate spatio-temporal fusion model that relates monitored and modelled pollution data over space, time and pollutant; (ii) how to simultaneously estimate the joint effects of multiple pollutants; and (iii) how to allow for the uncertainty in the estimated pollution concentrations when estimating their health effects. Specifically, chapters 4 and 5 are developed to achieve (i), while chapter 6 focuses on (ii) and (iii). In chapter 4, I propose an integrated model for estimating the long-term health effects of NO2, that fuses modelled and measured pollution data to provide improved predictions of areal level pollution concentrations and hence health effects. The air pollution fusion model proposed is a Bayesian space-time linear regression model for relating the measured concentrations to the modelled concentrations for a single pollutant, whilst allowing for additional covariate information such as site type (e.g. roadside, rural, etc) and temperature. However, it is known that some pollutants might be correlated because they may be generated by common processes or be driven by similar factors such as meteorology. The correlation between pollutants can help to predict one pollutant by borrowing strength from the others. Therefore, in chapter 5, I propose a multi-pollutant model which is a multivariate spatio-temporal fusion model that extends the single pollutant model in chapter 4, which relates monitored and modelled pollution data over space, time and pollutant to predict pollution across mainland Scotland. Considering that we are exposed to multiple pollutants simultaneously because the air we breathe contains a complex mixture of particle and gas phase pollutants, the health effects of exposure to multiple pollutants have been investigated in chapter 6. Therefore, this is a natural extension to the single pollutant health effects in chapter 4. Given NO2 and PM10 are highly correlated (multicollinearity issue) in my data, I first propose a temporally-varying linear model to regress one pollutant (e.g. NO2) against another (e.g. PM10) and then use the residuals in the disease model as well as PM10, thus investigating the health effects of exposure to both pollutants simultaneously. Another issue considered in chapter 6 is to allow for the uncertainty in the estimated pollution concentrations when estimating their health effects. There are in total four approaches being developed to adjust the exposure uncertainty. Finally, chapter 7 summarises the work contained within this thesis and discusses the implications for future research.

The real effects of banking supervision:evidence from enforcement actions

We present a novel way to examine macro-financial linkages by focusing on the real effects of bank supervisors’ enforcement actions. Exploiting plausibly exogenous variation in supervisory monitoring intensity, we show that enforcement actions in single-market banks trigger temporarily large adverse effects for the macroeconomy by reducing personal income growth, the number of establishments, and increasing unemployment. These effects are related to contractions in bank lending and liquidity creation, and are more pronounced when we consider enforcement actions on both single-market and multi-market banks, and in counties with fewer banks and greater external financial dependence.

Effects of allelopathic compounds produced by native and invasive marine macroalgae on the associated communities

In this study, the production of bioactive secondary metabolites called "allelochemicals" by algae has been investigated, specifically focusing on polyunsaturated aldehydes (PUAs). PUAs are known to have adverse effects on planktonic grazers and on phytoplankton; however, their effect on benthic communities has been poorly studied. Macroalgae are ecosystem engineers that play an important role in the structure of the habitat and associated communities, presenting a great variability in their morphology and structural complexity, which is a primary factor in the structuring of associated communities. In recent decades, it has been seen how the introduction of invasive species can modify the benthic habitat structure, causing cascading effects on the trophic chain. The thesis includes several field and laboratory studies. Field studies examined aldehyde production by native and invasive macroalgal species (Sargassum muticum, in the Adriatic Sea, and Rugulopterix okamurae in the Strait of Gibraltar), their structural complexity, together with their associated phyto and meiobenthos. Two laboratory studies were conducted. The first one, based on microcosms experiments, evaluated the effect of PUA (produced by the diatom Skeletonema marinoi, or as decadienal analytical standard) on meiofauna. The second one evaluated the inhibitory effect of dilkamural, an allelopathic compound isolated from R. okamurae, on unicellular phototrophs. Our results showed that PUAs produced by macroalgae were species-specific and had a significant impact on the benthic community. The morphology of macroalgae was an important factor in shaping associated communities, particularly for microphytobenthos. Invasive species, such as S. muticum and R. okamurae, could reduce the biodiversity of native benthic communities and simplify the habitat. Dilkamural was hypothesized to be an allelochemical defense, and laboratory toxicity tests confirmed this hypothesis. Overall, this thesis sheds light on the importance of allelochemicals and macroalgal structural complexity in the benthic environment and highlights the potential impact of invasive species.

The Consequences Of Refractory Epilepsy And Its Treatment.

Seizures in some 30% to 40% of patients with epilepsy fail to respond to antiepileptic drugs or other treatments. While much has been made of the risks of new drug therapies, not enough attention has been given to the risks of uncontrolled and progressive epilepsy. This critical review summarizes known risks associated with refractory epilepsy, provides practical clinical recommendations, and indicates areas for future research. Eight international epilepsy experts from Europe, the United States, and South America met on May 4, 2013, to present, review, and discuss relevant concepts, data, and literature on the consequences of refractory epilepsy. While patients with refractory epilepsy represent the minority of the population with epilepsy, they require the overwhelming majority of time, effort, and focus from treating physicians. They also represent the greatest economic and psychosocial burdens. Diagnostic procedures and medical/surgical treatments are not without risks. Overlooked, however, is that these risks are usually smaller than the risks of long-term, uncontrolled seizures. Refractory epilepsy may be progressive, carrying risks of structural damage to the brain and nervous system, comorbidities (osteoporosis, fractures), and increased mortality (from suicide, accidents, sudden unexpected death in epilepsy, pneumonia, vascular disease), as well as psychological (depression, anxiety), educational, social (stigma, driving), and vocational consequences. Adding to this burden is neuropsychiatric impairment caused by underlying epileptogenic processes (essential comorbidities), which appears to be independent of the effects of ongoing seizures themselves. Tolerating persistent seizures or chronic medicinal adverse effects has risks and consequences that often outweigh risks of seemingly more aggressive treatments. Future research should focus not only on controlling seizures but also on preventing these consequences.