The macro-eco-evolutionary interplay between dispersal, competition and landscape structure in generating biodiversity.

Theory links dispersal and diversity, predicting the highest diversity at intermediate dispersal levels. However, the modulation of this relationship by macro-eco-evolutionary mechanisms and competition within a landscape is still elusive. We examine the interplay between dispersal, competition and landscape structure in shaping biodiversity over 5 million years in a dynamic archipelago landscape. We model allopatric speciation, temperature niche, dispersal, competition, trait evolution and trade-offs between competitive and dispersal traits. Depending on dispersal abilities and their interaction with landscape structure, our archipelago exhibits two 'connectivity regimes', that foster speciation events among the same group of islands. Peaks of diversity (i.e. alpha, gamma and phylogenetic), occurred at intermediate dispersal; while competition shifted diversity peaks towards higher dispersal values for each connectivity regime. This shift demonstrates how competition can boost allopatric speciation events through the evolution of thermal specialists, ultimately limiting geographical ranges. Even in a simple landscape, multiple intermediate dispersal diversity relationships emerged, all shaped similarly and according to dispersal and competition strength. Our findings remain valid as dispersal- and competitive-related traits evolve and trade-off; potentially leaving identifiable biodiversity signatures, particularly when trade-offs are imposed. Overall, we scrutinize the convoluted relationships between dispersal, species interactions and landscape structure on macro-eco-evolutionary processes, with lasting imprints on biodiversity.This article is part of the theme issue 'Diversity-dependence of dispersal: interspecific interactions determine spatial dynamics'.

Pharmacotherapy of Opioid Addiction: "Putting a Real Face on a False Demon".

Methadone maintenance therapy (MMT), a pharmacological treatment for opioid use disorder for the past 50 years, continues to remain controversial. Despite consistent and overwhelming evidence confirming the effectiveness and safety of MMT, misconceptions and myths persist regarding its legitimacy as a treatment for opioid addiction. This often results in the underutilization and limited availability of this treatment modality. Despite successful outcomes, the controversial nature of MMT, and the stigma experienced by the patients on methadone, has been a particularly difficult obstacle to overcome. We present the history of MMT, review the evidence for its efficacy in the treatment of opioid dependence, and explore the origins of the stigma and misconceptions related to MMT.

Extracorporeal Membrane Oxygenation (ECMO) for Severe Toxicological Exposures: Review of the Toxicology Investigators Consortium (ToxIC).

Although there have been many developments related to specific strategies for treating patients after poisoning exposures, the mainstay of therapy remains symptomatic and supportive care. One of the most aggressive supportive modalities is extracorporeal membrane oxygenation (ECMO). Our goal was to describe the use of ECMO for toxicological exposures reported to the American College of Medical Toxicology (ACMT) Toxicology Investigators Consortium (ToxIC). We performed a retrospective review of the ACMT ToxIC Registry from January 1, 2010 to December 31, 2013. Inclusion criteria included patients aged 0 to 89 years, evaluated between January 2010 through December 2013, and received ECMO for toxicological exposure. There were 26,271 exposures (60 % female) reported to the ToxIC Registry, 10 (0.0004 %) received ECMO: 4 pediatric (< 12 years), 2 adolescent (12-18 years), and 4 adults (>18 years). Time of initiation of ECMO ranged from 4 h to 4 days, with duration from 15 h to 12 days. Exposures included carbon monoxide/smoke inhalation (2), bitter almonds, methanol, and several medications including antihistamines (2), antipsychotic/antidepressant (2), cardiovascular drugs (2), analgesics (2), sedative/hypnotics (2), and antidiabetics (2). Four ECMO patients received cardiopulmonary resuscitation (CPR) during their hospital course, and the overall survival rate was 80 %. ECMO was rarely used for poisoning exposures in the ACMT ToxIC Registry. ECMO was utilized for a variety of ages and for pharmaceutical and non-pharmaceutical exposures. In most cases, ECMO was administered prior to cardiovascular failure, and survival rate was high. If available, ECMO may be a valid treatment modality.

Cardiac conduction disturbance after loperamide abuse.

CONTEXT: Prescription opioid abuse is a major public health concern and an ongoing epidemic in the United States. Loperamide is a widely available and inexpensive over-the-counter antidiarrheal with peripheral mu-opioid receptor activity. Online resources discuss the use of loperamide for the amelioration of withdrawal symptoms or recreational abuse. We describe the clinical course of 5 patients abusing loperamide, 3 of whom had life-threatening cardiac arrhythmias. METHODS: In this observational case series, patients with cardiac arrhythmias or history of loperamide abuse with cardiac arrhythmias were identified; 5 patients were identified and 4 of the 5 patients were seen directly at the bedside. Clinical profile and outcome of patients is reported. RESULTS: We report 5 patients with history of loperamide abuse; 3 of the 5 patients had life-threatening cardiac arrhythmias. One of the patients experienced a second life-threatening arrhythmia after he resumed loperamide abuse. Loperamide levels were obtained in 4 of the 5 patients and were at least one order of magnitude greater than therapeutic concentrations. Discontinuation of loperamide resulted in complete resolution of cardiac conduction disturbances. CONCLUSION: This case series describes several patients with cardiac conduction abnormalities and life-threatening ventricular arrhythmias temporally related to loperamide abuse. With the recent efforts to restrict the diversion of prescription opioids, increasing abuse of loperamide as an opioid substitute may be seen. Toxicologists should be aware of these risks and we urge all clinicians to report such cases to FDA Medwatch(®).

Prolonged lipemia and pancreatitis due to extended infusion of lipid emulsion in bupropion overdose.

BACKGROUND: Lipid emulsion is gaining popularity as an antidote for lipophilic drug overdose, and is generally considered safe at doses recommended for antidotal therapy. We report a case of asymptomatic pancreatitis following extended infusion lipid emulsion. CASE REPORT: A 14-year-old female presented to the emergency department actively seizing after ingesting 9 g of bupropion and unknown amounts of hydroxyzine and citalopram. She was intubated for airway protection, and gastrointestinal decontamination was performed with activated charcoal. She was treated with potassium and magnesium for a prolonged QT interval and sodium bicarbonate for metabolic acidosis and QRS complex widening. Upon transfer to the pediatric intensive care unit, she seized again, became hypotensive, and developed a junctional cardiac rhythm. A lipid emulsion bolus was recommended which improved her hypotension and conduction abnormalities. The lipid emulsion was continued for several hours and she received a total dose of 46 mL/kg in less than 12 h. She developed lipemia, which interfered with laboratory analysis, a severe elevation in her triglycerides, as well as a mild pancreatitis that resolved over several days, although she was asymptomatic. CASE DISCUSSION: Large doses of lipid emulsion may result in lipemia, severe hypertriglyceridemia, interference in laboratory analyses, and pancreatitis. This is the third reported adverse event due to lipid emulsion therapy used for overdose.

Monitoring the international use of unrelated donors for transplantation: the WMDA annual reports.

The World Marrow Donor Association Annual Reports describe the current status of the use of unrelated hematopoietic cell products worldwide. In 2008, almost 1.7 million individuals were recruited into unrelated stem cell donor registries and almost 78 000 cord blood units were added to the inventory increasing the total number of available stem cell donors worldwide to over 14 million. In 2008, there were 10 481 adult stem cell donations (3221 BM and 7260 PBSC donations) provided from stem cell donor registries in 38 countries. In 2008, 3529 cord blood products were provided from 21 countries. Although the number of BM donations has been stable over the past 10 years, donations of PBSCs and umbilical cord blood are increasing.

Intravitreal bevacizumab (Avastin) treatment of choroidal neovascularisation in patients with angioid streaks.

OBJECTIVE: To evaluate the safety and efficacy of intravitreal bevacizumab (Avastin) as treatment for choroidal neovascularisation (CNV) associated with angioid streaks METHODS: A non-randomised, interventional case series conducted on eyes with subfoveal CNV associated with angioid streaks. Intravitreal bevacizumab (1.25 mg in 0.05 ml) was injected into nine eyes of six patients between August 2005 and December 2007. Treatment efficacy was assessed based on pre- and post-treatment visual acuity and optical coherence tomography (OCT). RESULTS: With a mean follow-up of 19 months (range 10 to 28 months), the best corrected visual acuity improved by three or more lines in four eyes (44.4%), remained within two lines of baseline in four eyes (44.4%) and decreased by three or more lines in one eye (11.1%). Central foveal thickness (CFT) measured by OCT decreased an average of 67.7 microm (range +11 to -175 microm) with an average improvement in standardised change in macular thickening of 46.6% (range -12% to +84.5%). No injection-related complications or drug-related side effects were observed. CONCLUSIONS: Intravitreal bevacizumab for the treatment of subfoveal CNV secondary to angioid streaks mildly reduced central foveal thickness with a trend toward stabilisation of visual acuity. Additional follow-up and a larger patient cohort are needed to evaluate the long-term effects of this treatment.

Small-scale spatial structure within patterns of seed dispersal.

A large proportion of dispersing propagules land near their maternal plant, even in species that have evolved structures which enhance dispersal. For these propagules, their post-dispersal spatial pattern is likely to reflect the overall shape and scale of the parental plant canopy and, especially in poorly dispersing species, aggregation of propagules on the plant prior to dispersal. Localised patterns within seed shadows are also likely to be affected by secondary movement after dispersal, leading to either more or less small-scale aggregation, depending on the mechanism. Our general aim was to study the small-scale spatial structure within patterns of seed dispersal of Raphanus raphanistrum L. to generate hypotheses about the sequence of processes and events leading to the spatial pattern of dispersal in this species. More specifically, we determined the sizes of small-scale structures within the seed shadows on the ground after dispersal and the extent to which these match the sizes of pre-dispersal aggregations within the parental canopy. Variation in plant size and shape was provided by four levels of inter-specific competition resulting from differing wheat crop densities. Positions of propagules were determined using a three-dimensional digitizer, and the data for each plant were analysed using point pattern analysis. Not surprisingly, larger plants, growing at lower plant density, had larger seed shadows, showing an overall influence of maternal plant size. The pattern of propagules exhibited significant small-scale aggregates, with similar sizes on the plant and on the ground. There was no evidence that aggregation size was greater on the ground or increased with time, but the strength of the aggregation increased with length of time on the ground.

Detailed assessment of microhabitat suitability for Aedes aegypti (Diptera: Culicidae) in Buenos Aires, Argentina.

Little information is available on the ecology of Aedes aegypti Linnaeus at the southern extreme of its distribution (Buenos Aires, Argentina), particularly on microhabitat suitability. The aim of our study was to identify at a detailed scale, microhabitat factors that correlate with the presence of preimaginal stages of the mosquito. In March 2001, we performed a spatial census of all containers located in a 1 ha patch within a cemetery in Buenos Aires City. On a reference map (1:700) we plotted the position of graves and surrounding corridors, the location of containers, the shade projected by each plant between 10:00 and 16:00 h and vegetation cover. We classified vegetation by height, substrate by composition and shadow by level of exposure to sunlight. We performed univariate and multivariate logistic regression analyses with nine constructed independent variables, some of them at scales of 0.5, 1, 2, 3, and 10 m. Of 850 receptacles examined, 101 contained preimaginal stages of Ae. aegypti. Level of exposure to sunlight, type of substratum, vegetation height and distance of containers to vegetation were significantly associated with the presence of breeding sites at the studied scales. Final multivariate models were significant at scales of 2 m (chi(3)2=25.693, p<0.001) and 3m (chi(3)2=26.440, p<0.001), and 65.9 and 66.8% of our data were correctly classified, respectively, for each scale. Our results suggest that sites less exposed to sunlight, with taller and closer vegetation, and in shaded and vegetated neighbourhoods were the most favourable microhabitats for Ae. aegypti breeding.

A special report: suggested procedures for international unrelated donor search from the donor registries and quality assurance working groups of the World Marrow Donor Association (WMDA).

This special report details the World Marrow Donor Association's recommended procedures regarding the international search for an unrelated donor for hematopoietic stem cell transplantation. The responsibilities of the national hubs, transplant center and donor registry staff are outlined for all actions associated with the preliminary search, formal search, donor confirmatory typing and final donor selection.

Population dynamics, disturbance, and pattern evolution: identifying the fundamental scales of organization in a model ecosystem.

We used auto- and cross-correlation analysis and Ripley's K-function analysis to analyze spatiotemporal pattern evolution in a spatially explicit simulation model of a semiarid shrubland (Karoo, South Africa) and to determine the impact of small-scale disturbances on system dynamics. Without disturnities bance, local dynamics were driven by a pattern of cyclic succession, where 'colonizer' and 'successor' species alternately replaced each other. This results in a strong pattern of negative correlation in the temporal distribution of colonizer and successor species. As disturbance rates were increased, the relationship shifted from being negatively correlated in time to being positively correlated-the dynamics became decoupled from the ecologically driven cyclic succession and were increasingly influenced by abiotic factors (e.g., rainfall events). Further analysis of the spatial relationships among colonizer and successor species showed that, without disturbance, periods of attraction and repulsion between colonizer and successor species alternate cyclically at intermediate spatial scales. This was due to the spatial 'memory' embedded in the system through the process of cyclic succession. With the addition of disturbance, this pattern breaks down, although there is some indication of increasing ecological organization at broader spatial scales. We suggest that many of the insights that can be gained through spatially explicit models will only be obtained through a direct analysis of the spatial patterns produced.

Selection of RNA amide synthases.

BACKGROUND: It is generally accepted that, during evolution, replicating RNA molecules emerged from pools of random polynucleotides. This prebiotic RNA world was followed by an era of RNA-mediated catalysis of amide-bond formation. RNA would thus have provided the machinery responsible for the assembly of peptides and the beginning of the protein world of today. Naturally occurring ribozymes, which catalyze the cleavage or ligation of oligonucleotide phosphodiester bonds, support the idea that RNA could self-replicate. But was RNA constrained to this path and were RNA-acylated carriers required before RNA could catalyze the formation of amide bonds? RESULTS: We have isolated RNA catalysts that are capable of mediating amide-bond synthesis without the need for specifically designed templates to align the substrates, and we have kinetically characterized these catalysts. The rate enhancement observed for these RNA amide synthases exceeds the noncatalyzed amidation rate by a factor of approximately 10(4). In addition, Cu2+ ions caused a change in the affinity of RNA for the substrate rather than being directly involved in amide-bond formation. CONCLUSIONS: The discovery of these new amide synthases shows how functionally modified nucleic acids can facilitate covalent-bond formation without templating. Previously unforeseen RNA-evolution pathways can, therefore, be considered; for example, to guide amide-bond formation, en route to the protein world, it appears that substrate-binding pockets were formed that are analogous to those of protein enzymes.

Probed-sinewave paradigm: a test of models of light-adaptation dynamics.

Studies of light adaptation have, in general, employed either aperiodic or periodic stimuli. In earlier work, models originally developed to predict the results from one tradition failed to predict results from the other but the models from the two traditions could be merged to predict phenomena from both. To further test these merged models, a paradigm combining both types of stimuli was used. The threshold for a brief flash (the probe) was measured at various phases on a background that was varied sinusoidally in time. The probe threshold depends upon the phase at which it is presented for all background frequencies used, 0-16 Hz. These threshold variations are not well described by a sinewave; the peak threshold is > 180 deg out of phase with the trough threshold. Further, the positions of the peaks and troughs shift fairly abruptly at background modulations of 4-8 Hz. The difference between the peak and trough thresholds varies as a function of temporal frequency in a manner approximating the temporal contrast sensitivity function. The dc level (mean threshold) does not. The peak-trough difference dominates at low frequencies of background modulation, while the dc level dominates for higher frequencies. Existing models of light adaptation do not predict the key features of the data.

Donor work-up and transport of bone marrow--recommendations and requirements for a standardized practice throughout the world from the Donor Registries and Quality Assurance Working Groups of the World Marrow Donor Association (WMDA).

In October 1995 the World Marrow Donor Association (WMDA) was restructured in order to facilitate its primary function of establishing guidelines in relation to international bone marrow and blood stem cell transplants -- transplants in which the donor is in one country and the patient is in another country. Five new working groups were established -- Donor Registries, Ethics, Quality Assurance, Finances, and Stem Cells. This paper, prepared by members of the Donor Registries Working Group, in consultation with the Quality Assurance Working Group, provides recommendations for the 'donor work-up'. This term covers events that start when the definitive donor has been identified, includes the harvesting (collection) and transportation of the stem cell product and ends when the product reaches the transplant centre. The paper includes examples of the documentation intended to ensure compliance with the recommendations at all key points in the sequence.

High-affinity oligonucleotide ligands to human IgE inhibit binding to Fc epsilon receptor I.

Using the systematic evolution of ligands by exponential enrichment (SELEX) method, we have identified oligonucleotides that bind to human IgE with high affinities and high specificity. These ligands were isolated from three pools of oligonucleotides, each representing 10(15) molecules: two pools contained 2'-NH2 pyrimidine-modified RNA with either 40 or 60 randomized sequence positions, and the third pool contained ssDNA with 40 randomized sequence positions. Based on sequence and structure similarities, these oligonucleotide IgE ligands were grouped into three families: 2'-NH2 RNA group A ligands are represented by the 35-nucleotide truncate IGEL1.2 (Kd = 30 nM); 2'-NH2 RNA group B ligands by the 25-nucleotide truncate IGEL2.2 (Kd = 35 nM); and the ssDNA group ligands by the 37-nucleotide truncate DI 7.4 (Kd = 10nM). Secondary structure analysis suggests G quartets for the 2'-NH2 RNA ligands, whereas the ssDNA ligands appear to form stem-loop structures. Using rat basophilic leukemia cells transfected with the human high-affinity IgE receptor Fc epsilon RI, we demonstrate that ligands IGEL1.2 and D17.4 competitively inhibit the interaction of human IgE with Fc1 epsilon RI. Furthermore, this inhibition is sufficient to dose-dependently block IgE-mediated serotonin release from cells triggered with IgE-specific Ag or anti-IgE Abs. Therefore, these oligonucleotide ligands represent a novel class of IgE inhibitors that may prove useful in the fight against allergic diseases.

Testing a computational model of light-adaptation dynamics.

Experiments from the periodic and aperiodic traditions were used to guide the development of a quantitatively valid model of light adaptation dynamics. Temporal contrast sensitivity data were collected over a range of 3 log units of mean luminance for sinusoids of 2 to 50 Hz. Probe thresholds on flashed backgrounds were collected over a range of stimulus-onset asynchronies and background intensities from 0.1 to 1000 td. All experiments were performed foveally in the photopic range and used a consistent stimulus paradigm and psychophysical method. The resulting model represents a merging of elements from both traditions, and consists of a frequency-dependent front-end followed by a subtractive process and static nonlinearity.

Interaction of Tn5 transposase with the transposon termini.

Transposition of Tn5 requires the binding of the transposase protein to the transposon outside end (OE) DNA sequences. Transposase mutants that increase the transposition frequency result in the formation of two distinct transposase/OE DNA complexes, observed by gel retardation analysis. The slower migrating complex I, also formed by wild-type transposase, contains protein oligomers of transposase and transposase related proteins. The faster migrating, novel complex II is caused by the binding of monomeric, proteolytic transposase fragments gamma and delta that have lost the carboxy-terminus of the protein. Transposase gamma and delta bind OE DNA with a high apparent affinity but are unable to promote transposition in vivo. We propose that the transposase protein is functionally unstable and can undergo a conformational change that reduces the activity but protects the protein from proteolysis. The transposase mutants favor the more active but proteolytically hypersensitive protein conformation.

Characterization of the Tn5 transposase and inhibitor proteins: a model for the inhibition of transposition.

Tn5 is a composite transposon consisting of two IS50 sequences in inverted orientation with respect to a unique, central region encoding several antibiotic resistances. The IS50R element encodes two proteins in the same reading frame which regulate the transposition reaction: the transposase (Tnp), which is required for transposition, and an inhibitor of transposition (Inh). The inhibitor is a naturally occurring deletion variant of Tnp which lacks the N-terminal 55 amino acids. In this report, we present the purification of both the Tnp and Inh proteins and an analysis of their DNA binding properties. Purified Tnp, but not Inh, was found to bind specifically to the outside end of Tn5. Inh, however, stimulated the binding activity of Tnp to outside-end DNA and was shown to be present with Tnp in these bound complexes. Inh was also found to exist as a dimer in solution. These results indicate that the N-terminal 55 amino acids of Tnp are required for sequence-specific binding. They also suggest that Inh inhibits transposition by forming mixed oligomers with Tnp which still bind to the ends of the transposon but are defective for later stages of the transposition reaction.

Characterization of two hypertransposing Tn5 mutants.

Transposition of Tn5 in Escherichia coli is regulated by two transposon-encoded proteins: transposase (Tnp), promoting transposition preferentially in cis, and the trans-acting inhibitor (Inh). Two separate transposase mutants were isolated that replace glutamate with lysine at position 110 (EK110) and at position 345 (EK345). The EK transposase proteins increase the Tn5 transposition frequency 6- to 16-fold in cis and enhance the ability of transposase to act in trans. The purified mutant transposase proteins interact with transposon outside end DNA differently from the wild-type protein, resulting in the formation of a novel complex in gel retardation assays. During characterization of the transposase proteins in the absence of inhibitor, we found that wild-type transposase itself has a transposition-inhibiting function and that this inhibition is reduced for the mutant proteins. We present a model for the regulation of Tn5 transposition, which proposes the existence of two transposase species, one cis-activating and the other trans-inhibiting. The phenotype of the EK transposase mutants can be explained by a shift in the ratio of these two species.