Immunotoxic effects of environmental toxicants in fish - how to assess them?

Numerous environmental chemicals, both long-known toxicants such as persistent organic pollutants as well as emerging contaminants such as pharmaceuticals, are known to modulate immune parameters of wildlife species, what can have adverse consequences for the fitness of individuals including their capability to resist pathogen infections. Despite frequent field observations of impaired immunocompetence and increased disease incidence in contaminant-exposed wildlife populations, the potential relevance of immunotoxic effects for the ecological impact of chemicals is rarely considered in ecotoxicological risk assessment. A limiting factor in the assessment of immunotoxic effects might be the complexity of the immune system what makes it difficult (1) to select appropriate exposure and effect parameters out of the many immune parameters which could be measured, and (2) to evaluate the significance of the selected parameters for the overall fitness and immunocompetence of the organism. Here, we present - on the example of teleost fishes - a brief discussion of how to assess chemical impact on the immune system using parameters at different levels of complexity and integration: immune mediators, humoral immune effectors, cellular immune defenses, macroscopical and microscopical responses of lymphoid tissues and organs, and host resistance to pathogens. Importantly, adverse effects of chemicals on immunocompetence may be detectable only after immune system activation, e.g., after pathogen challenge, but not in the resting immune system of non-infected fish. Current limitations to further development and implementation of immunotoxicity assays and parameters in ecotoxicological risk assessment are not primarily due to technological constraints, but are related from insufficient knowledge of (1) possible modes of action in the immune system, (2) the importance of intra- and inter-species immune system variability for the response against chemical stressors, and (3) deficits in conceptual and mechanistic assessment of combination effects of chemicals and pathogens.

Coronary revascularisation in patients with diabetes: a chance to be better

Commentary on: Farkouh ME, Domanski M, Sleeper LA, et al. Strategies for multivessel revascularisation in patients with diabetes. N Engl J Med 2012;367:2375–84.

ROLE OF DOPAMINE OF NUCLEUS ACCUMBENS IN BEHAVIORAL SENSITIZATION TO METHYLPHENIDATE

Behavioral sensitization is defined as the subsequent augmentation of the locomotor response to a drug following repeated administrations of the drug. It is believed to occur due to alterations in the motive circuit in the brain by stressors, central nervous system stimulants, and similar stimuli. The motive circuit (or mesocorticolimbic system) consists of several interconnected nuclei that determine the behavioral response to significant biological stimuli. A final target of the mesocorticolimbic system is the nucleus accumbens (NAc), which is a key structure linking motivation and action. In particular, the dopaminergic innervations of the Nac are considered to be essential in regulating motivated states of behavior such as goal-directed actions, stimulus-reward associations and reinforcement by addictive substances. Therefore, the objective of this study was to investigate the role of dopaminergic afferents of the NAc in the behavioral sensitization elicited by chronic treatment with methylphenidate (MPD), a psychostimulant that is widely used to treat attention deficit hyperactivity disorder. The dopaminergic afferents can be selectively destroyed using catecholamine neurotoxin 6-hydroxydopamine (6-OHDA). In order to determine whether destruction of dopaminergic afferents of the NAc prevents sensitization, I compared locomotor activity in rats that had received infusions of 6-hydroxydopamine (6-OHDA) into the NAc with that of control and sham-operated animals. All groups of rats received six days of single daily MPD injections after measuring their pre and post surgery locomotor baseline. Following the consecutive MPD injections, there was a washout period of 4 days, where no injections were given. Then, a rechallenge injection of MPD was given. Behavioral responses after repeated MPD were compared to those after acute MPD to assess behavioral sensitization. Expression of sensitization to MPD was not prevented by 6-OHDA infusion into the NAc. Moreover, two distinct responses were seen to the acute injection of MPD: one group of rats had essentially no response to acute MPD, while the other had an augmented (‘sensitized’-like) acute response. Among rats with 6-OHDA infusions, the animals with diminished acute response to MPD had intact behavioral sensitization to repeated MPD, while the animals with increased acute response to MPD did not exhibit further sensitization to it. This suggests that the acute and chronic effects of MPD have distinct underlying neural circuitries.

Physiologic and hematologic concerns of rotary blood pumps: what needs to be improved?

Over the past few decades, advances in ventricular assist device (VAD) technology have provided a promising therapeutic strategy to treat heart failure patients. Despite the improved performance and encouraging clinical outcomes of the new generation of VADs based on rotary blood pumps (RBPs), their physiologic and hematologic effects are controversial. Currently, clinically available RBPs run at constant speed, which results in limited control over cardiac workload and introduces blood flow with reduced pulsatility into the circulation. In this review, we first provide an update on the new challenges of mechanical circulatory support using rotary pumps including blood trauma, increased non-surgical bleeding rate, limited cardiac unloading, vascular malformations, end-organ function, and aortic valve insufficiency. Since the non-physiologic flow characteristic of these devices is one of the main subjects of scientific debate in the literature, we next emphasize the latest research regarding the development of a pulsatile RBP. Finally, we offer an outlook for future research in the field.

Continuum of depressive and manic mixed states in patients with bipolar disorder: quantitative measurement and clinical features.

Bipolar mixed states combine depressive and manic features, presenting diagnostic and treatment challenges and reflecting a severe form of the illness. DSM-IV criteria for a mixed state require combined depressive and manic syndromes, but a range of mixed states has been described clinically. A unified definition of mixed states would be valuable in understanding their diagnosis, mechanism and treatment implications. We investigated the manner in which depressive and manic features combine to produce a continuum of mixed states. In 88 subjects with bipolar disorder (DSM-IV), we evaluated symptoms and clinical characteristics, and compared depression-based, mania-based, and other published definitions of mixed states. We developed an index of the extent to which symptoms were mixed (Mixed State Index, MSI) and characterized its relationship to clinical state. Predominately manic and depressive mixed states using criteria from recent literature, as well as Kraepelinian mixed states, had similar symptoms and MSI scores. Anxiety correlated significantly with depression scores in manic subjects and with mania scores in depressed subjects. Discriminant function analysis associated mixed states with symptoms of hyperactivity and negative cognitions, but not subjective depressive or elevated mood. High MSI scores were associated with severe course of illness. For depressive or manic episodes, characteristics of mixed states emerged with two symptoms of the opposite polarity. This was a cross-sectional study. Mixed states appear to be a continuum. An index of the degree to which depressive and manic symptoms combine appears useful in identifying and characterizing mixed states. We propose a depressive or manic episode with three or more symptoms of the opposite polarity as a parsimonious definition of a mixed state.

The role of substance abuse treatment in preventing human immunodeficiency virus transmission among injecting drug users

This exploratory study assesses the utility of substance abuse treatment as a strategy for preventing human immunodeficiency virus (HIV) transmission among injecting drug users (IDUs). Data analyzed in this study were collected in San Antonio, TX, 1989 through 1995 using both qualitative and quantitative methods. Qualitative data included ethnographic interviews with 234 active IDUs; quantitative data included baseline risk assessments and HIV screening plus interviews follow-up interviews administered approximately six months later to 823 IDUs participating in a Federally-funded AIDS community outreach demonstration project.^ Findings that have particularly important implications for substance abuse treatment as an HIV prevention strategy for IDUs are listed below. (1) IDUs who wanted treatment were significantly more likely to be daily heroin users. (2) IDUs who want treatment were significantly more likely to have been to treatment previously. (3) IDUs who wanted treatment at baseline reported significantly higher levels of HIV risk than IDUs who did not want treatment. (4) IDUs who went to treatment between their baseline and follow-up interviews reported significantly higher levels of HIV risk at baseline than IDUs who did not go to treatment. (5) IDUs who went to treatment between their baseline and follow-up interviews reported significantly greater decreases in injection-related HIV risk behaviors. (6) IDUs who went to treatment reported significantly greater decreases in sexual HIV risk behaviors than IDUs who did not go to treatment.^ This study also noted a number of factors that may limit the effectiveness of substance abuse treatment in reducing HIV risk among IDUs. Findings suggest that the impact of methadone maintenance on HIV risk behaviors among opioid dependent IDUs may be limited by the negative manner in which it is perceived by IDUs as well as other elements of society. One consequence of the negative perception of methadone maintenance held by many elements of society may be an unwillingness to provide public funding for an adequate number of methadone maintenance slots. Thus many IDUs who would be willing to enter methadone maintenance are unable to enter it and many IDUs who do enter it are forced to drop out prematurely. ^

Does ‘better’ discounting lead to ‘worse’ outcomes in long-run decisions? The dilemma of hyperbolic discounting

The shortcomings of conventional discounting, especially in the context of long-run environmental problems, have been extensively discussed in the literature. Recently, hyperbolic discounting, i. e. discounting at declining instead of constant discount rates, has attracted a lot of interest among both scientists and politicians. Although there are compelling arguments for employing hyperbolic discounting, there are also pitfalls, which have to be pointed out. In this paper I show that the problem of time-inconsistency, an inherent characteristics of hyperbolic discounting, leads to a potential clash between economic efficiency and intergenerational equity. As an example, I refer to the weak progress in the controlling of greenhouse gas emissions under the Kyoto protocol. As the problem of time-inconsistency cannot be solved on economic grounds alone, there is a need for an intergenerational moral commitment.

Dispersal Modeling of Fish Early Life Stages: Sensitivity with Application to Atlantic Cod in the Western Gulf of Maine

As an initial step in establishing mechanistic relationships between environmental variability and recruitment in Atlantic cod Gadhus morhua along the coast of the western Gulf of Maine, we assessed transport success of larvae from major spawning grounds to nursery areas with particle tracking using the unstructured grid model FVCOM (finite volume coastal ocean model). In coastal areas, dispersal of early planktonic life stages of fish and invertebrate species is highly dependent on the regional dynamics and its variability, which has to be captured by our models. With state-of-the-art forcing for the year 1995, we evaluate the sensitivity of particle dispersal to the timing and location of spawning, the spatial and temporal resolution of the model, and the vertical mixing scheme. A 3 d frequency for the release of particles is necessary to capture the effect of the circulation variability into an averaged dispersal pattern of the spawning season. The analysis of sensitivity to model setup showed that a higher resolution mesh, tidal forcing, and current variability do not change the general pattern of connectivity, but do tend to increase within-site retention. Our results indicate strong downstream connectivity among spawning grounds and higher chances for successful transport from spawning areas closer to the coast. The model run for January egg release indicates 1 to 19 % within-spawning ground retention of initial particles, which may be sufficient to sustain local populations. A systematic sensitivity analysis still needs to be conducted to determine the minimum mesh and forcing resolution that adequately resolves the complex dynamics of the western Gulf of Maine. Other sources of variability, i.e. large-scale upstream forcing and the biological environment, also need to be considered in future studies of the interannual variability in transport and survival of the early life stages of cod.

Hide-and-seek in vegetation: time-to-detection is an efficient design for estimating detectability and occurrence

Ecology and conservation require reliable data on the occurrence of animals and plants. A major source of bias is imperfect detection, which, however, can be corrected for by estimation of detectability. In traditional occupancy models, this requires repeat or multi-observer surveys. Recently, time-to-detection models have been developed as a cost-effective alternative, which requires no repeat surveys and hence costs could be halved. We compared the efficiency and reliability of time-to-detection and traditional occupancy models under varying survey effort. Two observers independently searched for 17 plant species in 44100m(2) Swiss grassland quadrats and recorded the time-to-detection for each species, enabling detectability to be estimated with both time-to-detection and traditional occupancy models. In addition, we gauged the relative influence on detectability of species, observer, plant height and two measures of abundance (cover and frequency). Estimates of detectability and occupancy under both models were very similar. Rare species were more likely to be overlooked; detectability was strongly affected by abundance. As a measure of abundance, frequency outperformed cover in its predictive power. The two observers differed significantly in their detection ability. Time-to-detection models were as accurate as traditional occupancy models, but their data easier to obtain; thus they provide a cost-effective alternative to traditional occupancy models for detection-corrected estimation of occurrence.

Atlanto-axial rotatory subluxations in postmortem CT: radiologists be aware of a common pitfall

The aim of the present study was to determine the frequency of atlanto-axial rotatory subluxations (AARS) in multi detector computed tomography (MDCT) performed on human corpses for forensic purposes and to investigate whether these are a physiological postmortem finding or indicate a trauma to the neck region. 80 forensic cases examined with MDCT from November 2003 to March 2007 were included in the study. The study was approved by the regional ethics committee. For each case volumes were rendered and investigated with reference to suspected AARS and any other anomalies of the head and neck region. The rotation of the head as well as in the atlanto-axial joint were measured and occurring AARS were judged according Fielding's classification. The finding of AARS was correlated to case criteria such as postmortem head rotation, sex, age, cause of death, time since death and further autopsy results. Statistical analysis was performed using Fisher's exact test, Wilcoxon's rank sums test and Chi-square test with Pearson approximation. 70% (n=56) of the cases included in the study presented with an AARS. A strong correlation (P<.0001) between suspected AARS and postmortem head rotation was found. Two cases presented with an atlanto-axial rotation greater than the head rotation. One showed an undiscovered lateral dislocation of the atlas, and one an unfused atlas-ring. There was no correlation to any further investigated case criteria. Ipsilateral AARS with head rotation alone does not indicate trauma to the neck. PmCT can substantially support forensic examinations of the skeleton, especially in body regions, which are elaborate to access at autopsy, such as the cervical spine. Isolated AARS (Fielding type I) on pmCT is usually a normal finding associated with ipsilateral head rotation.

AIDS defining opportunistic infections in patients with high CD4 counts in the combination antiretroviral therapy (cART) era: things ain't what they used to be.

INTRODUCTION According to reports from observational databases, classic AIDS-defining opportunistic infections (ADOIs) occur in patients with CD4 counts above 500/µL on and off cART. Adjudication of these events is usually not performed. However, ADOIs are often used as endpoints, for example, in analyses on when to start cART. MATERIALS AND METHODS In the database, Swiss HIV Cohort Study (SHCS) database, we identified 91 cases of ADOIs that occurred from 1996 onwards in patients with the nearest CD4 count >500/µL. Cases of tuberculosis and recurrent bacterial pneumonia were excluded as they also occur in non-immunocompromised patients. Chart review was performed in 82 cases, and in 50 cases we identified CD4 counts within six months before until one month after ADOI and had chart review material to allow an in-depth review. In these 50 cases, we assessed whether (1) the ADOI fulfilled the SHCS diagnostic criteria (www.shcs.ch), and (2) HIV infection with CD4 >500/µL was the main immune-compromising condition to cause the ADOI. Adjudication of cases was done by two experienced clinicians who had to agree on the interpretation. RESULTS More than 13,000 participants were followed in SHCS in the period of interest. Twenty-four (48%) of the chart-reviewed 50 patients with ADOI and CD4 >500/µL had an HIV RNA <400 copies/mL at the time of ADOI. In the 50 cases, candida oesophagitis was the most frequent ADOI in 30 patients (60%) followed by pneumocystis pneumonia and chronic ulcerative HSV disease (Table 1). Overall chronic HIV infection with a CD4 count >500/µL was the likely explanation for the ADOI in only seven cases (14%). Other reasons (Table 1) were ADOIs occurring during primary HIV infection in 5 (10%) cases, unmasking IRIS in 1 (2%) case, chronic HIV infection with CD4 counts <500/µL near the ADOI in 13 (26%) cases, diagnosis not according to SHCS diagnostic criteria in 7 (14%) cases and most importantly other additional immune-compromising conditions such as immunosuppressive drugs in 14 (34%). CONCLUSIONS In patients with CD4 counts >500/ µL, chronic HIV infection is the cause of ADOIs in only a minority of cases. Other immuno-compromising conditions are more likely explanations in one-third of the patients, especially in cases of candida oesophagitis. ADOIs in HIV patients with high CD4 counts should be used as endpoints only with much caution in studies based on observational databases.