An immuno-epidemiological model for transient immune protection: A case study for viral respiratory infections.

The dynamics of infectious disease in a population critically involves both within-host pathogen replication and between host pathogen transmission. While modeling efforts have recently explored how within-host dynamics contribute to shaping population transmission, fewer have explored how ongoing circulation of an epidemic infectious disease can impact within-host immunological dynamics. We present a simple, influenza-inspired model that explores the potential for re-exposure during a single, ongoing outbreak to shape individual immune response and epidemiological potential in non-trivial ways. We show how even a simplified system can exhibit complex ongoing dynamics and sensitive thresholds in behavior. We also find epidemiological stochasticity likely plays a critical role in reinfection or in the maintenance of individual immunological protection over time.

Assessing the binding interaction of polystyrene sulfonate with amitriptyline in healthy volunteers: a cross-over design - The BIND study.

PURPOSE: Polystyrene sulfonate is used for binding potassium in patients with chronic kidney disease (CKD). Because of its binding properties, it can potentially bind other medications and thereby decrease their bioavailability and effectiveness. Amitriptyline, often used by CKD patients for neuropathic pain, shows significant binding to polystyrene sulfonate in vitro. The purpose of this study was to determine the effect of polystyrene sulfonate on the exposure of amitriptyline in vivo when taken concomitantly in healthy volunteers. METHODS: We performed a prospective cross-over study in nine healthy volunteers. Participants were 18 years of age or older, did not use any medication, and had no known allergy to amitriptyline or polystyrene sulfonate. Participants visited Deventer Teaching Hospital twice. Once they received a single dose of amitriptyline 50 mg and once they received a single dose of both polystyrene sulfonate 15 g and amitriptyline 50 mg taken concomitantly, with a wash out period of at least 1 week. After intake of the medication, six blood samples were collected, at 2, 3, 4, 5, 6, and 8 h. Blood samples were analysed to determine maximum concentration (Cmax) and area under the curve 0-8 h after intake (AUC0-8 h). Difference in Cmax and AUC0-8 h was analysed with a paired T-test or Wilcoxon signed rank test, depending on normality of the data. A p-value < 0.05 was considered statistically significant. RESULTS: Of the nine participants included, eight participants completed both visits to the hospital. Mean maximum concentration (Cmax) of amitriptyline was 35.61 µg l-1 (95% CI 27.90-43.33 µg l-1) when taken alone, compared to 9.25 µg l-1 (95% CI 6.59-11.92 µg l-1) when taken with polystyrene sulfonate (p < 0.001). Mean AUC0-8 h of amitriptyline was 168.20 µg × h l-1 (95% CI 139.95-196.45 µg × h l-1) when taken alone and 45.78 µg × h l-1 (95% CI 30.20-61.36 µg × h l-1) when taken with polystyrene sulfonate (p < 0.0001). CONCLUSION: These results show a significant decrease in exposure of amitriptyline of approximately 75% when taken concomitantly with polystyrene sulfonate, thereby probably compromising therapy efficacy. Patients using both amitriptyline and polystyrene sulfonate should be informed to separate intake of these medications. TRIAL REGISTRATION: NL8539 (17 April 2020).

Montane ecosystem productivity responds more to global circulation patterns than climatic trends.

Regional ecosystem productivity is highly sensitive to inter-annual climate variability, both within and outside the primary carbon uptake period. However, Earth system models lack sufficient spatial scales and ecosystem processes to resolve how these processes may change in a warming climate. Here, we show, how for the European Alps, mid-latitude Atlantic ocean winter circulation anomalies drive high-altitude summer forest and grassland productivity, through feedbacks among orographic wind circulation patterns, snowfall, winter and spring temperatures, and vegetation activity. Therefore, to understand future global climate change influence to regional ecosystem productivity, Earth systems models need to focus on improvements towards topographic downscaling of changes in regional atmospheric circulation patterns and to lagged responses in vegetation dynamics to non-growing season climate anomalies.

Pituitary network connectivity as a mechanism for the luteinising hormone surge.

Ovulation in vertebrates is caused by a surge of luteinising hormone (LH) from the pituitary. The LH surge is initiated by rising oestradiol concentration, although the precise mechanism of oestradiol action in humans and primates is not yet understood. Recent advances in labelling and three-dimensional imaging have revealed a rich pituitary structure of interwoven networks of different cell types. In the present study, we develop a mathematical model to test the hypothesis that oestradiol modulation of connectivity between pituitary cells can underlie the LH surge. In the model, gonadotrophin-releasing hormone (GnRH) pulses stimulate LH secretion by two independent mechanisms. The first mechanism corresponds to the well known direct action of GnRH on gonadotrophs, which is inhibited by the rising oestradiol concentration. The second mechanism of GnRH action is to stimulate a recurrent network of pituitary cells; in this case, the folliculostellate cells, which in turn stimulate LH secretion from the gonadotrophs. The network activity is modelled by a one-dimensional ordinary differential equation. The key to the LH surge in the model lies in the assumption that oestradiol modulates network connectivity. When the circulating oestradiol concentration is low, the network is barely connected, and cannot maintain a recurrent signal. When the oestradiol concentration is high, the network is highly connected, and maintains a high level of activity even after GnRH stimulation, thereby leading to a surge of LH secretion.

Social stress alters expression of large conductance calcium-activated potassium channel subunits in mouse adrenal medulla and pituitary glands.

Large conductance calcium-activated potassium (BK) channels are very prominently expressed in adrenal chromaffin and many anterior pituitary cells, where they shape intrinsic excitability complexly. Stress- and sex-steroids regulate alternative splicing of Slo-alpha, the pore-forming subunit of BK channels, and chronic behavioural stress has been shown to alter Slo splicing in tree shrew adrenals. In the present study, we focus on mice, measuring the effects of chronic behavioural stress on total mRNA expression of the Slo-alpha gene, two key BK channel beta subunit genes (beta2 and beta4), and the 'STREX' splice variant of Slo-alpha. As a chronic stressor, males of the relatively aggressive SJL strain were housed with a different unfamiliar SJL male every 24 h for 19 days. This 'social-instability' paradigm stressed all individuals, as demonstrated by reduced weight gain and elevated corticosterone levels. Five quantitative reverse transcriptase-polymerase chain assays were performed in parallel, including beta-actin, each calibrated against a dilution series of its corresponding cDNA template. Stress-related changes in BK expression were larger in mice tested at 6 weeks than 9 weeks. In younger animals, Slo-alpha mRNA levels were elevated 44% and 116% in the adrenal medulla and pituitary, respectively, compared to individually-housed controls. beta2 and beta4 mRNAs were elevated 162% and 194% in the pituitary, but slightly reduced in the adrenals of stressed animals. In the pituitary, dominance scores of stressed animals correlated negatively with alpha and beta subunit expression, with more subordinate individuals exhibiting levels that were three- to four-fold higher than controls or dominant individuals. STREX variant representation was lower in the subordinate subset. Thus, the combination of subunits responding to stress differs markedly between adrenal and pituitary glands. These data suggest that early stress will differentially affect neuroendocrine cell excitability, and call for detailed analysis of functional consequences.

Summertime elemental mercury exchange of temperate grasslands on an ecosystem-scale.

In order to estimate the air-surface mercury exchange of grasslands in temperate climate regions, fluxes of gaseous elemental mercury (GEM) were measured at two sites in Switzerland and one in Austria during summer 2006. Two classic micrometeorological methods (aerodynamic and modified Bowen ratio) have been applied to estimate net GEM exchange rates and to determine the response of the GEM flux to changes in environmental conditions (e.g. heavy rain, summer ozone) on an ecosystem-scale. Both methods proved to be appropriate to estimate fluxes on time scales of a few hours and longer. Average dry deposition rates up to 4.3 ng m-2 h-1 and mean deposition velocities up to 0.10 cm s-1 were measured, which indicates that during the active vegetation period temperate grasslands are a small net sink for atmospheric mercury. With increasing ozone concentrations depletion of GEM was observed, but could not be quantified from the flux signal. Night-time deposition fluxes of GEM were measured and seem to be the result of mercury co-deposition with condensing water. Effects of grass cuts could also be observed, but were of minor magnitude.

Beta2 and beta4 subunits of BK channels confer differential sensitivity to acute modulation by steroid hormones.

Membrane-associated receptors for rapid, steroidal neuromodulation remain elusive. Estradiol has been reported to facilitate activation of voltage- and Ca(2+)-dependent BK potassium channels encoded by Slo, if associated with beta1 subunits. We show here that 1) multiple members of the beta family confer sensitivity to multiple steroids on BK channels, 2) that beta subunits differentiate between steroids, and 3) that different betas have distinct relative preferences for particular steroids. Expressed in HEK 293 cells, inside-out patches with channels composed of Slo-alpha alone showed no steroid sensitivity. Cells expressing alphabeta4 exhibited potent, rapid, reversible, and dose-dependent potentiation by corticosterone (CORT; a glucocorticoid), and were potentiated to a lesser degree by other sex and stress steroids. In contrast, alphabeta2 channels were potentiated more strongly by dehydroepiandrosterone (DHEA; an enigmatic, stress-related adrenal androgen), and to a lesser extent by CORT, estradiol, testosterone, and DHEA-S. Cholesterol had no effect on any BK channel compositions tested. Conductance-voltage plots of channels composed of alpha plus beta2 or beta4 subunits were shifted in the negative direction by steroids, indicating greater activation at negative voltages. Thus our results argue that the variety of Slo-beta subunit coexpression patterns occurring in vivo expands the repertoire of Slo channel gating in yet another dimension not fully appreciated, rendering BK gating responsive to dynamic fluctuations in a multiple of steroid hormones.

Resonance in the menstrual cycle: a new model of the LH surge.

In vertebrates, ovulation is triggered by a surge of LH from the pituitary. The precise mechanism by which rising oestradiol concentrations initiate the LH surge in the human menstrual cycle remains a fundamental open question of reproductive biology. It is well known that sampling of serum LH on a time scale of minutes reveals pulsatile release from the pituitary in response to pulses of gonadotrophin releasing hormone from the hypothalamus. The LH pulse frequency and amplitude vary considerably over the cycle, with the highest frequency and amplitude at the midcycle surge. Here a new mathematical model is presented of the pituitary as a damped oscillator (pulse generator) driven by the hypothalamus. The model LH surge is consistent with LH data on the time scales of both minutes and days. The model is used to explain the surprising pulse frequency characteristics required to treat human infertility disorders such as Kallmann's syndrome, and new experimental predictions are made.

Environmental endocrine disruption: an effects assessment and analysis.

This report is an overview of the current state of the science relative to environmental endocrine disruption in humans, laboratory testing, and wildlife species. Background information is presented on the field of endocrinology, the nature of hormones, and potential sites for endocrine disruption, with specific examples of chemicals affecting these sites. An attempt is made to present objectively the issue of endocrine disruption, consider working hypotheses, offer opposing viewpoints, analyze the available information, and provide a reasonable assessment of the problem. Emphasis is placed on disruption of central nervous system--pituitary integration of hormonal and sexual behavioral activity, female and male reproductive system development and function, and thyroid function. In addition, the potential role of environmental endocrine disruption in the induction of breast, testicular, and prostate cancers, as well as endometriosis, is evaluated. The interrelationship of the endocrine and immune system is documented. With respect to endocrine-related ecological effects, specific case examples from the peer-reviewed literature of marine invertebrates and representatives of the five classes of vertebrates are presented and discussed. The report identifies some data gaps in our understanding of the environmental endocrine disruption issue and recommends a few research needs. Finally, the report states the U.S. Environmental Protection Agency Science Policy Council's interim position on endocrine disruption and lists some of the ongoing activities to deal with this matter.

U.S. EPA regulatory perspectives on the use of QSAR for new and existing chemical evaluations.

As testing is not required, ecotoxicity or fate data are available for approximately 5% of the approximately 2,300 new chemicals/year (26,000 + total) submitted to the US-EPA. The EPA's Office of Pollution Prevention and Toxics (OPPT) regulatory program was forced to develop and rely upon QSARs to estimate the ecotoxicity and fate of most of the new chemicals evaluated for hazard and risk assessment. QSAR methods routinely result in ecotoxicity estimations of acute and chronic toxicity to fish, aquatic invertebrates, and algae, and in fate estimations of physical/chemical properties, degradation, and bioconcentration. The EPA's Toxic Substances Control Act (TSCA) Inventory of existing chemicals currently lists over 72,000 chemicals. Most existing chemicals also appear to have little or no ecotoxicity or fate data available and the OPPT new chemical QSAR methods now provide predictions and cross-checks of test data for the regulation of existing chemicals. Examples include the Toxics Release Inventory (TRI), the Design for the Environment (DfE), and the OECD/SIDS/HPV Programs. QSAR screening of the TSCA Inventory has prioritized thousands of existing chemicals for possible regulatory testing of: 1) persistent bioaccumulative chemicals, and 2) the high ecotoxicity of specific discrete organic chemicals.

The application of structure-activity relationships (SARs) in the aquatic toxicity evaluation of discrete organic chemicals.

The Office of Pollution Prevention and Toxics (OPPT), United States Environmental Protection Agency (USEPA) routinely uses structure-activity relationships (SAR) for the aquatic hazard assessment of new chemicals submitted under Section 5 of the Toxic Substances Control Act (TSCA). With 15 years of experience and the general acceptance of toxicity predictions based on SARs, OPPT has expanded the use and application of the methodology to include existing chemicals used in printing, dry cleaning, and paint stripping. SAR analysis has also been used in the hazard evaluation of the U.S. and EU/OECD high production volume (HPV) chemicals. This paper describes the assumptions, limitations, and methodology for the use of SARs to evaluate large sets of discrete organic chemicals.

Principles of drug absorption and recent studies of bioavailability in aquatic species.

An overview is presented on the absorption of drugs and other xenobiotics in mammals and fish. Species differences in gastrointestinal tract physiology as well as other factors that influence bioavailability of these compounds are considered. Results of recent studies on the bioavailability of drugs in aquatic animal species are discussed.

Environmental considerations for minor use animal drugs.

This presentation outlines the basis for the FDA requirement that environmental considerations, via an environmental document, be included for evaluation as part of the application for animal drugs. Next, the environmental document for an animal drug application and three important types of environmental information that need to be included in the environmental document are discussed. The abbreviated environmental information requirements for some minor use applications are presented. Finally, 2 points presented previously by Dr Katz on the preparation of environmental documents for minor use animal drugs are clarified.

Modulation of the immune response in fish.

This is a brief overview of the field of immune modulation in fish. Special attention is given to the effects of biological rhythms on the immune responses of animals. Biological rhythms in fish appear to be poorly studied and the effects of such rhythms on fish immune responses needs to be evaluated. Implications for research on the modulation of fish immune responses are discussed.

Immunologic alterations by environmental chemicals: relevance of studying mechanisms versus effects.

A number of environmental chemicals are known to modify the immune responses via a number of different mechanisms. Immunologic systems are vital to the well-being of individuals and a number of toxic effects are likely to be produced by chemical alteration of its processes. A variety of tests have been suggested for screening existing or new chemicals with regards to their potential to modify the immune responses. It is well recognized that immune responses are highly temporal (time-related) and the outcome of a test is likely to be influenced by the specific protocol employed and other factors that may involve the test organism. Although standardization of tests will probably reduce some of this variability, test standardization is not expected to provide more valuable information than can be already predicted by the routine evaluation of chronic toxicity and clinical parameters. The need for studying the mechanisms involved in the modification of immunologic processes by exogenous and even endogenous chemicals is emphasized in this report.

DDT: short term effects on osmoregulation in black surfperch (Embiotoca jacksoni).

DDT injected intraperitoneally into black surfperch caused substantial increases in plasma osmotic concentration only at doses much larger than are likely to be encountered in nature. Increased plasma concentrations were below those tolerated by fish adapted to high salinities. Death of marine teleosts from DDT poisoning probably involves factors other than simply osmoregulatory failure.