Kinetic models for detection of toxicity in a microbial fuel cell based biosensor

Currently available models describing microbial fuel cell (MFC) polarization curves, do not describe the effect of the presence of toxic components. A bioelectrochemical model combined with enzyme inhibition kinetics, that describes the polarization curve of an MFC-based biosensor, was modified to describe four types of toxicity. To get a stable and sensitive sensor, the overpotential has to be controlled. Simulations with the four modified models were performed to predict the overpotential that gives the most sensitive sensor. These simulations were based on data and parameter values from experimental results under non-toxic conditions. Given the parameter values from experimental results, controlling the overpotential at 250 mV leads to a sensor that is most sensitive to components that influence the whole bacterial metabolism or that influence the substrate affinity constant (Km). Controlling the overpotential at 105 mV is the most sensitive setting for components influencing the ratio of biochemical over electrochemical reaction rate constants (K1), while an overpotential of 76 mV gives the most sensitive setting for components that influence the ratio of the forward over backward biochemical rate constants (K2). The sensitivity of the biosensor was also analyzed for robustness against changes in the model parameters other than toxicity. As an example, the tradeoff between sensitivity and robustness for the model describing changes on K1 (IK1) is presented. The biosensor is sensitive for toxic components and robust for changes in model parameter K2 when overpotential is controlled between 118 and 140 mV under the simulated conditions.     

Location of immunization and interferon-γ are central to induction of salivary gland dysfunction in Ro60 peptide immunized model of Sjögren's syndrome

Introduction

Anti-Ro antibodies can be found in the serum of the majority of patients with Sjögren''s syndrome (SS). Immunization with a 60-kDa Ro peptide has been shown to induce SS-like symptoms in mice. The aim of this study was to investigate factors involved in salivary gland (SG) dysfunction after immunization and to test whether the induction of SS could be improved.

Methods

Ro60 peptide immunization was tested in Balb/c mice, multiple antigenic peptide (MAP)-Ro60 and Pertussis toxin (PTX) were tested in SJL/J mice. In addition, two injection sites were compared in these two strains: the abdominal area and the tailbase. Each group of mice was tested for a loss of SG function, SG lymphocytic infiltration, anti-Ro and anti-La antibody formation, and cytokine production in cultured cells or homogenized SG extracts.

Results

Ro60 peptide immunization in the abdominal area of female Balb/c mice led to impaired SG function, which corresponded with increased Th1 cytokines (IFN-γ and IL-12) systemically and locally in the SG. Moreover, changing the immunization conditions to MAP-Ro60 in the abdominal area, and to lesser extend in the tailbase, also led to impaired SG function in SJL/J mice. As was seen in the Balb/c mice, increased IFN-γ in the SG draining lymph nodes accompanied the SG dysfunction. However, no correlation was observed with anti-MAP-Ro60 antibody titers, and there was no additional effect on disease onset or severity.

Conclusions

Effective induction of salivary gland dysfunction after Ro60 peptide immunization depended on the site of injection. Disease induction was not affected by changing the immunization conditions. However, of interest is that the mechanism of action of Ro60 peptide immunization appears to involve an increase in Th1 cytokines, resulting in the induction of SG dysfunction.     

High prevalence of self-reported undiagnosed HIV despite high coverage of HIV testing: a cross-sectional population based sero-survey in South Africa

Objectives

To measure HIV prevalence and uptake of HIV counseling and testing (HCT) in a peri-urban South African community. To assess predictors for previous HIV testing and the association between the yield of previously undiagnosed HIV and time of last negative HIV test

Methods

A random sample of 10% of the adult population (≥15 years) were invited to attend a mobile HCT service. Study procedures included a questionnaire, HIV testing and CD4 counts. Predictors for previous testing were determined using a binominal model.

Results

1,144 (88.0%) of 1,300 randomly selected individuals participated in the study. 71.0% (68.3–73.6) had previously had an HIV test and 37.5% (34.6–40.5) had tested in the past 12 months. Men, migrants and older (>35 years) and younger (<20 years) individuals were less likely to have had a previous HIV test. Overall HIV prevalence was 22.7 (20.3–25.3) with peak prevalence of 41.8% (35.8–47.8) in women aged 25.1–35 years and 37.5% (26.7–48.3) in men aged 25.1–45 years. Prevalence of previously undiagnosed HIV was 10.3% (8.5–12.1) overall and 4.5% (2.3–6.6), 8.0% (CI 3.9–12.0) and 20.0% (13.2–26.8) in individuals who had their most recent HIV test within 1, 1–2 and more than 2 years prior to the survey.

Conclusion

The high burden of undiagnosed HIV in individuals who had recently tested underscores the importance of frequent repeat testing at least annually. The high prevalence of previously undiagnosed HIV in individuals reporting a negative test in the 12 months preceding the survey indicates a very high incidence. Innovative prevention strategies are needed.     

Nanomedicines in the treatment of acromegaly: focus on pegvisomant

This article examines the role of pegvisomant in the treatment of acromegaly. This syndrome, caused by excessive growth hormone (GH) secretion by a pituitary adenoma, is associated with a doubled mortality rate and poor quality of life. Pituitary microsurgery has long been the first choice of treatment since it cures many patients, especially those with localized tumors. Adjuvant irradiation was given if insulin-like growth factor-I (IGF-I) or GH did not normalize. The introduction of long-acting slow- release somatostatin analogs was a breakthrough for adjuvant treatment, although not always effective. Rather, targeting excessive GH production, muting the GH signal at its receptor, was a totally different approach. The development of GH antagonists (by mutation ofglycine at position 120) and other modifications to enhance receptor binding, and subsequent pegylation of the molecule led to the development of B2036. After pegylation of B2036 at 5 positions the distribution volume is restricted and its serum half-life considerably increased. In short-term clinical studies performed in selected, mostly pretreated, acromegalic patients, IGF-I normalized in the majority of cases. Combination therapy with long-acting somatostatin analogs and weekly rather than daily pegvisomant injections appears to be successful in one clinical study and might limit the high cost of pegvisomant. Long-term efficacy and safety has to be demonstrated. The drug does not cross the blood-brain barrier, and whether it distributes freely into the extracellular space of other organs than the liver has not been investigated, which might have implications for persistent local IGF-I production under unrestrained GH concentrations.     

Phenotypic analysis of pneumococcal polysaccharide-specific B cells

The phenotype of B cells responsible for the production of anti-pneumococcal polysaccharide Ab has been unclear. Although individuals that respond poorly to the 23-valent pneumococcal polysaccharide (PPS) vaccine, Pneumovax, such as children <2 y, the asplenic, and a subset of common variable immunodeficiency patients, are profoundly deficient or lack IgM memory cells (CD27(+)IgM(+)), they are also deficient in the switched memory (CD27(+)IgM(-)) compartment. Direct characterization of PPS-specific B cells has not been performed. In this study, we labeled PPS14 and PPS23F with fluorescent markers. Fluorescently labeled PPS were used in FACSAria flow cytometry to characterize the phenotype of PPS-specific B cells obtained from 18 young adults pre- and postimmunization with Pneumovax. The labeled PPS were capable of inhibiting binding of Ab to the native PPS. Similarly, the native PPS were able to inhibit binding of PPS-specific B cells in a flow cytometric assay demonstrating specificity and functionality. Phenotypic analysis of unselected B cells, pre- and postimmunization, demonstrated a predominance of naive CD27(-)IgM(+) cells accounting for 61.5% of B cells. Likewise, the PPS-specific B cells obtained preimmunization consisted primarily of naive, CD27(-) B cells, 55.4-63.8%. In contrast, the PPS-specific B cells obtained postimmunization were predominantly IgM memory cells displaying the CD27(+)IgM(+), 54.2% for PPS14 and 66% for PPS23F, significantly higher than both unselected B cells and PPS-specific B cells. There was no significant difference in switched memory B cell populations (CD27(+)IgM(-)) between groups. These results suggest a dominant role of IgM memory cells in the immune response to pneumococcal polysaccharides.     

Effects of amphetamine on dopamine release in the rat nucleus accumbens shell region depend on cannabinoid CB1 receptor activation

The psychostimulant drug amphetamine is often prescribed to treat Attention-Deficit/Hyperactivity Disorder. The behavioral effects of the psychostimulant drug amphetamine depend on its ability to increase monoamine neurotransmission in brain regions such as the nucleus accumbens (NAC) and medial prefrontal cortex (mPFC). Recent behavioral data suggest that the endocannabinoid system also plays a role in this respect. Here we investigated the role of cannabinoid CB1 receptor activity in amphetamine-induced monoamine release in the NAC and/or mPFC of rats using in vivo microdialysis. Results show that systemic administration of a low, clinically relevant dose of amphetamine (0.5mg/kg) robustly increased dopamine and norepinephrine release (to ～175-350% of baseline values) in the NAC shell and core subregions as well as the ventral and dorsal parts of the mPFC, while moderately enhancing extracellular serotonin levels (to ～135% of baseline value) in the NAC core only. Although systemic administration of the CB1 receptor antagonist SR141716A (0-3mg/kg) alone did not affect monoamine release, it dose-dependently abolished amphetamine-induced dopamine release specifically in the NAC shell. SR141716A did not affect amphetamine-induced norepinephrine or serotonin release in any of the brain regions investigated. Thus, the effects of acute CB1 receptor blockade on amphetamine-induced monoamine transmission were restricted to dopamine, and more specifically to mesolimbic dopamine projections into the NAC shell. This brain region- and monoamine-selective role of CB1 receptors is suggested to subserve the behavioral effects of amphetamine.     

Restoration of the CD4 T cell compartment after long-term highly active antiretroviral therapy without phenotypical signs of accelerated immunological aging

It remains uncertain whether full T cell reconstitution can be established in HIV-infected children and adults with long-term sustained virological control by highly active antiretroviral therapy (HAART). In this study, we comprehensively analyzed various phenotypical markers of CD4 T cell recovery. In addition to measuring T cell activation and proliferation markers, CD4 T cell generation and aging of the CD4 T cell compartment were assessed by measuring TCR excision circles and the fraction of CD31-expressing naive CD4 T cells. In all children and in adults with relatively high CD4 T cell counts at start of therapy (>200 cells/microl), total CD4 T cell numbers normalized within 1 year of therapy. After long-term HAART (4.4-9.6 years), naive CD4 T cell counts had normalized in both groups. Although in adults with low baseline CD4 T cell counts (<200 cells/microl) total CD4 T cell numbers normalized eventually after at least 7 years of HAART, naive CD4 T cell counts had still not recovered. TCR excision circle data showed that thymic T cell production contributed to naive T cell recovery at all ages. The fraction of CD31-expressing naive CD4 T cells was found to be normal, suggesting that the CD4 T cell repertoire was diverse after long-term HAART. Hence, under sustained viral suppression during long-term HAART, the T cell compartment has the potential to fully recover by generating new naive T cells both in children and in adults with high baseline CD4 T cells counts. Irrespective of baseline CD4 T cell counts, reconstitution occurred without a significant effect on T cell aging as reflected by markers for replicative history.     

Moving the Weber Fraction: The Perceptual Precision for Moment of Inertia Increases with Exploration Force

How does the magnitude of the exploration force influence the precision of haptic perceptual estimates? To address this question, we examined the perceptual precision for moment of inertia (i.e., an object''s “angular mass”) under different force conditions, using the Weber fraction to quantify perceptual precision. Participants rotated a rod around a fixed axis and judged its moment of inertia in a two-alternative forced-choice task. We instructed different levels of exploration force, thereby manipulating the magnitude of both the exploration force and the angular acceleration. These are the two signals that are needed by the nervous system to estimate moment of inertia. Importantly, one can assume that the absolute noise on both signals increases with an increase in the signals'' magnitudes, while the relative noise (i.e., noise/signal) decreases with an increase in signal magnitude. We examined how the perceptual precision for moment of inertia was affected by this neural noise. In a first experiment we found that a low exploration force caused a higher Weber fraction (22%) than a high exploration force (13%), which suggested that the perceptual precision was constrained by the relative noise. This hypothesis was supported by the result of a second experiment, in which we found that the relationship between exploration force and Weber fraction had a similar shape as the theoretical relationship between signal magnitude and relative noise. The present study thus demonstrated that the amount of force used to explore an object can profoundly influence the precision by which its properties are perceived.     

Septal and Hippocampal Glutamate Receptors Modulate the Output of Acetylcholine in Hippocampus: A Microdialysis Study

Abstract: In the present study, glutamate receptor agonists and antagonists were administered by retrograde microdialysis into either the medial septum/vertical limb of the diagonal band (MS/vDB), or hippocampus, and the output of acetylcholine (ACh) was measured in the hippocampus by using intracerebral microdialysis. Perfusion with N -methyl- d -aspartate (NMDA) and ( S )-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) in the MS/vDB caused an increase in ACh output in the hippocampus. This increase was completely blocked by coadministration of their respective antagonists d (−)-2-amino-5-phosphonopentanoic acid ( d -AP5) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Perfusion in the MS/vDB with kainic acid also caused an increase in ACh output, but coadministration of CNQX attenuated the increase only partially. Perfusion with d -AP5 or CNQX alone in the septal probe did not affect ACh output from the hippocampus. In contrast to the results of septal administration of NMDA and AMPA, local perfusion with the same drugs in the hippocampus caused a decrease in ACh output. Whereas the results of septal administration of drugs indicate that septal cholinergic neurons probably receive excitatory glutamatergic innervation, the decrease in ACh output caused by administration of NMDA and AMPA in the hippocampus is poorly understood.