Ciprofloxacin-induces free radical production in rat cerebral microsomes.

In the presence of ciprofloxacin (CPFX), free radical adduct formation was demonstrated in rat cerebral microsomes using a spin trap α-(4-pyridyl-1-oxide)-N--butyl-nitrone by electron spin resonance spectroscopy. Active microsomes, dihydronicotinamide-adenine dinucleotide phosphate, and ciprofloxacin were necessary for the formation of a spin trap/radical adduct. Adduct formation increased dose-dependently at 0.

Alterations to mitochondrial fatty-acid use in skeletal muscle after chronic exposure to hypoxia depend on metabolic phenotype.

We investigated the effects of chronic hypoxia on the maximal use of and sensitivity of mitochondria to different substrates in rat slow-oxidative (soleus, SOL) and fast-glycolytic (extensor digitorum longus, EDL) muscles. We studied mitochondrial respiration in situ in permeabilized myofibers, using pyruvate, octanoate, palmitoyl-carnitine (PC), or palmitoyl-coenzyme A (PCoA). The hypophagia induced by hypoxia may also alter metabolism.

Post-transcriptional regulation of autophagy in C2C12 myotubes following starvation and nutrient restoration.

In skeletal muscle, autophagy is activated in multiple physiological and pathological conditions, notably through the transcriptional regulation of autophagy-related genes by FoxO3. However, recent evidence suggests that autophagy could also be regulated by post-transcriptional mechanisms. The purpose of the study was therefore to determine the temporal regulation of transcriptional and post-transcriptional events involved in the control of autophagy during starvation (4h) and nutrient restoration (4h) in C2C12 myotubes.

Impact of Anesthetics on Immune Functions in a Rat Model of Vagus Nerve Stimulation.

Vagus nerve stimulation (VNS) has been successfully performed in animals for the treatment of different experimental models of inflammation. The anti-inflammatory effect of VNS involves the release of acetylcholine by vagus nerve efferent fibers inhibiting pro-inflammatory cytokines (e.g.

Gene therapy to mitigate radiation-induced bone marrow aplasia: preliminary study in highly irradiated monkeys.

The hematopoietic syndrome represents the first therapeutic challenge following exposure to high doses of ionizing radiation. Today there is a crucial need to identify/develop new treatments in order to reach the transplantation threshold. The authors propose the concept of a global niche therapy strategy based on local and short-term secretion of selected morphogenes to favor a vascular niche in order to raise the transplantation threshold regeneration and to stimulate residual hematopoietic stem and progenitor cells.

Cytoskeleton as an emerging target of anthrax toxins.

Bacillus anthracis, the agent of anthrax, has gained virulence through its exotoxins produced by vegetative bacilli and is composed of three components forming lethal toxin (LT) and edema toxin (ET). So far, little is known about the effects of these toxins on the eukaryotic cytoskeleton. Here, we provide an overview on the general effects of toxin upon the cytoskeleton architecture.

[Recombinant antibodies for medical protection against bioterrorism agents: the example of anthrax].

Recombinant antibodies are a highly successful class of therapeutic molecules, they are well adapted for use against bio-weapons (BW) as they act immediately, are often synergistic with other therapeutic molecules, have a long half-life and are well tolerated. Anthrax is regarded at high risk of being used as BW, and its pathogenic properties depend on toxins, which might be neutralized by antibodies. These toxins are made of three different types of sub-units (PA, LF, EF).

A comparison of human and macaque (Macaca mulatta) immunoglobulin germline V regions and its implications for antibody engineering.

Seventy-five V regions encoded by the sequenced genome of one Macaca mulatta specimen have been identified by homology, and paired with similar human counterparts. When the human V region of each pair presented no allelic polymorphism, it was directly compared with its homolog. This was the case for 37 pairs, and percents of identity ranged between 84 to 97%.

Eukaryotic DING proteins are endogenous: an immunohistological study in mouse tissues.

Background: DING proteins encompass an intriguing protein family first characterized by their conserved N-terminal sequences. Some of these proteins seem to have key roles in various human diseases, e.g.

Obtention and engineering of non-human primate (NHP) antibodies for therapeutics.

Recombinant antibodies are therapeutic molecules of choice regarding their efficacy, pharmacokinetics and tolerance - all the more if they are human. The efficacy of antibodies generally depends on their affinity for their antigens. The most straightforward approach to isolate human antibodies with high affinities is the construction and screening of human immune libraries, but Humans cannot be immunized with all antigens of interest, for ethical and practical reasons.

Non-human primate immune libraries combined with germline humanization: an (almost) new, and powerful approach for the isolation of therapeutic antibodies.

Panning of libraries constructed from immunised non-human primates (NHP) has not been widely used, even though this has proven to be a successful approach for the isolation of human-like antibody fragments with affinities in the nanomolar to the picomolar range. As recently demonstrated, after initial isolation of antibodies with such high affinities, germline humanization may be applied to these Fabs or scFvs to increase the similarity of their framework regions with those encoded by human germline genes. 'Germlinized' antibody fragments may be converted to full size IgGs; indications are given that these IgGs could be better tolerated in clinical use than human antibodies.

The humanness of macaque antibody sequences.

Chimeric, humanized and human antibodies have successively been exploited as therapeutics because their increasing human ('self') character is expected to correspond with decreased immunogenicity, which is critical for their clinical development. Thus, humanness has been inferred to predict antibody immunogenicity. Humanness of antibody variable regions (V-regions) has recently been studied using a parameter (here referred to as the H-score) that evaluates similarity to expressed human sequences.

[Recombinant antibodies against bioweapons].

The threat posed by bioweapons (BW) could lead to the re-emergence of such deadly diseases as plague or smallpox, now eradicated from industrialized countries. The development of recombinant antibodies allows tackling this risk because these recombinant molecules are generally well tolerated in human medicine, may be utilized for prophylaxis and treatment, and because antibodies neutralize many BW. Recombinant antibodies neutralizing the lethal toxin of anthrax, botulinum toxins and the smallpox virus have in particular been isolated recently, with different technologies.

[What's new in biomedical applications for Terahertz (THz) technology].

Terahertz technologies have recently been applied to develop high resolution imaging. Since practical portable systems can be designed, the possibilty has emerged to easily screen for biohazards and concealed objects, a procedure which usually requires remote analysis. Applications of THz are also envisaged in the medical field, because this technology offers a degree of accuracy never reached before in molecule analysis.

Broad recognition of ricin toxins prepared from a range of Ricinus cultivars using immunochromatographic tests.

Introduction: It is extremely important that diagnosis of persons exposed to ricin be achieved in a timely fashion for triage and appropriate treatment. A sensitive and specific immunochromatographic test (ICT) for ricin has been developed for this purpose and reported recently. This ICT detected ricin of a single cultivar, by naked eye, at concentrations as low as 1 ng/mL.

Isolation of a human-like antibody fragment (scFv) that neutralizes ricin biological activity.

Background: Ricin is a lethal toxin that inhibits protein synthesis. It is easily extracted from a ubiquitously grown plant, Ricinus communis, and thus readily available for use as a bioweapon (BW). Anti-ricin antibodies provide the only known therapeutic against ricin intoxication.

Obesity and obstructive sleep apnea: or is it OSA and obesity?

Obstructive sleep apnea (OSA) consists of repetitive choking spells due to sleep-induced reduction of upper airway muscle tone. Millions of adults and children live unaware of this condition, which can have a profound affect on their health and quality of life. Obesity, gender, genetic, and hormonal factors mediate risk for OSA and interact in a multifaceted manner in the pathogenesis of this disease.

[Thyroid hormones and muscle phenotype: involvement of new signaling pathways].

Thyroid hormones (TH) are known to control development, body and muscle growth, as well as to determine muscle phenotype in the adult. TH affect muscle properties through nuclear receptors; they act either by a positive or a negative control on target genes that encode proteins accounting for contractile or metabolic phenotypes. Contractile activity and muscle load also affect muscle phenotype; several intracellular signaling pathways are involved in the transduction of signals related to contractile activity, including the calcineurin/NFAT pathway.

Percutaneous penetration and distribution of VX using in vitro pig or human excised skin validation of demeton-S-methyl as adequate simulant for VX skin permeation investigations.

The organophosphorus (OP) chemical warfare V agent O-ethyl-S-[2(di-isopropylamino)ethyl] methyl phosphonothioate (VX), is a highly toxic compound which mainly penetrates the body via percutaneous pathways. Hence, the following prerequisite: to ascertain compound absorption and percutaneous profile distribution with a view to further assessing the efficacy of topical skin protectants. We first selected the most appropriate receptor fluid to carry out in vitro VX absorption experiments, namely: Hanks's Balanced Salt Solution (HBSS).

Substrate specificity of homogeneous monkeypox virus uracil-DNA glycosylase.

Weak or nonexistent smallpox immunity in today's human population raises concerns about the possibility of natural or provoked genetic modifications leading to re-emergence of variola virus and other poxviruses. Thus, the development of new antiviral strategies aimed at poxvirus infections in humans is a high priority. The DNA repair protein uracil-DNA glycosylase (UNG) is one of the viral enzymes important for poxvirus pathogenesis.

Comparison of an electrochemiluminescence assay in plate format over a colorimetric ELISA, for the detection of ricin B chain (RCA-B).

An electrochemiluminescence (ECL) assay for the detection of the B chain of ricin (RCA-B) in a 96-well plate format was developed in parallel with a colorimetric ELISA utilizing the same pair of antibodies. Sensitivity results were interpreted with the ANOVA and Tukey statistical tests, allowing a direct comparison between the two technologies, that can probably be extended to other protein antigens such as toxins. Reproducibility, repeatability and rapidity of the two techniques were also compared.

An immunochromatographic test for the diagnosis of ricin inhalational poisoning.

Introduction: Aerosolized ricin is a feared bioweapon for which no diagnostic protocol is currently available.

Methods: We obtained antibodies to develop an immunochromatographic test (ICT) that would be part of such a protocol.

Results: Our ICT, that can be read with the naked eye, has a sensitivity of 1 ng ricin/mL buffer, without enhancement, making it the most sensitive rapid test available for this toxin as far as we know.

In vitro percutaneous penetration of organophosphorus compounds using full-thickness and split-thickness pig and human skin.

Organophosphorus compounds (OPs), such as pesticides and chemical warfare agents like sarin (GB), soman (GD) and VX, are highly toxic compounds. The OP vapours and their liquid forms are readily absorbed through the skin, therefore, protecting the skin of people who are potentially exposed to these agents is crucial. The development of effective countermeasures relies on a better knowledge of the percutaneous penetration of such molecules.

Resident CD11c+ lung cells are impaired by anthrax toxins after spore infection.

Bacillus anthracis secretes 2 toxins: lethal toxin (LT) and edema toxin (ET). We investigated their role in the physiopathologic mechanisms of inhalational anthrax by evaluating murine lung dendritic cell (LDC) functions after infection with B. anthracis strains secreting LT, ET, or both or with a nontoxinogenic strain.

[Biologic effects of millimeteric waves (94 GHz). Are there long term consequences?].

Active Denial Systems (ADS) is a millimetric wave radiation emitting technology now included in the non lethal weapon arsenal. Such devices emit electromagnetic, thus agitating water in the skin and causing feeling of heat enough that target individual retreats from the beam. They can be used at up to 1 km from the target.