The estrogenic activity of phthalate esters in vitro

A large number of phthalate esters were screened for estrogenic activity using a recombinant yeast screen. a selection of these was also tested for mitogenic effect on estrogen-responsive human breast cancer cells. A small number of the commercially available phthalates tested showed extremely weak estrogenic activity. The relative potencies of these descended in the order butyl benzyl phthalate (BBP) > dibutyl phthalate (DBP) > diisobutyl phthalate (DIBP) > diethyl phthalate (DEP) > diisiononyl phthalate (DINP). Potencies ranged from approximately 1 x 10(6) to 5 x 10(7) times less than 17beta-estradiol. The phthalates that were estrogenic in the yeast screen were also mitogenic on the human breast cancer cells. Di(2-ethylhexyl) phthalate (DEHP) showed no estrogenic activity in these in vitro assays. A number of metabolites were tested, including mono-butyl phthalate, mono-benzyl phthalate, mono-ethylhexyl phthalate, mon-n-octyl phthalate; all were wound to be inactive. One of the phthalates, ditridecyl phthalate (DTDP), produced inconsistent results; one sample was weakly estrogenic, whereas another, obtained from a different source, was inactive. analysis by gel chromatography-mass spectometry showed that the preparation exhibiting estrogenic activity contained 0.5% of the ortho-isomer of bisphenol A. It is likely that the presence of this antioxidant in the phthalate standard was responsible for the generation of a dose-response curve--which was not observed with an alternative sample that had not been supplemented with o,p'-bisphenol A--in the yeast screen; hence, DTDP is probably not weakly estrogenic. The activities of simple mixtures of BBP, DBP, and 17beta-estradiol were assessed in the yeast screen. No synergism was observed, although the activities of the mixtures were approximately additive. In summary, a small number of phthalates are weakly estrogenic in vitro. No data has yet been published on whether these are also estrogenic in vitro. No data has yet been published on whether these are also estrogenic in vivo; this will require tests using different classes of vertebrates and different routes of exposure

The effect of phenytoin, phenobarbitone, dexamethasone and flurbiprofen on misonidazole neurotoxicity in mice.

Using a quantitative cytochemical technique for measuring beta-glucuronidase activity in the peripheral nerves of mice, we have investigated the effectiveness of four potential adjuncts for reducing the dose limiting neurotoxicity of misonidazole (MISO) in the clinic. Under the conditions used, the most effective adjunct was the steroid anti-inflammatory agent dexamethasone. When given over the week previous to MISO treatment, this agent almost completely eliminated the MISO neurotoxicity as determined at week 4 after commencement of MISO dosing. The second most effective adjunct was phenytoin, the third flurbiprofen and the last adjunct, phenobarbitone, was ineffective. Dexamethasone, phenytoin and phenobarbitone all reduced the clearance half-life of MISO and hence the drug exposure dose calculated as the area under the curve of MISO tissue concentration against time. However, no correlation was evident with these parameters and MISO neurotoxicity in the mouse. Dexamethasone, whilst affording protection against MISO toxicity, did not alter the radiosensitivity of the anaplastic MT tumour

TCR Translocations at the Normal-malignant T Cell Interface

Hematopoiesis is the process leading to production and maturation of peripheral blood cells. All blood cells are derived from hematopoietic stem cells (HSCs) which reside in hematopoietic organs. In mammals, the site of hematopoiesis changes during development, which is sequentially taking place in different organs starting with primitive erythrocytes in the yolk sac, the aorta-gonad mesonephros (AGM) region, the fetal lever, and finally the bone marrow (BM) during adulthood. Blood cells are short-lived, and with a daily demand for more than a billion new hematopoietic cells, a continuous replenishment of progenitor cells committed to specific hematopoietic lineages is required. HSCs are at the top of the hematopoietic hierarchy, and are the only source of progenitors. HSCs comprise 0.005-0.01% of the bone marrow, and their unique properties, i.e. the ability of self-renewal and multi-lineage differentiation potential in combination with a specific stem cell microenvironment/ niche, enable these cells to sustain the hematopoietic system. These cells differentiate into progenitor cells, either into common lymphoid progenitors (CLP) or common myeloid progenitors (CMP), which in due course differentiate into mature blood cells, providing cells to the myeloid or lymphoid system respectively 6. CLPs carry the potential to give rise to B cells, T cells (via the thymus) and NK cells, whereas CMPs have the potential to differentiate into erythrocytes, megakaryocytes, macrophages, and granulocytes. Dendritic cells can arise from both progenitor types. The process of hematopoietic lineage determination is tightly regulated by the BM microenvironment’s extrinsic factors, such as growth factors and cytokines mediated by cell-cell interactions, which sustain survival and proliferation of committed cells. Equally important in determining cell fate are the lineage- and cell-type-specific gene expression signatures (intrinsic factors). These signatures are based on the up and down regulation of transcription factors apparently regulated by the epigenetic-micro RNAs regulatory circuit. The strict regulation of both extrinsic and intrinsic signals is of utmost importance, as deregulation of the expression of these factors could result in hematopoietic malignancies such as leukemia or lymphoma. Such deregulation of gene expression is usually caused by irreversible molecular-cytogenetic changes introduced into the genomic DNA sequence. These changes can be caused by mutations, translocations and deletions concerning genes involved in cell cycle, differentiation, proliferation, and self-renewal processes. During the last decade it has become evident that, next to genetic aberrations, epigenetic alterations can also contribute to tumorigenesis, for example through gene silencing due to aberrant methylation.

Conformal symmetry and light flavor baryon spectra

The degeneracy among parity pairs systematically observed in the N and Delta spectra is interpreted to hint on a possible conformal symmetry realization in the light flavor baryon sector in line with AdS_5/CFT_4. The case is made by showing that all the observed N and Delta resonances with masses below 2500 MeV distribute fairly well each over the first levels of a unitary representation of the conformal group, a representation that covers the spectrum of a quark-diquark system, placed directly on the AdS_5 cone, conformally compactified to R^1*S^3. The free geodesic motion on the S^3 manifold is described by means of the scalar conformal equation there, which is of the Klein-Gordon type. The equation is then gauged by the "curved" Coulomb potential that has the form of a cotangent function. Conformal symmetry is not exact, this because the gauge potential slightly modifies the conformal centrifugal barrier of the free geodesic motion. Thanks to this, the degeneracy between P11-S11 pairs from same level is relaxed, while the remaining states belonging to same level remain practically degenerate. The model describes the correct mass ordering in the P11-S11 pairs through the nucleon spectrum as a combined effect of the above conformal symmetry breaking, on the one side, and a parity change of the diquark from a scalar at low masses, to a pseudoscalar at higher masses, on the other. The quality of the wave functions is illustrated by calculations of realistic mean-square charge radii and electric charge form-factors on the examples of the proton, and the protonic P11(1440), and S11(1535) resonances. The scheme also allows for a prediction of the dressing function of an effective instantaneous gluon propagator from the Fourier transform of the gauge potential. We find a dressing function that is finite in the infrared and tends to zero at infinity.Comment: Latex, 5 figures, 2 tables; Paper upgraded in accord with the published version. Discussion on the meson sector include

Trigger, an active release experiment that stimulated auroral particle precipitation and wave emissions

The experiment design, including a description of the diagnostic and chemical release payload, and the general results are given for an auroral process simulation experiment. A drastic increase of the field aligned charged particle flux was observed over the approximate energy range 10 eV to more than 300 keV, starting about 150 ms after the release and lasting about one second. The is evidence of a second particle burst, starting one second after the release and lasting for tens of seconds, and evidence for a periodic train of particle bursts occurring with a 7.7 second period from 40 to 130 seconds after the release. A transient electric field pulse of 200 mv/m appeared just before the particle flux increase started. Electrostatic wave emissions around 2 kHz, as well as a delayed perturbation of the E-region below the plasma cloud were also observed. Some of the particle observations are interpreted in terms of field aligned electrostatic acceleration a few hundred kilometers above the injected plasma cloud. It is suggested that the acceleration electric field was created by an instability driven by field aligned currents originating in the plasma cloud

Seasonal variation in Plasmodium prevalence in a population of blue tits Cyanistes caeruleus

1. Seasonal variation in environmental conditions is ubiquitous and can affect the spread of infectious diseases. Understanding seasonal patterns of disease incidence can help to identify mechanisms, such as the demography of hosts and vectors, which influence parasite transmission dynamics. 2. We examined seasonal variation in Plasmodium infection in a blue tit Cyanistes caeruleus population over 3 years using sensitive molecular diagnostic techniques, in light of Beaudoin et al.'s (1971; Journal of Wildlife Diseases, 7, 5–13) model of seasonal variation in avian malaria prevalence in temperate areas. This model predicts a within-year bimodal pattern of spring and autumn peaks with a winter absence of infection. 3. Avian malaria infections were mostly Plasmodium (24·4%) with occasional Haemoproteus infections (0·8%). Statistical nonlinear smoothing techniques applied to longitudinal presence/absence data revealed marked temporal variation in Plasmodium prevalence, which apparently showed a within-year bimodal pattern similar to Beaudoin et al.'s model. However, of the two Plasmodium morphospecies accounting for most infections, only the seasonal pattern of Plasmodium circumflexum supported Beaudoin et al.'s model. On closer examination there was also considerable age structure in infection: Beaudoin et al.'s seasonal pattern was observed only in first year and not older birds. Plasmodium relictum prevalence was less seasonally variable. 4. For these two Plasmodium morphospecies, we reject Beaudoin et al.'s model as it does not survive closer scrutiny of the complexities of seasonal variation among Plasmodium morphospecies and host age classes. Studies of host–parasite interactions should consider seasonal variation whenever possible. We discuss the ecological and evolutionary implications of seasonal variation in disease prevalence