Vitamins A & D Inhibit the Growth of Mycobacteria in Radiometric Culture

The role of vitamins in the combat of disease is usually conceptualized as acting by modulating the immune response of an infected, eukaryotic host. We hypothesized that some vitamins may directly influence the growth of prokaryotes, particularly mycobacteria. complex).Vitamins A and D cause dose-dependent inhibition of all three mycobacterial species studied. Vitamin A is consistently more inhibitory than vitamin D. The vitamin A precursor, β-carotene, is not inhibitory, whereas three vitamin A metabolites cause inhibition. Vitamin K has no effect. Vitamin E causes negligible inhibition in a single strain.We show that vitamin A, its metabolites Retinyl acetate, Retinoic acid and 13-cis Retinoic acid and vitamin D directly inhibit mycobacterial growth in culture. These data are compatible with the hypothesis that complementing the immune response of multicellular organisms, vitamins A and D may have heretofore unproven, unrecognized, independent and probable synergistic, direct antimycobacterial inhibitory activity

On the Action of 5-Amino-Salicylic Acid and Sulfapyridine on M. avium including Subspecies paratuberculosis

BACKGROUND: Introduced in 1942, sulfasalazine (a conjugate of 5-aminosalicylic acid (5-ASA) and sulfapyridine) is the most prescribed medication used to treat "inflammatory" bowel disease (IBD.) Although controversial, there are increasingly compelling data that Mycobacterium avium subspecies paratuberculosis (MAP) may be an etiological agent in some or all of IBD. We have shown that two other agents used in the therapy of IBD (methotrexate and 6-MP) profoundly inhibit MAP growth. We concluded that their most plausible mechanism of action is as antiMAP antibiotics. We herein hypothesize that the mechanism of action of 5-ASA and/or sulfapyridine may also simply be to inhibit MAP growth. METHODOLOGY: The effect on MAP growth kinetics by sulfasalazine and its components were evaluated in bacterial culture of two strains each of MAP and M. avium, using a radiometric ((14)CO(2) BACTEC(R)) detection system that quantifies mycobacterial growth as arbitrary "growth index units" (GI). Efficacy data are presented as "percent decrease in cumulative GI" (%-DeltacGI). PRINCIPAL FINDINGS: There are disparate responses to 5-ASA and sulfapyridine in the two subspecies. Against MAP, 5-ASA is inhibitory in a dose-dependent manner (MAP ATCC 19698 46%-DeltacGI at 64 microg/ml), whereas sulfapyridine has virtually no effect. In contrast, against M. avium ATCC 25291, 5-ASA has no effect, whereas sulfapyridine (88%-DeltacGI at 4 microg/ml) is as effective as methotrexate, our positive control (88%-DeltacGI at 4 microg/ml). CONCLUSIONS: 5-ASA inhibits MAP growth in culture. We posit that, unknowingly, the medical profession has been treating MAP infections since sulfasalazine's introduction in 1942. These observations may explain, in part, why MAP has not previously been identified as a human pathogen. We conclude that henceforth in clinical trials evaluating antiMAP agents in IBD, if considered ethical, the use of 5-ASA (as well as methotrexate and 6-MP) should be excluded from control groups

Neutrino propagation in a random magnetic field

The active-sterile neutrino conversion probability is calculated for neutrino propagating in a medium in the presence of random magnetic field fluctuations. Necessary condition for the probability to be positive definite is obtained. Using this necessary condition we put constraint on the neutrino magnetic moment from active-sterile electron neutrino conversion in the early universe hot plasma and in supernova.Comment: 11 page

On the Action of Methotrexate and 6-Mercaptopurine on M. avium Subspecies paratuberculosis

BACKGROUND: Clinical improvement in inflammatory bowel disease (IBD) treated with methotrexate and 6-mercaptopurine (6-MP) is associated with a decrease in pro-inflammatory cytokines. This has been presumed to indicate the mechanism of action of methotrexate and 6-MP. Although controversial, there are increasingly compelling data that Mycobacterium avium subspecies paratuberculosis (MAP) may be an etiological agent in some or all of IBD. We hypothesized that the clinical efficacy of methotrexate and 6-MP in IBD may be to simply inhibit the growth of MAP. METHODOLOGY: The effect on MAP growth kinetics by methotrexate and 6-MP were evaluated in cell culture of two strains each of MAP and M. avium using a radiometric ((14)CO(2) BACTEC®) detection system that quantifies mycobacterial growth as arbitrary “growth index units” (GI). Efficacy data are presented as “percent decrease in cumulative GI” (% −ΔcGI). PRINCIPAL FINDINGS: The positive control antibiotic (clarithromycin) has ≥85% −ΔcGI at a concentration of 0.5 µg/ml. The negative control (ampicillin) has minimal inhibition at 64 µg/ml. MAP ATCC 19698 shows ≥80% −ΔcGI for both agents by 4 µg/ml. With the other three isolates, although more effective than ampicillin, 6-MP is consistently less effective than methotrexate. CONCLUSIONS: We show that methotrexate and 6-MP inhibit MAP growth in vitro. Each of the four isolates manifests different % −ΔcGI. These data are compatible with the hypothesis that the clinical improvement in patients with IBD treated with methotrexate and 6-MP could be due to treating a MAP infection. The decrease in pro-inflammatory cytokines, thought to be the primary mechanism of action, may simply be a normal, secondary, physiological response. We conclude that henceforth, in clinical studies that evaluate the effect of anti-MAP agents in IBD, the use of methotrexate and 6-MP should be excluded from any control groups

Big Bang Nucleosynthesis Constraints on Primordial Magnetic Fields

We reanalyze the effect of magnetic fields in BBN, incorporating several features which were omitted in previous analyses. We find that the effects of coherent magnetic fields on the weak interaction rates and the electron thermodynamic functions (\rhoe, \Pe, and \drhoedt ) are unimportant in comparison to the contribution of the magnetic field energy density in BBN. In consequence the effect of including magnetic fields in BBN is well approximated numerically by treating the additional energy density as effective neutrino number. A conservative upper bound on the primordial magnetic field, parameterized as $\zeta=2eB_{rms}/(T_\nu^2)$, is $\zeta \le 2$ ($\rho_B < 0.27 \rho_\nu$). This bound can be stronger than the conventional bound coming from the Faraday rotation measures of distant quasars if the cosmological magnetic field is generated by a causal mechanism.Comment: Latex, 20 pages, 3 uuencoded figures appende

Hot subdwarfs from the ESO Supernova Ia Progenitor Survey: II. Atmospheric parameters of subdwarf O stars

We address the origin and evolutionary status of hot subdwarf stars by studying the optical spectral properties of 58 subdwarf O (sdO) stars. Combining them with the results of our previously studied subdwarf B (sdB) stars, we aim at investigating possible evolutionary links. We analyze high-resolution ESO VLT UVES spectra from the ESO Supernova Ia Progenitor Survey (SPY). Effective temperatures, gravities, and helium abundances are determined simultaneously by fitting the profiles of H and He lines using dedicated synthetic spectra in NLTE. Evidence for cool companions to 8 sdOs as well as a binary consisting of two sdO stars is found. A correlation between He abundances and the presence of carbon and/or nitrogen lines emerges: below solar He abundance, no sdO shows C or N lines. In contrast, C and/or N lines are present in ALL sdOs with super- solar He abundance. We thus use the solar He abundance to divide our sample into He-deficient and He-enriched sdOs. While He-deficient sdOs are scattered in a wide range of the Teff-log(g)-diagram, most of the He-enriched sdOs cluster in a narrow region at Teff = 40,000 ... 50,000K and log(g)=5.5 ... 6.0. An evolu- tionary link between sdBs and sdOs appears plausible only for the He-deficient sdOs indicating that they are the likely successors to sdBs. The properties of He-enriched sdOs cannot be explained with canonical single star evolutionary models. Alternative scenarios (late hot flasher) as well as for binary evolution (white dwarf merger; post-RGB evolution) are tested. While we regard the post-RGB scenario as inappropriate, the white dwarf merger and the late hot flasher scenarios remain viable to explain the origin of He-enriched sdOs.Comment: 14 pages, 10 figures, Astronomy & Astrophysics accepte

Primordial magnetic fields, anomalous isocurvature fluctuations and Big Bang nucleosynthesis

We show that the presence of primordial stochastic (hypercharge) magnetic fields before the electroweak (EW) phase transition induces isocurvature fluctuations (baryon number inhomogeneities). Depending on the details of the magnetic field spectrum and on the particle physics parameters (such as the strength of the EW phase transition and electron Yukawa couplings) these fluctuations may survive until the Big Bang nucleosynthesis (BBN). Their lenghtscale may exceed the neutron diffusion length at that time, while their magnitude can be so large that sizable antimatter domains are present. This provides the possibility of a new type of initial conditions for non-homogeneous BBN or, from a more conservative point of view, stringent bounds on primordial magnetic fields.Comment: 4 pages, Latex, 1 epsfi

Showing Israel the red card. Activists engaged in pro-Palestinian sport-related campaigns

© 2017 Informa UK Limited, trading as Taylor & Francis Group. This article explores the motivations of activists involved in pro-Palestinian sports-based campaigns. The activists’ intention is to bring pressure to bear upon Israel until it complies with international law and supports the rights of Palestinian people under the universal principles of human rights. In response to expressions of pro-Palestinian solidarity, the Israeli state and its supporters are interpreting such activity as a ‘new’ manifestation of ‘old’ antisemitism. In seeking to assess whether such activity is informed by antisemitism, 10 semi-structured interviews were conducted with activists to examine their motives. Their political biographies were explored as were their views on the use of sport as platform to express support for the Palestinian people and/or their displeasure at Israeli participation in international sport. One central theme was the activists’ responses to the suggestion that they were motivated by antisemitism. A qualitative content analysis of the interview transcripts revealed a shared observation that the accusation of antisemitism was a ‘shameless tactic’ employed by those seeking to cover up the ongoing injustices experienced by the Palestinian people. Sport was seen as a legitimate platform for political activity, to raise public awareness and to put pressure on the Israeli state. The findings contribute to a better understanding of activist motivations, the use of sport as a political platform and the challenges facing sport and its governing bodies

On the Action of Cyclosporine A, Rapamycin and Tacrolimus on M. avium Including Subspecies paratuberculosis

BACKGROUND: Mycobacterium avium subspecies paratuberculosis (MAP) may be zoonotic. Recently the "immuno-modulators" methotrexate, azathioprine and 6-MP and the "anti-inflammatory" 5-ASA have been shown to inhibit MAP growth in vitro. We concluded that their most plausible mechanism of action is as antiMAP antibiotics. The "immunosuppressants" Cyclosporine A, Rapamycin and Tacrolimus (FK 506) treat a variety of "autoimmune" and "inflammatory" diseases. Rapamycin and Tacrolimus are macrolides. We hypothesized that their mode of action may simply be to inhibit MAP growth. METHODOLOGY: The effect on radiometric MAP (14)CO(2) growth kinetics of Cyclosporine A, Rapamycin and Tacrolimus on MAP cultured from humans (Dominic & UCF 4) or ruminants (ATCC 19698 & 303) and M. avium subspecies avium (ATCC 25291 & 101) are presented as "percent decrease in cumulative GI" (%-DeltacGI.) PRINCIPAL FINDINGS: The positive control clofazimine has 99%-DeltacGI at 0.5 microg/ml (Dominic). Phthalimide, a negative control has no dose dependent inhibition on any strain. Against MAP there is dose dependent inhibition by the immunosuppressants. Cyclosporine has 97%-DeltacGI by 32 microg/ml (Dominic), Rapamycin has 74%-DeltacGI by 64 microg/ml (UCF 4) and Tacrolimus 43%-DeltacGI by 64 microg/ml (UCF 4) CONCLUSIONS: We show heretofore-undescribed inhibition of MAP growth in vitro by "immunosuppressants;" the cyclic undecapeptide Cyclosporine A, and the macrolides Rapamycin and Tacrolimus. These data are compatible with our thesis that, unknowingly, the medical profession has been treating MAP infections since 1942 when 5-ASA and subsequently azathioprine, 6-MP and methotrexate were introduced in the therapy of some "autoimmune" and "inflammatory" diseases

Remodelling of human atrial K+ currents but not ion channel expression by chronic β-blockade

Chronic β-adrenoceptor antagonist (β-blocker) treatment in patients is associated with a potentially anti-arrhythmic prolongation of the atrial action potential duration (APD), which may involve remodelling of repolarising K+ currents. The aim of this study was to investigate the effects of chronic β-blockade on transient outward, sustained and inward rectifier K+ currents (ITO, IKSUS and IK1) in human atrial myocytes and on the expression of underlying ion channel subunits. Ion currents were recorded from human right atrial isolated myocytes using the whole-cell-patch clamp technique. Tissue mRNA and protein levels were measured using real time RT-PCR and Western blotting. Chronic β-blockade was associated with a 41% reduction in ITO density: 9.3 ± 0.8 (30 myocytes, 15 patients) vs 15.7 ± 1.1 pA/pF (32, 14), p &#60; 0.05; without affecting its voltage-, time- or rate dependence. IK1 was reduced by 34% at −120 mV (p &#60; 0.05). Neither IKSUS, nor its increase by acute β-stimulation with isoprenaline, was affected by chronic β-blockade. Mathematical modelling suggested that the combination of ITO- and IK1-decrease could result in a 28% increase in APD90. Chronic β-blockade did not alter mRNA or protein expression of the ITO pore-forming subunit, Kv4.3, or mRNA expression of the accessory subunits KChIP2, KChAP, Kvβ1, Kvβ2 or frequenin. There was no reduction in mRNA expression of Kir2.1 or TWIK to account for the reduction in IK1. A reduction in atrial ITO and IK1 associated with chronic β-blocker treatment in patients may contribute to the associated action potential prolongation, and this cannot be explained by a reduction in expression of associated ion channel subunits