Search

Background Gallium is a semi-metallic element known since the 1930s to have antimicrobial activity. This activity stems primarily from gallium's ability to mimic trivalent iron and disrupt specific Fe(III)-dependent pathways, particularly DNA synthesis (due to inhibition of ribonucleotide reductase). Because of its novel mechanism of action, gallium is currently being investigated as a new antibacterial agent, particularly in light of the increasing resistance of many pathogenic bacteria to existing antibiotics. Gallium maltolate (GaM) is being developed as an orally and topically administrable form of gallium. Yaws is a neglected tropical disease affecting mainly the skin and skeletal system of children in underprivileged settings. It is currently the object of a WHO-promoted eradication campaign using mass administration of the macrolide azithromycin, an antibiotic to which the yaws agent Treponema pallidum subsp. pertenue has slowly begun to develop genetic resistance. Methods Because yaws transmission is mainly due to direct skin contact with an infectious skin lesion, we evaluated the treponemicidal activity of GaM applied topically to skin lesions in a rabbit model of yaws. Treatment efficacy was evaluated by measuring lesion diameter, treponemal burden in lesion aspirates as determined by dark field microscopy and amplification of treponemal RNA, serology, and immunohistochemistry of biopsied tissue samples. Results Our results show that topical GaM was effective in reducing treponemal burden in yaws experimental lesions, particularly when applied at the first sign of lesion appearance but, as expected, did not prevent pathogen dissemination. Conclusion Early administration of GaM to yaws lesions could reduce the infectivity of the lesions and thus yaws transmission, potentially contributing to current and future yaws control campaigns., Author summary Yaws is a neglected tropical disease affecting children in underprivileged countries, transmitted through direct skin contact with an active lesion. This infection, although rarely fatal, can lead to disfigurement and serious disability. The World Health Organization is currently conducting a yaws eradication effort that employs mass administration of azithromycin, an antibiotic against which the yaws pathogen has slowly begun to develop genetic resistance. Because this phenomenon has the potential to undermine the eradication effort, we investigated the antimicrobial activity of gallium maltolate, which has a novel mechanism of action, against the yaws pathogen. Our initial results show that topical application of gallium maltolate has significant treponemicidal activity, and suggest that this compound might find an application in the effort to eradicate yaws. Future studies will evaluate whether oral administration of gallium maltolate is as effective as the antibiotics currently approved for yaws treatment to clear systemic infection.

Background: VLDL and chylomicrons may interfere with measurements of apolipoprotein B (apo B) on LDL particles. Ultracentrifugation of samples enriched in chylomicrons and VLDL and subsequent measurement of apo B in the infranate fraction [density (d) = 1.006] removes this interference. This apo B fraction is called “LDL–apo B.” Methods: We retrospectively analyzed 64 895 measurements of triglycerides, total apo B, and LDL–apo B. Samples were ultracentrifuged, and 3 commercially available immunoassays that use different antibodies were used to measure LDL–apo B in the 1.006 infranate fraction. Results: After adjusting for triglyceride concentration, we found total apo B and LDL–apo B measurements to be strongly correlated. We derived a simple linear equation for calculating LDL–apo B concentration (in milligrams per deciliter) from measurements of total apo B and triglycerides: LDL–apo B = apo B − 10 mg/dL − triglycerides/32. This equation accurately predicts LDL–apo B values within ±12% of the measured value in 75% of cases. Conclusions: Our equation provides a convenient means of estimating LDL–apo B from commonly available measurements of total apo B and triglycerides without the need for ultracentrifugation. LDL–apo B measurements were also independent of the different apo B antibodies in the 3 assays used in this study. An equation that predicts LDL–apo B particle number may be useful, regardless of the apo B assay used.

The enzyme 7,8-dihydropteroate synthase (DHPS) catalyzes the condensation of para-aminobenzoic acid (pABA) with 6-hydroxymethyl-7, 8-dihydropterin-pyrophosphate to form 7,8-dihydropteroate and pyrophosphate. DHPS is essential for the de novo synthesis of folate in prokaryotes, lower eukaryotes, and in plants, but is absent in mammals. Inhibition of this enzyme's activity by sulfonamide and sulfone drugs depletes the folate pool, resulting in growth inhibition and cell death. Here, we report the 1.7 A resolution crystal structure of the binary complex of 6-hydroxymethylpterin monophosphate (PtP) with DHPS from Mycobacterium tuberculosis (Mtb), a pathogen responsible for the death of millions of human beings each year. Comparison to other DHPS structures reveals that the M. tuberculosis DHPS structure is in a unique conformation in which loop 1 closes over the active site. The Mtb DHPS structure hints at a mechanism in which both loops 1 and 2 play important roles in catalysis by shielding the active site from bulk solvent and allowing pyrophosphoryl transfer to occur. A binding mode for pABA, sulfonamides and sulfones is suggested based on: (i) the new conformation of the closed loop 1; (ii) the distribution of dapsone and sulfonamide resistance mutations; (iii) the observed direction of the bond between the 6-methyl carbon atom and the bridging oxygen atom to the alpha-phosphate group in the Mtb DHPS:PtP binary complex; and (iv) the conformation of loop 2 in the Escherichia coli DHPS structure. Finally, the Mtb DHPS structure reveals a highly conserved pterin binding pocket that may be exploited for the design of novel antimycobacterial agents.

A recently developed spectroscopic technique was used to determine orygen diffusion coefficients, D, as a function of temperature in polystyrene and polycarbonate films. The data were quantified by using an Arrhenius expression with the following variables: (a) a diffusion activation barrier, E act , and (b) a diffusion coefficient, D 0 , that represents the condition of «barrier-free» gas transport. From the perspective that diffusion depends on free volume, the parameters E act and D 0 are interpreted to reflect dynamic and static elements of free volume in the polymer matrix. The addition of low molecular weight solutes to these amorphous glasses can alter the oxygen diffusion coefficient by affecting the dynamic and/or static free volume of the material

We report here the failure of the Synchron LX (Beckman) and Vitros 950 (Johnson & Johnson) assays to detect HDL-cholesterol (HDL-C) in the presence of a paraprotein. HDL-C was repeatedly undetectable (