Bridging Implementation, Knowledge, and Ambition Gaps to Eliminate Tuberculosis in the United States and Globally

We reflect on remarkable accomplishments in global tuberculosis (TB) control and identify persistent obstacles to the successful elimination of TB from the United States and globally. One hundred and twenty nine years after Koch’s discovery of the etiologic agent of TB, this health scourge continues to account for 9.4 million cases and 1.7 million deaths annually worldwide. Implementation of the Directly Observed Treatment Short-course strategy from 1995 through 2009 has saved 6 million lives. TB control is increasingly being achieved in countries with high-income economies, yet TB continues to plague persons living in countries with low-income and lower-middle–income economies. To accelerate progress against the global effects of disease caused by TB and achieve its elimination, we must bridge 3 key gaps in implementation, knowledge, and ambition

Differential expression of the FAK family kinases in rheumatoid arthritis and osteoarthritis synovial tissues

The focal adhesion kinase (FAK) family kinases, including FAK and proline-rich kinase 2 (Pyk)2, are the predominant mediators of integrin αvβ3 signaling events that play an important role in cell adhesion, osteoclast pathology, and angiogenesis, all processes important in rheumatoid arthritis (RA). Using immunohistochemical and western blot analysis, we studied the distribution of phospho (p)FAK, pPyk2, pSrc, pPaxillin and pPLCγ in the synovial tissue (ST) from patients with RA, osteoarthritis (OA) and normal donors (NDs) as well as in RA ST fibroblasts and peripheral blood differentiated macrophages (PB MΦs) treated with tumor necrosis factor-α (TNFα) or interleukin-1β (IL1β). RA and OA STs showed a greater percentage of pFAK on lining cells and MΦs compared with ND ST. RA ST fibroblasts expressed pFAK at baseline, which increased with TNFα or IL1β stimulation. Pyk2 and Src were phosphorylated more on RA versus OA and ND lining cells and MΦs. pPyk2 was expressed on RA ST fibrobasts but not in MΦs at baseline, however it was upregulated upon TNFα or IL1β activation in both cell types. pSrc was expressed in RA ST fibroblasts and MΦs at baseline and was further increased by TNFα or IL1β stimulation. pPaxillin and pPLCγ were upregulated in RA versus OA and ND lining cells and sublining MΦs. Activation of the FAK family signaling cascade on RA and OA lining cells may be responsible for cell adhesion and migration into the diseased STs. Therapies targeting this novel signaling pathway may be beneficial in RA

A Rapid Screening Psychometric Test

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66666/2/10.1177_000992286900800506.pd

Highly Luminescent Lanthanide Complexes of 1 Hydroxy-2-pyridinones

The synthesis, X-ray structure, stability, and photophysical properties of several trivalent lanthanide complexes formed from two differing bis-bidentate ligands incorporating either alkyl or alkyl ether linkages and featuring the 1-hydroxy-2-pyridinone (1,2-HOPO) chelate group in complex with Eu(III), Sm(III) and Gd(III) are reported. The Eu(III) complexes are among some of the best examples, pairing highly efficient emission ({Phi}{sub tot}{sup Eu} {approx} 21.5%) with high stability (pEu {approx} 18.6) in aqueous solution, and are excellent candidates for use in biological assays. A comparison of the observed behavior of the complexes with differing backbone linkages shows remarkable similarities, both in stability and photophysical properties. Low temperature photophysical measurements for a Gd(III) complex were also used to gain insight into the electronic structure, and were found to agree with corresponding TD-DFT calculations for a model complex. A comparison of the high resolution Eu(III) emission spectra in solution and from single crystals also revealed a more symmetric coordination geometry about the metal ion in solution due to dynamic rotation of the observed solid state structure

Quantification of recombinant and platelet P2Y1 receptors utilizing a [125I]-labeled high-affinity antagonist 2-iodo-N6-methyl-(N)-methanocarba-2′-deoxyadenosine-3′,5′-bisphosphate ([125I]MRS2500)

The ADP-activated P2Y1 receptor is broadly expressed and plays a crucial role in ADP-promoted platelet aggregation. We previously synthesized 2-iodo-N6-methyl–(N)-methanocarba-2′-deoxyadenosine 3′,5′-bisphosphate (MRS2500), as a selective, high affinity, competitive antagonist of this receptor. Here we report utilization of a trimethylstannyl precursor molecule for the multistep radiochemical synthesis of a [125I]-labeled form of MRS2500. [125I]MRS2500 bound selectively to Sf9 insect cell membranes expressing the human P2Y1 receptor but did not specifically bind to membranes isolated from empty vector-infected cells. Binding of [125I]MRS2500 to P2Y1 receptors was saturable with a Kd of 1.2 nM. Known agonists and antagonists of the P2Y1 receptor inhibited [125I]MRS2500 binding to P2Y1 receptor-expressing membranes with potencies in agreement with those previously observed in functional assays of this receptor. A high-affinity binding site for [125I]MRS2500 also was observed on intact human platelets (Kd = 0.61 nM) and mouse platelets (Kd = 1.20 nM) that exhibited the pharmacological selectivity of the P2Y1 receptor. The densities of sites observed were 151 sites/platelet and 229 sites/platelet in human and mouse platelets, respectively. In contrast, specific binding was not observed in platelets isolated from P2Y1 receptor (−/−) mice. Taken together, these data illustrate the synthesis and characterization of a novel P2Y1 receptor radioligand and its utility for examining P2Y1 receptors natively expressed on human and mouse platelets

Randomized Trials to Optimize Treatment of Multidrug-Resistant Tuberculosis: The time for action is now

The time is now right for randomized trials of MDR-TB, say the authors, as the expansion of MDR-TB programs provides the setting in which trials can be implemented

A meta-analysis of long-term effects of conservation agriculture on maize grain yield under rain-fed conditions

Conservation agriculture involves reduced tillage, permanent soil cover and crop rotations to enhance soil fertility and to supply food from a dwindling land resource. Recently, conservation agriculture has been promoted in Southern Africa, mainly for maize-based farming systems. However, maize yields under rain-fed conditions are often variable. There is therefore a need to identify factors that influence crop yield under conservation agriculture and rain-fed conditions. Here, we studied maize grain yield data from experiments lasting 5 years and more under rain-fed conditions. We assessed the effect of long-term tillage and residue retention on maize grain yield under contrasting soil textures, nitrogen input and climate. Yield variability was measured by stability analysis. Our results show an increase in maize yield over time with conservation agriculture practices that include rotation and high input use in low rainfall areas. But we observed no difference in system stability under those conditions. We observed a strong relationship between maize grain yield and annual rainfall. Our meta-analysis gave the following findings: (1) 92% of the data show that mulch cover in high rainfall areas leads to lower yields due to waterlogging; (2) 85% of data show that soil texture is important in the temporal development of conservation agriculture effects, improved yields are likely on well-drained soils; (3) 73% of the data show that conservation agriculture practices require high inputs especially N for improved yield; (4) 63% of data show that increased yields are obtained with rotation but calculations often do not include the variations in rainfall within and between seasons; (5) 56% of the data show that reduced tillage with no mulch cover leads to lower yields in semi-arid areas; and (6) when adequate fertiliser is available, rainfall is the most important determinant of yield in southern Africa. It is clear from our results that conservation agriculture needs to be targeted and adapted to specific biophysical conditions for improved impact

SOD2 polymorphisms: unmasking the effect of polymorphism on splicing

BACKGROUND: The SOD2 gene encodes an antioxidant enzyme, mitochondrial superoxide dismutase. SOD2 polymorphisms are of interest because of their potential roles in the modulation of free radical-mediated macromolecular damage during aging. RESULTS: We identified a new splice variant of SOD2 in human lymphoblastoid cell lines (LCLs). The alternatively spliced product was originally detected by exon trapping of a minigene in order to examine the consequences of an intronic polymorphism found upstream of exon 4 (nucleotide 8136, 10T vs 9T). Examination of the transcripts derived from the endogenous loci in five LCLs with or without the intron 3 polymorphism revealed low levels of an in-frame deletion of exon 4 that were different from those detected by the exon trap assay. This suggested that exon trapping of the minigene unmasked the effect of the 10T vs 9T polymorphism on the splicing of the adjacent exon. We also determined the frequencies of single nucleotide polymorphisms in a sample of US African-Americans and non-African-Americans ages 65 years and older who participated in the 1999 wave of the National Long Term Care Survey (NLTCS). Particularly striking differences between African-Americans and non-African-Americans were found for the frequencies of genotypes at the 10T/9T intron 3 polymorphism. CONCLUSION: Exon trapping can unmask in vitro splicing differences caused by a 10T/9T intron 3 polymorphism. Given the recent evidence that SOD2 is in a region on chromosome 6 linked to susceptibility to hypertension, it will be of interest to investigate possible associations of this polymorphism with cardiovascular disorders

Rationale and Methods for the National Tuberculosis Genotyping and Surveillance Network

Our understanding of tuberculosis (TB) transmission dynamics has been refined by genotyping of Mycobacterium tuberculosis strains. The National Tuberculosis Genotyping and Surveillance Network was designed and implemented to systematically evaluate the role of genotyping technology in improving TB prevention and control activities. Genotyping proved a useful adjunct to investigations of outbreaks, unusual clusters, and laboratory cross-contamination