Time of Progression to Osteopenia/Osteoporosis in Chronically HIV-Infected Patients: Screening DXA Scan

Background

Algorithms for bone mineral density (BMD) management in HIV-infected patients are lacking. Our objective was to assess how often a dual-energy x-ray absorptiometry (DXA) scan should be performed by assessing time of progression to osteopenia/osteoporosis.

Methods

All DXA scans performed between 2000 and 2009 from HIV-infected patients with at least two DXA were included. Time to an event (osteopenia and osteoporosis) was assessed using the Kaplan–Meier method. Strata (tertiles) were defined using baseline minimum T scores. Differences between strata in time to an event were compared with the log-rank test.

Results

Of 391 patients (1,639 DXAs), 49.6% had osteopenia and 21.7% osteoporosis at their first DXA scan. Of the 112 (28.6%) with normal BMD, 35.7% progressed to osteopenia; median progression time was 6.7 years. These patients were stratified: “low-risk" (baseline minimum T score >−0.2 SD), “middle-risk" (between −0.2 and −0.6 SD), and “high-risk" (from −0.6 to −1 SD); median progression time to osteopenia was 8.7, >7.2, and 1.7 years, respectively (p<0.0001). Of patients with osteopenia, 23.7% progressed to osteoporosis; median progression time was >8.5 years. Progression time was >8.2 years in “low-risk" tertile (T score between −1.1 and −1.6 SD), >8.5 years in “middle-risk" (between −1.6 and −2), and 3.2 years in “high-risk" (from −2 to −2.4) (p<0.0001).

Conclusions

Our results may help to define the BMD testing interval. The lowest T score tertiles would suggest recommending a subsequent DXA in 1–2 years; in the highest tertiles, ≥6 years. Early intervention in patients with bone demineralization could reduce fracture–related morbidity/mortality.     

Synthesis, characterization and antiproliferative behavior of tricarbonyl complexes of rhenium(I) with some 6-amino-5-nitrosouracil derivatives: crystal structure of fac-[ReCl(CO)3(DANU-N5,O4)] (DANU=6-amino-1,3-dimethyl-5-nitrosouracil)

New complexes of rhenium(I) with some 5-nitrosopyrimidines with general formula [ReCl(CO)3L] have been prepared and characterized by elemental analysis, conductivity measurements, IR and 1H, 13C and 15N NMR spectroscopic methods. The complexes appear to be monomeric and the pyrimidine ligands act in a neutral form. The structure of [ReCl(CO)3(DANU)].CH3CN has been solved by X-ray diffraction. The coordination environment around the Re(I) may be described as a distorted octahedron in which the ligand behaves in a bidentate fashion through N5 and O4 atoms, making a five-membered chelate ring. The coordination sphere is completed with three carbonyl groups in fac-arrangement and one chlorine atom. The evaluation of the antiproliferative behavior against five human tumor cell lines (human breast cancer MCF-7 and EVSA-T, human neuroblastoma NB69, human glioma H4 and human bladder carcinoma cell line ECV) suggested a modulator behavior of cell growth at low concentrations due to their estrogenic-like characteristics.     

The effect of aminoglycoside antibiotics on the adventitious regeneration from apricot leaves and selection of <Emphasis Type="Italic">npt</Emphasis>II-transformed leaf tissues

The effect of different concentrations of the aminoglycoside antibiotics, geneticin, paromomycin and streptomycin on adventitious regeneration from leaf explants of apricot was tested to design an alternative procedure for selecting transgenic shoots. Streptomycin and paromomycin reduced shoot regeneration percentage with increasing concentration of antibiotics. Almost a complete inhibition of regeneration was reached when 20M paromomycin was used, although up to 40M streptomycin was necessary to completely inhibit regeneration. Geneticin had a very toxic effect on apricot leaves and regeneration was inhibited at almost all concentrations tested. Addition of kanamycin hastened the development of adventitious buds although silver thiosulfate and not kanamycin was responsible for the observed increase in the consistency of the results from independent experiments. Kanamycin and paromomycin at the concentrations tested improved selection of transformed cells and resulted in a larger number of gfp-expressing regions. Paromomycin at 40 and 25.7M kanamycin improved proliferation of transformed tissues as compared with the other antibiotics used and non-selected controls.     

SAR and biological evaluation of novel trans-3,4-dimethyl-4-arylpiperidine derivatives as opioid antagonists

The phenolic hydroxy group of opiate-derived ligands is of known importance for biological activity. We have developed a SAR study around LY255582 by comparing the effect of the hydroxy group in the 2- and 4-position of the phenyl ring. Also, we have proved that the 3-position of the phenyl ring is optimal for opioid activity. Furthermore, we have successfully replaced the hydroxy group in LY255582 by carbamate and carboxamide groups. The new analogs have high affinity for the opioid receptors comparable to the corresponding phenol. Carboxamide analog 12 has an improved metabolism profile and proved to be efficacious in in vivo studies.     

Design and synthesis of potent pyridazine inhibitors of p38 MAP kinase

Novel potent trisubstituted pyridazine inhibitors of p38 MAP (mitogen activated protein) kinase are described that have activity in both cell-based assays of cytokine release and animal models of rheumatoid arthritis. They demonstrated potent inhibition of LPS-induced TNF-alpha production in mice and exhibited good efficacy in the rat collagen induced arthritis model.     

Developmental mechanisms underlying the generation of cortical interneuron diversity

GABAergic interneurons are critical components of cortical circuits. However, understanding their function has become extremely challenging because they constitute one of the most diverse groups of cells in the central nervous system. Indeed, cortical GABAergic interneurons are heterogeneous in so many different ways--morphology, molecular profiling, electrical properties--that even attempts to discern what parameters should be used to identify cortical interneuron subtypes have failed to generate broad consensus among experts in the field. The extent to which cortical interneuron diversity emerges during development is largely unknown, but it is likely that insights on how this process takes place may help us understand their role as integrative and synchronizing elements in cortical function. Here, we review recent data on how the large variety of distinct classes of cortical interneurons may arise during development.     

Anthrax toxin: the long and winding road that leads to the kill

The past five years have led to a tremendous increase in our molecular understanding of the mode of action of the anthrax toxin, one of the two main virulence factors produced by Bacillus anthracis. The structures of each of the three components of the toxin--lethal factor (LF), edema factor (EF) and protective antigen (PA)--have been solved not only in their monomeric forms but, depending on the subunit, in a heptameric form, bound to their substrate, co-factor or receptor. The endocytic route followed by the toxin has also been unraveled and the enzymatic mechanisms of EF and LF elucidated.     

Aggregation as bacterial inclusion bodies does not imply inactivation of enzymes and fluorescent proteins

Background  

Many enzymes of industrial interest are not in the market since they are bio-produced as bacterial inclusion bodies, believed to be biologically inert aggregates of insoluble protein.     

The incorporation of glucosamine into enterobacterial core lipopolysaccharide: two enzymatic steps are required

The core lipopolysaccharide (LPS) of Klebsiella pneumoniae is characterized by the presence of disaccharide alphaGlcN-(1,4)-alphaGalA attached by an alpha1,3 linkage to l-glycero-d-manno-heptopyranose II (ld-HeppII). Previously it has been shown that the WabH enzyme catalyzes the incorporation of GlcNAc from UDP-GlcNAc to outer core LPS. The presence of GlcNAc instead of GlcN and the lack of UDP-GlcN in bacteria indicate that an additional enzymatic step is required. In this work we identified a new gene (wabN) in the K. pneumoniae core LPS biosynthetic cluster. Chemical and structural analysis of K. pneumoniae non-polar wabN mutants showed truncated core LPS with GlcNAc instead of GlcN. In vitro assays using LPS truncated at the level of d-galacturonic acid (GalA) and cell-free extract containing WabH and WabN together led to the incorporation of GlcN, whereas none of them alone were able to do it. This result suggests that the later enzyme (WabN) catalyzes the deacetylation of the core LPS containing the GlcNAc residue. Thus, the incorporation of the GlcN residue to core LPS in K. pneumoniae requires two distinct enzymatic steps. WabN homologues are found in Serratia marcescens and some Proteus strains that show the same disaccharide alphaGlcN-(1,4)-alphaGalA attached by an alpha1,3 linkage to ld-HeppII.