Blood shizonticidal activities of phenazines and naphthoquinoidal compounds against Plasmodium falciparum in vitro and in mice malaria studies

Due to the recent advances of atovaquone, a naphthoquinone, through clinical trials as treatment for malarial infection, 19 quinone derivatives with previously reported structures were also evaluated for blood schizonticide activity against the malaria parasite Plasmodium falciparum. These compounds include 2-hydroxy-3-methylamino naphthoquinones (2-9), lapachol (10), nor-lapachol (11), iso-lapachol (12), phthiocol (13) and phenazines (12-20). Their cytotoxicities were also evaluated against human hepatoma and normal monkey kidney cell lines. Compounds 2 and 5 showed the highest activity against P. falciparum chloroquine-resistant blood-stage parasites (clone W2), indicated by their low inhibitory concentration for 50% (IC₅₀) of parasite growth. The therapeutic potential of the active compounds was evaluated according to the selectivity index, which is a ratio of the cytotoxicity minimum lethal dose which eliminates 50% of cells and the in vitro IC₅₀. Naphthoquinones 2 and 5, with activities similar to the reference antimalarial chloroquine, were also active against malaria in mice and suppressed parasitaemia by more than 60% in contrast to compound 11 which was inactive. Based on their in vitro and in vivo activities, compounds 2 and 5 are considered promising molecules for antimalarial treatment and warrant further study.     

Rheumatoid factor and anti-citrullinated protein antibody positivity,but not level,are associated with increased mortality in patients with rheumatoid arthritis: results from two large independent cohorts

Introduction

This study aimed to investigate rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) status and levels as predictors of mortality in two large cohorts of patients with early inflammatory arthritis (EIA).

Methods

Data from the Norfolk Arthritis Register (NOAR) and Leiden Early Arthritis Clinic (EAC) cohorts were used. At baseline, patients had demographic data and smoking status recorded; RF, ACPA and inflammatory markers were measured in the local laboratories. Patients were flagged with national death registers until death or censor date. Antibody status was stratified as negative, low or high positive by RF and ACPA levels individually. In addition, patients were grouped as seronegative, RF positive, ACPA positive or double antibody (RF and ACPA) positive. Cox regression models explored associations between antibody status and mortality adjusting for age, sex, smoking status, inflammatory markers and year of enrolment.

Results

A total of 4962 patients were included, 64% were female. Median age at onset was 56 (NOAR) and 54 (EAC) years. In NOAR and EAC respectively, 35% and 42% of patients were ACPA/RF positive. When antibody status was stratified as negative, low or high positive, there were no consistent findings between the two cohorts. Double antibody positivity was associated with excess mortality in both cohorts compared to seronegative patients: NOAR and EAC respective adjusted HR (95% confidence interval) 1.35 (1.09 to 1.68) and 1.58 (1.16 to 2.15).

Conclusions

Patients with EIA who are seropositive for both RF and ACPA have increased mortality compared to those who are single positive or seronegative. Antibody level in seropositive patients was not consistently associated with excess mortality.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-014-0483-3) contains supplementary material, which is available to authorized users.     

Regulation of the glucocorticoid receptor by glucocorticoids in human mononuclear leukocytes

We analyzed glucocorticoid receptor binding in peripheral blood mononuclear leukocytes from normal adult males and from females at the follicular and luteal phases. Healthy controls were analyzed before and after 17 days of treatment with two synthetic glucocorticoids: prednisone and an oxazoline derivative of prednisolone (deflazacort). We also studied for comparison 4 patients with adrenocortical insufficiency, two of them on long-term corticoid replacement, and 7 patients with Cushing's syndrome. Using a whole-cell competitive binding assay and 3H-dexamethasone as tracer, normal human mononuclear leukocytes (19 males, 6 females) were found to have 4,529 +/- 1,532 (mean +/- SD) binding sites per cell and a dissociation constant (Kd) of 9.5 +/- 2.3 nM. In Cushing's syndrome the receptor parameters were within the normal range. Cells from patients with untreated Addison's disease had low levels of sites per cell. The number of binding sites increased to normal after long-term glucocorticoid replacement. All the adrenal insufficiency cases had a normal Kd. Finally, following treatment with the synthetic glucocorticoid, deflazacort, the sites per cell were reduced but the Kd remained unchanged. Prednisone had no effects.     

Isolation and Characterization of Collagen - Synthesizing Polysomes from Chick Embryos

Collagen - synthesizing polysomes were isolated by low-speed oentrifugation of the post-mitochomirial supernatant of chick homogenates. Electron microscopy of the fraction thus isolated shows it to be exclusively composed of ribosomes. Amino acid incorporation in vitro showed that these particles were efficient in the incorporation of proline, but not tryptophan, as opposed to ribosomes obtained from the supernatant of the low-speed oentrifugation. The incorporation process was highly dependent on GTP, and exibited an optimal Mg²⁺ concentration of 5.6 mN. The reaction was inhibited by RNase, elongation inhibitors as anysomycin, sparsomycin, fusidic acid and GDPCP. It was also moderately inhibited by initiation inhibitors such as aurintricarboxilic acid and pyrocatechol violet. The product of the incorporation was characterized as collagen by its sensitivity towards purified collagenase, lack of tryptophan, chromatography in CN-cellulose and molecular sieve chromatography in Sephadex G-200.     

AChemS: the beginning. Association for Chemoreception Sciences

This paper unfolds the events, the people and the times that led up to the founding of AChemS and fashioned its character during its early formative years. It describes the path over which AChemS came, going from the original assertions and denials for the need of such an organization to its later inception and nascent development. This narration highlights such topics as the debate over the need for AChemS, the role of National Science Foundation in the founding of AChemS, the derivation of the Association's name, the choice of Sarasota and the Hyatt House as the meeting site, the generation of the programs for the early annual meetings, the adoption of the bylaws, the process of incorporation and tax deferment, and the birth of the Givaudan Lectureship. Most emphatically highlighted, however, is the enthusiasm, commitment and hard work that the members of the chemosensory research community displayed in bringing AChemS to fruition.