Immunization with the iron uptake ABC transporter proteins PiaA and PiuA prevents respiratory infection with Streptococcus pneumoniae

Previous studies show that vaccination with the recombinant Streptococcus pneumoniae lipoproteins PiuA and PiaA protects mice against systemic S. pneumoniae disease. The aim of this study was to assess the level of conservation of PiaA and PiuA and a third iron uptake ABC transporter lipoprotein, PitA, between common S. pneumoniae capsular serotypes by sequencing the corresponding genes, and to investigate whether these antigens can protect against respiratory infection. The nucleotide sequences of piuA and piaA were highly conserved in all strains, whereas pitA had significant variation in its nucleotide sequence making PitA an unattractive vaccine candidate. Mucosal vaccination of mice with PiuA and PiaA elicited specific antibody responses in serum and respiratory secretions, and protected against intranasal challenge with S. pneumoniae. These results provide further data indicating that PiuA and PiaA would be suitable candidates for a S. pneumoniae protein antigen vaccine.     

Tumeur myofibroblastique inflammatoire de la vessie

Myofibroblastic inflammatory tumor is considered as an intermediate neoplasm according to the WHO classification. It can occur in different organs: lung, pancreas, mesentery and uterus. The localization in the bladder is unusual. We report a case of a 38-year-old patient who presented with hematuria. Echography showed a 3 cm tissular structure of the bladder. Histological analysis and immunohistochemistry concluded to the diagnosis of myofibroblastic tumor of the bladder. The present work will give a general view of the myofibroblastic tumor, and will review its differential diagnosis.     

Isoprenoid biosynthesis of the apicoplast as drug target

In Plasmodium falciparum the biosynthesis of isoprenoids is achieved by the mevalonate-independent 1-deoxy-d-xylulose 5-phosphate (DOXP) pathway. The enzymes of the DOXP pathway are localised inside the plastid-like organelle (apicoplast). Fosmidomycin inhibits DOXP reductoisomerase, the second enzyme of this pathway. The antimalarial activity of fosmidomycin was established in vitro and in a rodent malaria model. Fosmidomycin alone or in combination with clindamycin was evaluated for the treatment of acute uncomplicated P. falciparum malaria in early phase II studies. Fosmidomycin monotherapy led to a fast parasite and fever clearance but was inefficient in radical elimination of the parasites. With the fosmidomycin-clindamycin combinations the cure ratio on day 28 was 100 % (10/10) with treatment durations of 5 and 4 days. The cure ratio was 90 % (9/10) with treatment duration of 3 days.     

Fosmidomycin plus clindamycin for treatment of pediatric patients aged 1 to 14 years with Plasmodium falciparum malaria

Fosmidomycin plus clindamycin was shown to be efficacious in the treatment of uncomplicated Plasmodium falciparum malaria in a small cohort of pediatric patients aged 7 to 14 years, but more data, including data on younger children with less antiparasitic immunity, are needed to determine the potential value of this new antimalarial combination. We conducted a single-arm study to improve the precision of efficacy estimates for an oral 3-day fixed-ratio combination of fosmidomycin and clindamycin at 30 and 10 mg/kg of body weight, respectively, every 12 hours for the treatment of uncomplicated P. falciparum malaria in 51 pediatric outpatients aged 1 to 14 years. Fosmidomycin plus clindamycin was generally well tolerated, but relatively high rates of treatment-associated neutropenia (8/51 [16%]) and falls of hemoglobin concentrations of ≥2 g/dl (7/51 [14%]) are of concern. Asexual parasites and fever were cleared within median periods of 42 h and 38 h, respectively. All patients who could be evaluated were parasitologically and clinically cured by day 14 (49/49; 95% confidence interval [CI], 93 to 100%). The per-protocol, PCR-adjusted day 28 cure rate was 89% (42/47; 95% CI, 77 to 96%). Efficacy appeared to be significantly reduced in children aged 1 to 2 years, with a day 28 cure rate of only 62% for this small subgroup (5/8). The inadequate efficacy in children of <3 years highlights the need for continued systematic studies of the current dosing regimen, which should include randomized trial designs.     

Double ester prodrugs of FR900098 display enhanced in-vitro antimalarial activity

Fosmidomycin and FR900098 are inhibitors of the 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR; IspC), a key enzyme of the mevalonate-independent isoprenoid biosynthesis pathway. We have determined the in-vitro antimalarial activity of two double ester prodrugs 2, 3 in direct comparison with the unmodified FR900098 1 against intraerythrocytic forms of Plasmodium falciparum. Temporarily masking the polar properties of the phosphonate moiety of the DXR inhibitor FR900098 1 enhanced not only its oral bioavailability but also the intrinsic activity of this series against the parasites.     

Synthesis and biological evaluation of cyclopropyl analogues of fosmidomycin as potent Plasmodium falciparum growth inhibitors

A series of fosmidomycin analogues featuring restricted conformational mobility has been synthesized and evaluated as inhibitors of 1-deoxy-D-xylulose 5-phosphate (DOXP) reductoisomerase and as growth inhibitors of P. falciparum. The enantiomerically pure trans-cyclopropyl N-acetyl analogue 3b showed comparable inhibitory activity as fosmidomycin toward E. coli DOXP reductoisomerase and proved equally active when tested in vitro for P. falciparum growth inhibition. Conversely, the alpha-phenyl cis-cyclopropyl analogue 4 showed virtually no inhibition of the enzyme.     

Possible relation of Tunisian pemphigus with traditional cosmetics: a multicenter case-control study

Pemphigus is a severe, autoimmune, blistering disorder with a high incidence among young women in rural Tunisia. The authors investigated explanatory environmental factors. A multicenter case-control study was conducted prospectively from 1992 to 1996 in Tunisia. Sixty-eight incident female cases of pemphigus and 166 controls matched on age, hospital, and geographic area were included. Data collected concerned socioeconomic status, medical history, drug intakes, lifestyle, and environment. Several factors were significantly associated with pemphigus in multivariate logistic regression analyses: traditional cosmetics (odds ratio (OR) = 4.0, 95% confidence interval (CI): 1.1, 14.8); Turkish baths (OR = 3.2, 95% CI: 1.4, 7.3); cutting up raw poultry (OR = 5.1, 95% CI: 1.3, 19.4); contact with ruminants (OR = 2.7, 95% CI: 1.3, 5.8); and wasp, bee, and spider stings (OR = 3.1, 95% CI: 1.5, 6.4). A dose-dependent relation was observed for traditional cosmetics. All risks except insect bites were higher when analysis was restricted to younger women, the demographic group with higher incidence. The strength of the associations, the dose-dependent relation for traditional cosmetics, and the increase of risk estimates for younger women support a causal relation. Traditional cosmetics widely used by Tunisian women could play a major role in excess of cases of pemphigus.