Synthesis and antimalarial activity of new atovaquone derivatives

In this paper we describe the design and synthesis of 18 derivatives of the antimicrobial atovaquone which were substituted at the 3-hydroxy group by ester and ether functions. The compounds were evaluated in vitro for their activity against the growth of Plasmodium falciparum, the malaria causing parasite. All the compounds showed potent activity, with IC₅₀ values in the range of 1.25–50 nM, comparable to those of atovaquone and much higher than chloroquine or quinine.     

RELATIONSHIP BETWEEN PLATELET CYTOSOLIC FREE CALCIUM CONCENTRATION AND PLASMA RENIN ACTIVITY

1. Plasma renin activity (PRA) and platelet cytosolic free calcium concentration ([Ca2+]i) were simultaneously determined in 18 untreated essential hypertensive subjects and 17 normotensive controls. A significant positive correlation was found between [Ca2+]i and PRA (slope = 42 nmol/l/ng/ml/h) in these 35 subjects. 2. Two determinations more than one week apart in nine subjects confirmed the parallel fluctuations of [Ca2+]i and PRA. A strict sodium restriction produced a progressive PRA elevation associated with a parallel rise in [Ca2+]i in one subject. 3. These results are consistent with the hypothesis that angiotensin II causes a concentration-dependent calcium mobilization.     

Superficial angiomyxoma: report of four cases, including two subungueal tumors

We report four cases of superficial angiomyxomas, including two cutaneous tumors and two subungueal tumors. Histological analysis revealed a recently described tumor, so called superficial angiomyxoma. This is a myxoid paucicellular tumor lobulated and poorly circumbscribed, containing numerous small blood vessels surrounded by a mixed inflammatory cell infiltrate with notable neutrophils. Those tumors are positive for CD34. The differential diagnosis includes myxoid neurothecoma, myxoid neurofibroma and, for ungueal tumors, superficial acral fibromyxoma.     

Chemical synaptic transmission in the cochlea

The last two decades have witnessed major progress in the understanding of cochlear mechanical functioning, and in the emergence of cochlear neurochemistry and neuropharmacology. Recent models describe active processes within the cochlea that amplify and sharpen the mechanical response to sound. Although it is widely accepted that outer hair cells (OHCs) contribute to these processes, the nature of the medial efferent influence on cochlear mechanics needs further clarification. Acetylcholine (ACh) is the major transmitter released onto OHCs during the stimulation of these efferents. The inhibitory influence of this system is mediated by post- and presynaptic nicontinic and muscarinic receptors and the role of other neuroactive substances [γ-aminobutyric acid (GABA), calcitonin gene-related peptide (CGRP), adenosine 5′-triphosphate (ATP) or nitric oxide (NO)] remains to be determined. The inner hair cells (IHCs) that transduce the mechanical displacements into neural activity, release glutamate on receptor-activated channels of AMPA, kainate, and NMDA types. This synapse is in turn controlled and/or regulated by the lateral efferents containing a cocktail of neuroactive substances (ACh, GABA, dopamine, enkephalins, dynorphin, CGRP). This glutamatergic nature of the IHCs is responsible for the acute destruction of the nerve endings and subsequently for neuronal death, damage usually described in various cochlear diseases (noise-induced hearing losses, neural presbycusis and certain forms of sudden deafness or peripheral tinnitus). These pathologies also include a regrowth of new dendritic processes by surviving neurons up to IHCs. Understanding the subtle molecular mechanisms which underly the control of neuronal excitability, synaptic plasticity and neuronal death in cochlear function and disease is a very important issue for the development of future therapies.     

Diisocyanate asthma and gene-environment interactions with IL4RA, CD-14, and IL-13 genes.

BACKGROUND: Diisocyanate asthma (DA) affects 2% to 10% of exposed workers, yet the pathogenetic mechanisms underlying this disorder remain ill defined. OBJECTIVE: To determine if specific single nucleotide polymorphisms (SNPs) of interleukin 4 receptor alpha (IL4RA), IL-13, and CD14 promoter genes are associated with DA. METHODS: Sixty-two workers with DA confirmed by specific inhalation challenge (SIC) and 75 diisocyanate-exposed, SIC-negative workers were analyzed for SNPs associated with IL4RA, IL-13, and CD14 promoter genes. RESULTS: No associations were found with individual SNPs and DA. When stratified according to specific diisocyanate exposure, a significant association was found between IL4RA (I50V) II and DA among individuals exposed to hexamethylene diisocyanate (HDI) (odds ratio [OR], 3.29; 95% confidence interval [CI], 1.33-8.14; P = .01) only. Similarly, the IL4RA (I50V) II and IL-13 (R110Q) RR combination was significantly associated with DA in HDI-exposed workers (OR, 4.13; 95% CI, 1.35-12.68; P = .01), as was the IL4RA (I50V) II and CD14 (C159T) CT genotype combination (OR, 5.2; 95% CI, 1.82-14.88; P = .002) and the triple genotype combination IL4RA (I50V) II, IL-13 (R110Q) RR, and CD14 (C159T) CT (OR, 6.4; 95% CI, 1.57-26.12; P = .01). CONCLUSIONS: Gene-environmental interactions may contribute to the pathogenesis of DA, and gene-gene interactions may modulate this relationship.     

Value of Microimmunofluorescence for Diagnosis and Follow-up of Bartonella Endocarditis

Bartonella endocarditis is a disease of emerging importance that causes serious complications and high rates of mortality. Due to the fastidious nature of Bartonella species and their high degrees of antibiotic susceptibility, cultures of clinical samples most often remain sterile and valvular biopsy specimens, the best specimens for PCR amplification, are seldom available. Therefore, serology appears to be the easiest diagnostic tool. In order to determine the best cutoff value for serology and its predictive values for the detection of Bartonella endocarditis, we studied 48 patients with culture- and/or PCR-confirmed Bartonella endocarditis. We also applied these serological criteria to 156 patients with blood culture-negative endocarditis. Furthermore, we compared the kinetics of the antibody responses to Bartonella spp. in order to estimate the value of serology for prediction of the occurrence of relapses. A titer of ≥1:800 for immunoglobulin G antibodies to either Bartonella henselae or B. quintana has a positive predictive value of 0.810 for the detection of chronic Bartonella infections in the general population and a value of 0.955 for the detection of Bartonella infections among patients with endocarditis. When this cutoff was applied to 156 patients with blood culture-negative endocarditis, we were able to diagnose Bartonella infections in an additional 45 patients with definite endocarditis for whom a positive Bartonella serology was the only evidence of infection. On follow-up, the kinetics of the decrease in antibody titers were significantly delayed in two patients with relapses. In conclusion, we recommend the determination of antibodies to both B. quintana and B. henselae and the use of a cutoff value of 1:800 for the diagnosis of Bartonella endocarditis. We propose that this criterion, which may also help with the detection of late relapses, be included as a major criterion in the Duke criteria for the diagnosis of infective endocarditis.     

Chromosomal insertion involving MLL in childhood acute myeloblastic leukemia (M4)

Recurrent chromosomal rearrangements involving the 11q23 region have been described in various hematologic malignancies. Among these rearrangements, translocations are the most common mechanism involving the mixed lineage leukemia gene (MLL). Few cases of insertion have been reported and, to our knowledge, none of them involved MLL and chromosome 1. We report a complex karyotype in a childhood acute myelomonocytic leukemia (AML M4) involving the 11q23 region with an insertion between chromosomes 1 and 11 in addition to a translocation between chromosomes 11 and 22. This translocation was clarified by fluorescence in situ hybridization (FISH) analysis: 46,XY,ins(1;11)(q22q23;q13q23),t(11;22)(q13;q11q12). This finding also underlines the complementary contribution of conventional cytogenetic and FISH analysis to detect karyotypic complex abnormalities.     

Alternative methods to analyse the impact of HIV mutations on virological response to antiviral therapy

Background  

Principal component analysis (PCA) and partial least square (PLS) regression may be useful to summarize the HIV genotypic information. Without pre-selection each mutation presented in at least one patient is considered with a different weight. We compared these two strategies with the construction of a usual genotypic score.     

High risk HPV load estimated by Hybrid Capture II correlates with HPV16 load measured by real-time PCR in cervical smears of HPV16-infected women.

BACKGROUND: High risk human papillomavirus (HR-HPV) load determined by quantitative methods has already been considered as highly predictive of future development of high grade cervical lesions. Some studies also demonstrated that Hybrid Capture II (HCII) results can be considered as a reflection of HPV DNA load, while others did not. HCI assay, well suited for routine HR-HPV screening, is not especially dedicated for quantitative use. However, we have recently shown that women with high viral loads assessed by HCII were at increased risk of cervical precancer. OBJECTIVES: The aim of the study was to determine if the values given by the HCII assay can be considered as quantitative. STUDY DESIGN: We used a real-time PCR allowing precise quantification of both HPV16 genome and albumin gene to normalize the measuring HPV16 load in cervical cells and to compare the data with those obtained by HCIIin a series of 40 HR-HPV positive samples. RESULTS: Reproducibility of the HPV16 real-time PCR, assessed from nine independent experiments of serial dilutions of SiHa cell DNA, was reflected in coefficients of variation for standard curves of crossing point (Cp) values below 5%. The HPV16 loads with a broad individual variability were significantly related to the cumulative load estimated by HCII and did not depend on the cellularity of samples. CONCLUSIONS: We assume that the HCII values can be used as a quantitative measure of HR-HPV DNA, so long as cervical specimens are collected using standardized protocols.     

Early detection of Borrelia burgdorferi sensu lato infection in Balb/c mice by co-feeding Ixodes ricinus ticks

In Europe, Borrelia burgdorferi is transmitted by Ixodes ricinus to animals and human. When infected and uninfected ticks co-feed on a host, spirochetes are transmitted from ticks to animal and also to uninfected ticks. Here, we used uninfected ticks to co-feed with infected ticks on mice to evaluate this method to detect early infection in mice. A total of 128 mice were challenged by infected nymphs placed in capsules glued on the back of the mice. Three days later uninfected larvae were added in the capsule to co-feed with infected nymphs and were examined for Borrelia infection after natural detachment. Infection in mice was also determined by xenodiagnosis and by spirochete isolation from ear skin biopsy and back skin biopsy taken at the tick attachment site one month after infection. A total of 111 mice were found to be infected by at least one of these four methods. Borrelia infection was observed in 95% of mice by the co-feeding method, in 92% of mice by xenodiagnosis, in 69% and in 68% of mice by cultivation of ear and back skin biopsies, respectively. Our results demonstrate that the co-feeding method is a very sensitive method which can be used to detect very early infection in mice infected by tick bites.