Retrospective assessment of exposure to traffic air pollution using the ExTra index in the VESTA French epidemiological study

This study applies a traffic exhaust air dispersion model (the ExTra index) to 403 children enrolled in a French multicentric case-control study, the VESTA study (Five [V] Epidemiological Studies on Transport and Asthma). The ExTra index (previously validated by our team) was used to assess lifelong average traffic-related air pollutant (TAP) concentrations (nitrogen oxides) children in the study were exposed to in front of their living places. ExTra index took into account traffic density, topographical parameters (building height, road and pavement width), weather conditions (wind direction and strength) and background pollution levels. Topographical and traffic data were collected, using a specific questionnaire for each home, school or nursery address, attended by children. The assessment of time-weighted NOx levels in front of the children's living places highlighted significant disparities: mean ExTra index values and share attributable to proximity traffic were, respectively, 70+/-42 and 14+/-22 microg/m3 NOx equivalent NO2 for the 403 children in our study. Not only would this diversity not have been revealed using urban background pollution data provided by air quality networks, it would have resulted in 40% of the children being misclassified with regard to their TAP exposure by underestimating it in half of the cases and overestimating it in the other half. Such errors of classification, which are highly prejudicial in epidemiology, argue strongly for the use of an index such as the ExTra, which enables TAP exposure to be reconstructed within the framework of retrospective or prospective epidemiological studies.     

Methicillin-resistant Staphylococcus aureus in pig farming

We conducted a study among a group of 26 regional pig farmers to determine the methicillin-resistant Staphylococcus aureus prevalence rate and found it was >760 times greater than the rate of patients admitted to Dutch hospitals. While spa-type t108 is apparently a more widespread clone among pig farmers and their environment, we did find other spa-types.     

Protection against experimental visceral leishmaniasis infection in dogs immunized with purified excreted secreted antigens of Leishmania infantum promastigotes

The capacity of naturally excreted secreted antigens easily purified from culture supernatant of Leishmania infantum promastigotes (LiESAp), successfully cultivated in completely defined medium called CDM/LP [Lemesre JL. Methods for the culture in vitro of different stages of tissue parasites. International publication WO 94/26899, 1994; Merlen T, Sereno D, Brajon N, Rostand F, Lemesre JL. Leishmania spp: completely defined medium without serum and macromolecules (CDM/LP) for the continuous in vitro cultivation of infective promastigote forms. Am J Trop Med Hyg 1999;60(1):41-50] to protect dogs against experimental L. infantum infections is described. Eighteen healthy Beagle dogs were allocated into four groups that received at a 3-week interval either two subcutaneous injections of 50 microg (group 2, n = 3), 100 microg (group3, n = 6) and 200 microg (group 4, n = 3) LiESAp in formulation with muramyl dipeptide (MDP) or similar injections of placebo (group 1, n = 6). Dogs were intravenously infected with 10(8) metacyclic L. infantum promastigotes. Promastigotes of the MHOM/MA/67/ITMAP-263 and MHOM/FR/78/LEM75 strains were, respectively, administered 2 months (at day 84, homologous challenge 1) and 8 months post-immunization (at day 273, heterologous challenge 2). The data indicated that vaccine candidate confers total protection (100%) against challenges 1 and 2 in dogs from groups 3 and 4 and intermediate protection (66.7%) against challenge 1 in dogs from group 2 as determined by parasite detection in bone marrow aspirates during 14 months post-challenge follow-up. All placebo dogs of group 1 were found infected and failed to respond to LiESAp in cell-mediated assays before and after both challenges. Increased levels of total anti-leishmanial antibodies were exclusively detected in infected dogs from group 1. Vaccine-induced protection correlates with an early establishment of a long lasting predominantly Th1-type cellular immune response specifically directed against LiESAp before and after experimental infections, as demonstrated by: (i) anti-LiESAp IgG2 reactivity, and (ii) LiESAp-specific lymphocyte proliferation assays and enhanced NO-mediated anti-leishmanial activity of canine monocyte-derived macrophages (CM-DM) in response to higher IFNgamma production by T-cells, when L. infantum-infected CM-DM were co-cultured with autologous lymphocytes. Overall, our results support the view that a LiESAp vaccine might be useful in a promising vaccination approach against natural L. infantum infection.     

Biphenylsulfonacetic acid inhibitors of the human papillomavirus type 6 E1 helicase inhibit ATP hydrolysis by an allosteric mechanism involving tyrosine 486

Human papillomaviruses (HPVs) are the causative agents of benign and malignant lesions of the epithelium. Despite their high prevalence, there is currently no antiviral drug for the treatment of HPV-induced lesions. The ATPase and helicase activities of the highly conserved E1 protein of HPV are essential for viral DNA replication and pathogenesis and hence are considered valid antiviral targets. We recently described novel biphenylsulfonacetic acid inhibitors of the ATPase activity of E1 from HPV type 6 (HPV6). Based on kinetics and mutagenesis studies, we now report that these compounds act by an allosteric mechanism. They are hyperbolic competitive inhibitors of the ATPase activity of HPV6 E1 and also inhibit its helicase activity. Compounds in this series can also inhibit the ATPase activity of the closely related enzyme from HPV11; however, the most potent inhibitors of HPV6 E1 are significantly less active against the type 11 protein. We identified a single critical residue in HPV6 E1, Tyr-486, substituted by a cysteine in HPV11, which is primarily responsible for this difference in inhibitor potency. Interestingly, HPV18 E1, which also has a tyrosine at this position, could be inhibited by biphenylsulfonacetic acid derivatives, thereby raising the possibility that this class of inhibitors could be optimized as antiviral agents against multiple HPV types. These studies implicate Tyr-486 as a key residue for inhibitor binding and define an allosteric pocket on HPV E1 that can be exploited for future drug discovery efforts.     

Study of human isoferritins from liver, spleen, heart and placenta by the microcomplement fixation technique

Ferritin, iron storage protein, presents two types of subunits, H and L, the respective proportions of which varying with the tissue of origin and defining molecules called isoferritins. This work attempts to compare four human ferritins (from liver, spleen, heart and placenta) by means of the microcomplement fixation technique. Results show that placenta and liver ferritins are closely related, while slight but significant differences appear between liver, spleen and heart ferritins. These differences are obviously less important compared to those observed between ferritins from different species of origin, as shown by the results expressed in terms of index of dissimilarity or immunological distance. Those results are fully consistent with the elementary aminoacid composition as well as with the relative proportions of H and L subunits among the various types of human isoferritins we have studied.     

Familial influences on basal salivary cortisol in an adult population

To understand the underlying genetic and environmental sources of individual variation in basal cortisol levels, we collected salivary cortisol at awakening and at six fixed time points during the day in adult twins and their singleton siblings. Reported time of awakening was verified with heart rate and body movement recordings. Cortisol data were available for 199 MZ twins, 272 DZ twins and 229 singleton siblings from 309 twin families. No differences in cortisol means and variances were found between twins and singleton siblings. Additionally, the correlations for DZ twins and siblings were not significantly different, indicating generalizability of twin study results to the general population. Genetic model fitting showed heritability for cortisol levels during the awakening period (34% for cortisol level at awakening and 32% for cortisol level at 30 min after awakening) but not for cortisol levels later during the day. The current study shows that, while cortisol levels in the awakening period are influenced by genetic factors, cortisol levels throughout most of the day are not heritable, indicating that future gene finding studies for basal cortisol should focus on the first hour post-awakening.     

Surgical management of endometriosis

The efficacy of medical and surgical treatment of endometriosis-associated infertility and pelvic pain is a source of ongoing controversy. Complete resolution of endometriosis is not yet possible and current therapy has three main objectives: (1) to reduce pain; (2) to increase the possibility of pregnancy; and (3) to delay recurrence for as long as possible. It is possible that a consensus will never be reached on the optimal treatment of minimal and mild endometriosis. In case of moderate and severe endometriosis-associated infertility, the combined approach (operative laparoscopy with a gonadotropin-releasing hormone (GnRH) agonist) should be considered as 'first-line' treatment. The mean pregnancy rate of 50% reported in the literature following surgery provides scientific proof that operative treatment should first be undertaken to give our patients the best chance of conceiving naturally. In case of rectovaginal adenomyotic nodules, surgery must be considered as first-line therapy, medical therapy being relatively in-efficacious.     

Electrical stimulation of the globus pallidus internus in patients with primary generalized dystonia: long-term results

OBJECT: Primary generalized dystonia (PGD) is a medically refractory disease of the brain causing twisting or spasmodic movements and abnormal postures. In more than 30% of cases it is associated with the autosomal DYT1 mutation. Continuous electrical stimulation of the globus pallidus internus (GPi) has been used successfully in the treatment of PGD. The aim of this study was to examine the long-term efficacy and safety of deep brain stimulation (DBS) in the treatment of PGD in children and adults with and without the DYT1 mutation. METHODS: Thirty-one patients with PGD were selected for surgery. Electrodes were bilaterally implanted under stereotactic guidance and connected to neurostimulators that were inserted subcutaneously. Efficacy was evaluated by comparing scores on the clinical and functional Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) before and after implantation. The efficacy of stimulation improved with time. After 2 years, compared with preoperative values, the mean (+/- standard deviation) clinical and functional BFMDRS scores had improved by 79 +/- 19% and 65 +/- 33%, respectively. At the 2-year follow-up examination the improvement was comparable in patients with and without the DYT1 mutation in both the functional (p = 0.12) and clinical (p = 0.33) scores. Children displayed greater improvements in the clinical score than adult patients (p = 0.04) at 2 years of follow up. In contrast, there was no significant difference in functional scores between children and adults (p = 0.95). CONCLUSIONS: Electrical stimulation of the GPi is an effective, reversible, and adaptable treatment for PGD and should be considered for conditions refractory to pharmaceutical therapies.     

Interactions between cognitive and sensorimotor functions in the motor cortex: evidence from the preparatory motor sets anticipating a perturbation

The many signs of cognitive processes in the activation pattern of the primary motor cortex or in corticospinal (CS) excitability gave rise to the idea that the motor cortex is a crucial node in the processing of cognitive information related to sensorimotor functions. Moreover, it became clear that the preparatory motor sets offer a privileged window to investigate the interaction between cognitive and sensorimotor function in the motor cortex. In the present review, we examine how the study of the preparatory motor sets anticipating a mechanical movement perturbation contributes to enlightening this question. Following the initial observation made by Hammond that some components of the stretch reflex can be modulated by a prior intention either to resist or to relax in response to a subsequent perturbation, first evidence of the phenomenon was obtained in behaving monkeys. Moreover, this study related this peripheral fact to the observed anticipatory activity of motor cortex neurons after a prior instruction telling the animal how to respond to the subsequent perturbation, which triggered the instructed movement. Indeed, this anticipatory activity was found to be different according to the instruction. In the 1980s, this work inspired a lot of studies in human beings that brought support to the idea of a cognitive tuning of the long latency stretch response (LLSR). Specifically, the MI component of the response was shown to be modulated by a prior intent to resist versus to let go when faced with the perturbation. Recently, new approaches have been developed to obtain evidence of a cognitive tuning of CS excitability, thanks to transcranial magnetic stimulation (TMS). TMS has been used both as a reliable tool for quantifying the CS excitability via the motor evoked potentials (MEPs), and to centrally perturb the organization of movement. Such central perturbations offer the unique opportunity to activate the descending motor tracts while shunting, for a short time period, the ascending tracts assisting the movement. Thus, CS excitability was measured before the movement was perturbed. These studies demonstrated the readiness of the CS tract to be involved in anticipatory compensatory responses to central movement perturbations induced by TMS in relation to the subject's cognitive attitudes. The question of the cerebral regions upstream of the motor cortex that could be responsible for this modulation in CS excitability remains largely open.