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Biomedical subjects

P Bonnet

Publications and source records attributed to P Bonnet.

At least 19 recordsLinked to original sources

Heart rate variability in rats with chronic hypoxic pulmonary hypertension.

The precise role of pulmonary hypertension as a possible factor inducing a decrease in heart rate variability is poorly known. Spectral analysis of heart rate variability (HRV) was carried out in 21 Wistar rats before and after exposure to normoxia (N = 10) or to 3 weeks of hypobaric hypoxia inducing chronic pulmonary hypertension and right ventricular hypertrophy (N= 11). Continuous ECG was recorded in conscious animal at rest. Compared to the control group, rats exposed to hypoxia had a similar heart rate but a lower overall HRV (total power, 27.9 +/- 15.2 vs. 57.6 +/- 24.7 ms2, P < 0.01). Low frequency power (0.25-0.8 Hz) and high frequency power (0.8-3 Hz) were similar in both groups suggesting that HRV was decreased in the very low frequency power (0-0.25 Hz). The effects of atropine and propranolol on heart rate and HRV were similar in rats exposed or not to hypoxia. HRV is decreased in rats with hypoxic induced pulmonary hypertension, mainly in the very low frequency band, suggesting an increase in sympathetic activity. However, this decrease is moderate and the modulation of HRV with pharmacologic autonomic blockade remains similar to that of normal rats.

Animals↗

Descriptive and spatial epidemiology of Rift valley fever outbreak in Yemen 2000-2001.

Rift valley fever (RVF) is an arboviral disease produced by a bunyavirus belonging to the genus Phlebovirus. Several species of Aedes and Culex are the vectors of this virus that affects sheep, goats, buffalos, cattle, camels and human beings. The human disease is well known, especially during periods of intense epizootic activity. The initial description of the disease dates back to 1930, when animals and human outbreaks appeared on a farm in Lake Naivasha, in the Great Rift Valley of Kenya. Until 2000, this disease was only described in Africa, and then outbreaks were also declared in the Kingdom of Saudi Arabia (2000-2001 and 2004) and in Yemen (2000-2001). Animal and human cases were recorded. This work presents a retrospective summary of the data collected on animal RVF cases during this epidemic in Yemen. Results from several RVF surveys were gathered from the Yemeni vet services and FAO experts. Geographical data (topographic maps and data freely available on internet) were used for the location of outbreaks. After cleaning and standardization of location names, all the data were introduced into a GIS database. The spatial distribution of outbreaks was then studied at two scales: at the national level and at a local scale in the particular area of Wadi Mawr in the Tihama plain, Western coast of Yemen.

Animals↗

[The need for research to support the emergence of alternative animal health systems].

Animal diseases remain one of the main problems for livestock production in terms of trade development, poverty reduction and public health. Animal health systems are complex because of the diversity of the parties involved and because of various changes in the delivery of veterinary services, such as the redefinition of the roles of the public and private sectors. It is, therefore, often difficult to assess the global performance of animal health systems and sub-systems in terms of their medical, economic and social effectiveness. In addition, the necessary reliability of the health information obtained leads to certification of the status of regions and countries with regard to epizootics, which requires a high degree of standardisation and conformity with international norms. An assessment therefore needs to be made of the advantages of alternative systems compared with conventional systems. An animal health system should be seen as a whole, and when assessing its overall performance several things must be taken into account, e.g. the markets for products and the sometimes contradictory interests of all the different parties involved. There are, therefore, many research needs and avenues to be pursued, including: the methods, data and tools required for assessing the effectiveness of systems, including a definition of what constitutes a reliable indicator; the factors that determine the health of a herd; having a clearer idea of what will affect herd health will make it possible to map risk indicators and animal health care needs; the design and management of realistic and harmonised animal health information systems whose indicators provide reliable measurements of health; the function, organisation and effectiveness of participative surveillance approaches; the definition and effectiveness of animal health contracts, such as health mandates between the State and private veterinarians; the function and role of livestock auxiliaries; the establishment of assessment methods and standards that take into account the specific situation of southern countries that could lead to the certification and accreditation of alternative systems. The efficiency of these systems must then be tested (direct impact, cost-benefit studies) using the above-mentioned indicators, and an implementation 'toolkit' can then be assembled, taking into account the local differences which will affect the suitability of each system for different locations. Research into the assessment of animal health systems is a long-term investment, but it ensures that quality certification is reliable and allows for the safe development of animal product markets.

Animal Diseases↗

Study of the attachment of Na+ on glucose and on some of its methylated derivatives.

The mechanism of attachment of Na(+) on glucose, methyl-alpha-D-glucose, methyl-beta-D-glucose, 3-O-methylglucose, tetra-O-methylglucose, and also on galactose and methyl-beta-D-galactose, was studied. For this we measured the ion yields for the complex [sugar-Na(+)] formed by ionisation by matrix-assisted laser desorption/ionisation (MALDI) and ionspray. These data were compared with the relative volatilities and hydrophobicities of the sugars, measured by evaporative light scattering and reversed-phase liquid chromatography, respectively. Some formation enthalpies for the complexes [sugar-Na(+)], starting from the sugar and the cation, were obtained by ab initio calculations. No simple correlations could be observed between the ion yields and the parameters studied, so that the cationisation mechanism of the sugars remains unclear.

Glucose↗

An overview of nomegestrol acetate selective receptor binding and lack of estrogenic action on hormone-dependent cancer cells.

The specific pharmacological profile of the 19-norprogestin nomegestrol acetate (NOMAC) is, at least in part, defined by its pattern of binding affinities to the different steroid hormone receptors. In the present study, its affinity to the progesterone receptor (PgR), the androgen receptor (AR) and the estrogen receptor (ER) was re-evaluated and compared to those obtained for progesterone (P) and several progestins. The characteristics of binding to the PgR in rat uterus were determined and Ki were found to be roughly similar with 22.8 and 34.3 nM for NOMAC and P, respectively. The binding characteristics of 3H-NOMAC were also determined and compared to that of 3H-ORG2058 with Kd of 5 and 0.6 nM, respectively for rat uterus and 4 and 3 nM, respectively for human T47-D cells. Structure-affinity and -activity relationships were studied on a variety of compounds related to NOMAC in order to assess its specificity as a progestin. The effects of NOMAC on the binding of androgen to the AR were investigated, using rat ventral prostate as target model. Contrary to what was observed for MPA, the RBA of NOMAC was found to decline with time, showing anti-androgenic rather than androgenic potential, a result that was confirmed in vivo. Regarding the ER, since none of the progestins were able to compete with estrogen for binding in rat uterus as well as in Ishikawa cells, the induction of alkaline phosphatase activity (APase) was used as an estrogen-specific response. It confirmed the intrinsic estrogenicity of progestins derived from 19-nor-testosterone (19NT), norethisterone acetate (NETA), levonorgestrel (LNG) or norgestimate (NGM) and others. In contrast, all P and 19-norP derivatives remained inactive. Finally, to complete this overview of NOMAC at the sex steroid receptor levels, the lack of estrogenic or estrogenic-like activity was checked out in different in vitro models. Data from this study have demonstrated that NOMAC is a progestin that has greater steroid receptor selectivity compared to MPA or some other synthetic progestins. It may provide a better pharmacological profile than those progestins currently in use in HRT and OC.

Animals↗

Developmental toxicities of ethylbenzene, ortho-, meta-, para-xylene and technical xylene in rats following inhalation exposure.

The developmental toxicities of ethylbenzene, o-, m-, p-xylene and technical xylene were studied in Sprague-Dawley rats after inhalation exposure. Animals were exposed to either of these agents at 100, 500, 1000 or 2000 ppm, for 6 h/day, during days 6-20 of gestation. All the agents tested caused maternal toxicity expressed as a reduction in maternal body weight gain at 1000 and 2000 ppm. Decreased corrected weight gain and food consumption were observed at 1000 and 2000 ppm ethylbenzene, o-, m- or p-xylene, and at 2000 ppm technical xylene. No evidence of teratogenic effects was found after exposure to any of these agents up to 2000 ppm. Fetal toxicity evidenced by significant decreases in fetal body weights occurred at concentrations of 500 ppm or greater of o-xylene or technical xylene, and 1000 ppm or greater of ethylbenzene, m- or p-xylene. A significant increase in the mean percentage of fetuses per litter with skeletal variations was also noted at 2000 ppm ethylbenzene, o- and p-xylene. In summary, all tested agents produced developmental toxicity at 1000 and 2000 ppm, concentrations that also produced significant maternal toxicity. With o-xylene and technical xylene, developmental toxicity also occurred at 500 ppm, in the absence of maternal toxic effects. However, the only indication of a treatment-related effect was a slight decrease in fetal weight.

Administration, Inhalation↗

In vitro and in vivo models for the evaluation of new inhibitors of human steroid sulfatase, devoid of residual estrogenic activity.

The goal of our research project is to develop a new class of orally active drugs, estrone sulfatase inhibitors, for the treatment of estrogen-dependent (receptor positive) breast cancer. Several compounds were synthesized and their pharmacological potencies explored. Based on encouraging preliminary results, three of them, TX 1299, TX 1492 and TX 1506 were further studied in vitro as well as in vivo. They proved to be strong inhibitors of estrone sulfatase when measured on the whole human JEG-3 choriocarcinoma and MCF-7 breast cancer cells and their IC(50)s found to be in the range of known standard inhibitors. Their residual estrogenic activity was checked as negative in the test of induction of alkaline phosphatase (APase) activity in whole human endometrial adenocarcinoma Ishikawa cells. In addition, their effect on aromatase activity in JEG-3 cells was also examined, since the goal of inhibiting both sulfatase and aromatase activities appears very attractive. However, it has been unsuccessful so far. Then, in vivo potencies of TX 1299, the lead compound in our chemical series, were evaluated in comparison with 6,6,7-COUMATE, a non-steroidal standard, in two different rat models and by oral route. First, the absence of any residual estrogenic activity for these compounds was checked in the uterotrophic model in prepubescent female rats. Second, antiuterotrophic activity in adult ovariectomized rat supplemented with estrone sulfate (E(1)S), showed that both compounds were potent inhibitors, the power of TX 1299 relative to 6,6,7-COUMATE being around 80%. This assay was combined with uterine sulfatase level determination and confirmed the complete inhibition of this enzyme within the target organ. Preliminary studies indicated that other non-steroid compounds in the Théramex series were potent in vitro and in vivo inhibitors of estrone sulfatase in rats and further studies are in progress.

Animals↗

In vitro and in vivo models for the evaluation of potent inhibitors of male rat 17alpha-hydroxylase/C17,20-lyase.

The C(17,20)-lyase is a key enzyme in the biosynthesis of androgens by both the testes and adrenals. A complete inhibition of this enzyme would provide an alternative means of androgen suppression for the treatment of prostatic cancers. In the present study, the inhibitory effects of new non-steroidal compounds were tested in vitro on rat C(17,20)-lyase versus abiraterone, a reference steroidal inhibitor. Their activities were also evaluated in vivo on plasma testosterone (T) and luteinizing hormone (LH) levels and on testes, adrenals, seminal vesicles (SV) and ventral prostate (VP) weights after 3 days of oral treatment to adult male rats (50mg/kg per day p.o.). Inhibition in the nanomolar range was obtained with TX 977, the lead racemate product in this series, and optimization is ongoing based on a slight dissociation observed between its two diastereoisomers, TX 1196-11 (S) and TX 1197-11 (R). These non-steroidal compounds (including YM 55208, a reference competitor) proved to be more active in vivo than abiraterone acetate in this model, but the observed impact on adrenal weight suggests that the specificity of lyase inhibition versus corticosteroid biosynthesis deserves further investigations with this new class of potentially useful agents for the treatment of androgen-dependent prostate cancer.

Administration, Oral↗

Anthracycline-induced cardiac toxicity is not increased by dietary omega-3 fatty acids.

Exogenous n-3 polyunsaturated fatty acids (PUFA) and specially docosahexaenoic acid (DHA) have been previously reported to potentiate the efficacy of anticancer agents that generate an oxidative stress, such as anthracyclines, by enhancing the susceptibility of cell membranes to lipid peroxidation. Since lipid peroxidation has also been suggested to mediate anthracycline-induced heart failure, we designed a study aimed at investigating whether a DHA-enriched diet coupled with controlled oxidative conditions prevents or aggravates this serious side effect in vivo. Female Sprague-Dawley rats were submitted for at least 3 weeks to diet enriched in DHA, which was provided either as natural oil (sardine oil, experiment 1) or in a purified form (DHASCO, experiment 2). At the same time, to constrain the nutritional oxidative status, the anti-oxidant Vitamin E or the pro-oxidant menadione/sodium ascorbate redox mixture was added. Then, epirubicin was administered weekly at two cumulative doses, 9 mg x kg(-1) (experiment 1) or 15 mg x kg(-1) (experiment 2). Cardiotoxicity was assessed by electrocardiographic (ECG) and hemodynamic measurements, completed with histological examination. Epirubicin-induced dose-dependent mortality, alterations of hemodynamic parameters and histological damages, all features characterizing the occurrence of congestive heart failure. Moreover, the addition of anti- or pro-oxidant did not change the hemodynamics either at the lowest (experiment 1) or the highest dose (experiment 2). Similarly, the ECG measurements and histological examinations did not reveal any difference. DHA was actually incorporated, as evaluated through the adipose tissue fatty acid composition. All these observations indicated that the DHA-enriched diet, placed under controlled oxidative conditions, did not appear to prevent but neither to aggravate epirubicin-induced cardiotoxicity. These findings support the idea that DHA improves the anthracycline therapeutic index.

Adipose Tissue↗

Treatment of urological complications related to aorto-iliac pathology and surgery.

OBJECTIVES: Proximity of ureters with iliac arteries makes them prone to damage by aorto-iliac pathology or surgery. The aim of this retrospective study is to analyse the incidence, the predisposing factors, and the optimal treatment of ureteral stenosis (US) or leakages (UL). DESIGN: Retrospective study. MATERIAL: Fifty-one ureteral lesions in 41 patients referred to the urologist in a fourteen years period in the same institution. METHODS: Lesions are classified in three groups: A, preoperative; B, less than 3 months postoperatively; and C, more than 3 months postoperatively. Group A comprises 10 abdominal aortic aneurysm (AAA) patients; eight of the AAA are of the inflammatory type. Group B comprises 16 patients, 11 US and 9 UL. Group C comprises 15 patients and 15 US. RESULTS: Endoureteral treatment was successful in most of the group B patients. Some of them, however, had to be submitted to secondary open surgery, so that the global success rate is 70% in group B. In group C, the response is poor following endourological treatment alone (12.5% success) and open surgery is more often needed (3 ureterolyses and 1 nephrectomy). Global success rate is 40%. CONCLUSION: Early diagnosis is associated to better results with less invasive procedure; late diagnosis is accompanied by a lower success rate of endourological treatment and requires more often primary open surgery.

Aged↗

Contagious bovine pleuropneumonia vaccines, historic highlights, present situation and hopes.

Contagious bovine pleuropneumonia (CBPP) is a contagious infection of cattle caused by a mycoplasma, M. mycoides subsp. mycoides SC (MmmSC). It induces lesions of pleuropneumonia in acute cases and the formation of pulmonary "sequestra" in chronic cases. The disease is prevalent mostly in Africa, where it is responsible for high losses, but it has also been sporadically present in Southern Europe until 1999. Vaccination is now prohibited in most countries except in Africa. An empirical "inoculation" procedure was developed as early as 1852 in Europe but it may have been used even earlier in Africa. The inoculation of pleural fluid was performed at the tip of the tail in Europe and on the bridge of the nose in Africa. It conferred good protection but induced a high number of fatal cases. Various inactivated preparations have been tested in the past with inconclusive results leading sometime to some protection and some other time to a sensitisation of the immunised animals. Such preparations have never been used in the field. Attenuated MmmSC strains have been developed in the 1950s and used extensively in the field both in Africa and Australia. The best known vaccine strains are KH3J, T1/44 and T1sr. Vaccination campaigns have succeeded in reducing considerably the CBPP prevalence in these two continents but eradication was achieved in Australia only by switching to strict measures of animal movement control and a stamping-out policy. The search for new CBPP vaccines has become a major issue for African countries that are facing an increase in outbreaks. The rationale for this search is based on a better understanding of the mycoplasma virulence mechanisms that could lead to a targeted attenuation of MmmSC strains. It is also based on a better understanding of the bovine immune response that may be driven to a pathogenic inflammatory response or conversely to a better balanced response leading to protection.

Africa↗

A spectrophotometric method for the determination of organic soluble matter in bitumen fumes.

A UV spectrophotometric procedure was validated for the determination of organic soluble matter in bitumen fumes collected by filtration technique. Ultrasonic extraction was carried out with toluene, an efficient extraction solvent for polycyclic aromatic hydrocarbons, followed by UV absorbance measurements at 320 nm. A calibration curve is plotted from the same set of samples determined by classical weighing method. Further determinations can also be made using the slope factor of the calibration curve. The procedure presents obvious simplicity and rapidity advantages and is less prone to losses than the measurements of weight. Inter-method comparisons of samples collected from experimental laboratory-generated penetration bitumen fumes commonly used in road paving showed that the three available procedures-weighing, infrared, and UV--described for the determination of organic soluble matter yield equivalent results.

Environmental Monitoring↗

Development and validation of a new bitumen fume generation system which generates polycyclic aromatic hydrocarbon concentrations proportional to fume concentrations.

Bitumen fumes emitted during road paving and roofing contain polycyclic aromatic compounds (PACs) of potential health concern. Little information is available for an experimental device devoted to inhalation experiments with animals exposed to bitumen fumes, and in all studies the systems were never validated for a range of fume concentrations, which prohibited their use for toxicological concentration-effect studies. Therefore, the purpose of this study was to validate a new experimental device able to generate bitumen fumes at different total particulate matter (TPM) concentrations with a linear correlation between TPM and the concentrations of different PACs, thus allowing toxicological dose-response studies with fumes representative of those in the field. Atmosphere samples collected from an animal exposure chamber allowed the determination of TPM, toluene soluble matter, polycyclic aromatic hydrocarbons (PAHs) and semi-volatiles. The particulate size distributions were determined in order to assess the deposition pattern in the respiratory tract. The temperature of 170 degrees C was chosen by analogy with the upper range of the temperature used during paving operations. The temperature of the air passing over the fume emission area was regulated to 20 degrees C and stirring of the heated bitumen was restricted to 90 r.p.m. The data show that the objective of developing a static fume generation system that reproducibly produces fumes in the inhalation chamber for specified target concentrations (TPM) were successful. The within-day variation coefficients for TPM were between 2.5 and 6.1%. The day-to-day variations for TPM concentration were between 4.1 and 5.8%. The concentrations of the 4-5 ring PAHs and the polycyclic aromatic sulphur heterocycles were proportional to the TPM concentration. The 2 and 3 ring PAH concentrations showed a deviation from proportionality with the TPM, probably due to their re-evaporation during sampling. The mass median aerodynamic diameter of airborne particles varied from 1.4 micro m at a fume concentration of 5 mg/m(3) to 3.2 micro m at 100 mg/m(3). In conclusion, this equipment was suitable for nose-only inhalation studies in the 5-100 mg/m(3) range of TPM. Bitumen fumes were generated with a good reproducibility under well-controlled conditions. Finally, the PAH profiles from atmospheric samples were in good agreement with those measured during road paving.

Hydrocarbons↗

[TVT: Revolutionary treatment of urinary incontinence].

Stress urinary incontinence represents an important, often unknown and, yet, certainly most unpleasant pathology. Over years, several different surgical techniques have been proposed and reported to have variable success. TVT, a simple and reproducible technique, aims at stabilizing mid-urethra, and not bladder-neck. Our own clinical experience amounts to 139 cases. All these patients were evaluated by clinical examination and, subjectively, by a questionnaire. 89.2% were cured and 6.5% improved. The most frequent complication was bladder perforation (6.5%), but it had no incidence on the final results. Morbidity was low. This revolutionary technique is very promising and our own results are similar to those reported by others.

Adult↗

alpha-, beta-, and gamma-Cyclodextrin dimers. Molecular modeling studies by molecular mechanics and molecular dynamics simulations.

The alpha-, beta-, and gamma-cyclodextrin (CyD) dimers have been studied by molecular mechanics (MM) and molecular dynamics (MD) calculations, and the relative stability of dimers and the involved molecular interactions have been determined. Three possible orientations were considered for the alpha-, beta-, and gamma-CyD dimers: the head-to-head, the head-to-tail, and the tail-to-tail. In vacuo MM calculations were used to obtain the most stable arrangements, and MD simulations were performed over all energy minima obtained for each dimer. Results from MD always show head-to-head orientation as the most stable as a result of the larger number of intermolecular hydrogen bonds present.

Journal Article↗

Imidazo[1,2-a]quinoxalines: synthesis and cyclic nucleotide phosphodiesterase inhibitory activity.

A group of imidazo[1,2-a]quinoxalines have been synthesised from quinoxaline by condensation of an appropriate haloester or intramolecular cyclisation of a keto moiety on an intracyclic nitrogen atom. The reactivity of the heterocycle was explored through diverse reactions such as electrophilic substitution, lithiation and halogen-metal exchange to give access to a new series of derivatives. Confirmation of their structure was mainly performed by NMR, after careful assignment of the signals in comparison to previous attributions made on the parent imidazo[1,2-a]quinoxaline and discussion of available data in the literature. The cyclic nucleotide phosphodiesterase inhibitor activity of some of these derivatives has been assessed on isoenzymes type III and type lV. Compound 15, 4-(methylamino)imidazo[1,2-a]quinoxaline-2-carbonitrile, exhibited potent relaxant activity on smooth muscle, with a potency similar to the one measured with SCA 40, its structural analogue in the imidazo[1,2-a]pyrazine series.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗

Styrene-induced hearing loss: a membrane insult.

Styrene is an aromatic solvent widely used as a precursor for polystyrene plastics in many factories which produce glass-reinforced plastic. This solvent has been shown to disrupt the auditory system in both humans and animals. In order to study the sequence of events which could explain the cochlear impairments, a time course experiment was carried out with 6-month-old rats. Male Long Evans rats were exposed to 1000 ppm styrene for 6 h/day, 5 days/week, for either 1, 2, 3, or 4 consecutive weeks. Auditory function was tested by recording the near field evoked potentials from the inferior colliculus, and histological analyses of the cochleae were performed with light and transmission electron microscopy. The electrophysiological results support a toxic mid-frequency process which keeps worsening even after the end of the exposure. The histological findings demonstrate that supporting cells are the first targets of the solvent. Then, the outer hair cells of the third row (OHC3) are disrupted, followed successively by OHC2 and OHC1 from the basal (20 kHz) to the upper turn (4 kHz) of the cochlea. Basically, the disorganization of the membranous structures could be the starting point for the cochlear injury induced by styrene. This paper presents a hypothesis that the accumulation of K+ in the spaces of Nuel underlies the toxic effects of styrene.

Animals↗

Ototoxicity in rats exposed to ortho-, meta- and para-xylene vapours for 13 weeks.

Male Sprague-Dawley rats were exposed to ortho-, meta- or para-xylene by inhalation (450, 900 and 1,800 p.p.m., 6 hr/day, 6 days/week for 13 weeks) and sacrificed for morphological investigations 8 weeks after the end of exposure. Brainstem auditory-evoked responses were used to determine auditory thresholds at different frequencies. Among the three isomers studied, only para-xylene produced moderate to severe ototoxicity in rats exposed at 900 and 1,800 p.p.m. Increased auditory thresholds were observed at 2, 4, 8 and 16 kHz in rats exposed to 1800 p.p.m. para-xylene. The auditory threshold shifts (35 to 38 dB) did not reverse after 8 weeks of recovery Moderate and severe losses of outer hair cells of the organ of Corti occurred in animals exposed to 900 and 1800 p.p.m. para-xylene respectively. Thus, the no observed effect level of para-xylene was 450 p.p.m. based on the loss of outer hair cells observed by light and electron microscopy.

Administration, Inhalation↗