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Biomedical subjects

P Lefebvre

Publications and source records attributed to P Lefebvre.

At least 19 recordsLinked to original sources
PubMed2006

Inhibition of Amazon deforestation and fire by parks and indigenous lands.

Conservation scientists generally agree that many types of protected areas will be needed to protect tropical forests. But little is known of the comparative performance of inhabited and uninhabited reserves in slowing the most extreme form of forest disturbance: conversion to agriculture. We used satellite-based maps of land cover and fire occurrence in the Brazilian Amazon to compare the performance of large (> 10,000 ha) uninhabited (parks) and inhabited (indigenous lands, extractive reserves, and national forests) reserves. Reserves significantly reduced both deforestation and fire. Deforestation was 1.7 (extractive reserves) to 20 (parks) times higher along the outside versus the inside of the reserve perimeters and fire occurrence was 4 (indigenous lands) to 9 (national forests) times higher. No strong difference in the inhibition of deforestation (p = 0. 11) or fire (p = 0.34) was found between parks and indigenous lands. However, uninhabited reserves tended to be located away from areas of high deforestation and burning rates. In contrast, indigenous lands were often created in response to frontier expansion, and many prevented deforestation completely despite high rates of deforestation along their boundaries. The inhibitory effect of indigenous lands on deforestation was strong after centuries of contact with the national society and was not correlated with indigenous population density. Indigenous lands occupy one-fifth of the Brazilian Amazon-five times the area under protection in parks--and are currently the most important barrier to Amazon deforestation. As the protected-area network expands from 36% to 41% of the Brazilian Amazon over the coming years, the greatest challenge will be successful reserve implementation in high-risk areas of frontier expansion as indigenous lands are strengthened. This success will depend on a broad base of political support.

Agriculture↗
PubMed2005

[Pregnancy termination between 12 and 14 weeks gestation: practices and early complications in comparison with termination between 8 and 12 weeks].

OBJECTIVES: To describe and compare practices and complications of induced abortions (IA) between 12 and 14 gestational weeks (GW) with those performed at lower terms (8-10 and 10-12 GW). PATIENTS AND METHODS: Cohort study enrolled in two IA centers 411 women, 147 of them with 12-14 weeks gestation. Comparisons were made according to pregnancy term (8-10, 10-12 and 12-14 GW). RESULTS: Pregnancy term influenced the technical conditions of IA. Number and diameter of dilators and suction cannula as well as surgery time increase with gestational age--whether priming agents were used or not. Pain felt during surgery and early complications (within 15 days post IA) did not increase with gestational age. CONCLUSION: Results of this study show that IA between 12 and 14 GW are as feasible as with lower terms.

Abortion, Induced↗
PubMed2005

[Malaria in an outbreak zone in Oyapock (French Guiana): incidence of malaria attacks in the American Indian population of Camopi].

The Oyapock region is the second largest malaria outbreak area in French Guiana after Maroni. This area that has been less extensively studied that Maroni is characterized by the presence of an exclusively American Indian population on the French bank and by a high incidence of Plasmodium vivax associated with Plasmodium falciparum. The purpose of this study was to determine the incidence of malaria attacks in Camopi, a population center in which most inhabitants live in 15 small villages located along the middle part of the Oyapock River on the Brazilian border. Study involved diagnosis of malaria attacks (ongoing fever or reported fever within 48 hours and presence of asexual Plasmodium parasites with no other apparent etiology) and accurate estimation of its incidence as well as evaluation of the American Indian population. Study was carried out over the two-year period between April 2000 and March 2002. The mean annual incidence of malaria was 486 per 1000. Incidence was comparable for the two Plasmodium species: 248 p. 1000 for P. falciparum versus 259 p. 1000 for P. vivax but was much higher in children than adults (402 p. 1000 versus 92 p. 1000). The incidence of P. falciparum varied during the year and from one year to the next. Mixed infection documented by microscopic evidence was uncommon. With an annual incidence of around 500 p 1.000, the Oyapock area of French Guiana must be considered as a malaria hot spot.

Adolescent↗
PubMed2004

A randomised phase II multicentre trial of irinotecan (CPT-11) using four different schedules in patients with metastatic colorectal cancer.

The purpose of this phase II trial was to compare the efficacy, safety and pharmacokinetics of four irinotecan schedules for the treatment of metastatic colorectal cancer. In total, 174 5-fluorouracil pretreated patients were randomised to: arm A (n=41), 350 mg m(-2) irinotecan as a 90-min i.v. infusion q3 weeks; arm B (n=38), 125 mg m(-2) irinotecan as a 90-min i.v. infusion weekly x 4 weeks q6 weeks; arm C (n=46), 250 mg m(-2) irinotecan as a 90-min i.v. infusion q2 weeks; or arm D (n=49), 10 mg m(-2) day(-1) irinotecan as a 14-day continuous infusion q3 weeks. No significant differences in efficacy across the four arms were observed, although a shorter time to treatment failure was noted for arm D (1.7 months; P=0.02). Overall response rates were in the range 5-11%. Secondary end points included median survival (6.4-9.4 months), and time to progression (2.7-3.8 months) and treatment failure (1.7-3.2 months). Similarly, there were no significant differences in the incidence of grade 3-4 toxicities, although the toxicity profile between arms A, B, and C and D did differ. Generally, significantly less haematologic toxicity, alopecia and cholinergic syndrome were observed in arm D; however, there was a trend for increased gastrointestinal toxicity. Irinotecan is an effective and safe second-line treatment for colorectal cancer. The schedules examined yielded equivalent results, indicating that there is no advantage of the prolonged vs short infusion schedules.

Adenocarcinoma↗
PubMed2004

[Long-term risks of polycystic ovaries syndrome].

The prevalence of the polycystic ovaries syndrome (PCOS) is high but it is a heterogeneous disorder with implications in numerous medical domains. Abdominal obesity and insulin resistance, which are the main metabolic disorders, are strong links between hormonal abnormalities and long-term medical consequences. The latter begin to be better understood. Some studies suggest that PCOS may increase the risk for several conditions, including type 2 diabetes, dyslipidemia, hypertension, cardiovascular disease and some cancers.

Cardiovascular Diseases↗
PubMed2003

A randomized study over 13 cycles to assess the influence of oral contraceptives containing ethinylestradiol combined with drospirenone or desogestrel on carbohydrate metabolism.

In this open-label, randomized study we compared the influence of a new oral contraceptive containing 30 microg ethinylestradiol and 3 mg drospirenone (Yasmin) with a reference preparation containing 30 microg ethinylestradiol and 150 microg desogestrel (Marvelon) on variables of carbohydrate metabolism by means of oral glucose tolerance tests at baseline and in the 6th and 13th treatment cycle. The mean levels of fasting glucose and insulin were similar at baseline and after 13 treatment cycles, whereas C-peptide and free fatty acid levels decreased slightly in both groups. All blood glucose and insulin values measured in the oral glucose tolerance tests were within normal ranges, despite a slight increase in the mean areas under the curves of 0-3 h [AUCs (0-3 h)] of both variables from baseline to treatment cycle 13. Differences between both treatments were not statistically significant. The mean AUCs (0-3 h) for C-peptide were not markedly changed in any treatment group. Free fatty acid levels decreased by 42% in the drospirenone group and increased by 48.9% in the desogestrel group, in terms of means of individual changes. Both preparations were well tolerated and equally efficacious regarding contraception and cycle control. The mean body weight was slightly decreased in most cycles during treatment with the drospirenone combination, as compared to baseline, while it was slightly increased versus baseline in all cycles during treatment with the desogestrel combination. The combination with drospirenone had less impact on blood pressure than the combination with desogestrel. In conclusion, Yasmin, a combined low-dose oral contraceptive with 30 microg ethinylestradiol and 3 mg of the novel progestogen drospirenone, as well as the reference Marvelon, containing 30 microg ethinylestradiol and 150 microg desogestrel had little impact on carbohydrate metabolism when used for 1 year. The observed changes were small and not suggestive of a clinically relevant deterioration of carbohydrate metabolism.

Adolescent↗
PubMed2003

[Recent progress in the "fibrinogen hypothesis"].

Several clinical and epidemiological studies have demonstrated that a high level of plasma fibrinogen is an independent risk factor for coronary, cerebral and peripheral artery disease. The role of fibrinogen in cardiovascular diseases is mainly due to thrombotic complications in advanced stages of the atherothrombotic disease. However, fibrinogen also plays an active role in the initiation and development of atheromatous plaques. The relations between fibrinogen and ischemic cardiopathies, other vasculopathies and diabetes mellitus are discussed. The controversial effects of statins on fibrinogen are also described.

Biomarkers↗
PubMed2003

[Menopause: towards treatment "à la carte" ].

In spite of questioning and doubt arising from WHT study hormone substitution therapy (HST) has proven efficacy on climacteric symptoms and certain short-term and long-term consequences of menopause. Among 1000 women taking HST for ten years, eight supplementary cases of breast cancer and 6 fewer cases of colonic cancer are observed. No cardiovascular protection has been demonstrated. A history of coronary artery disease, vascular disease, stroke or thromboembolism are contraindications for HST. The vascular impact of estradiol administered via an extra-digestive route in women with a low vascular risk cannot be extrapolated from the HERS and WHI trials because these trials were conducted is high-risk women, using specific types of steroids given orally. Tibolone has demonstrated efficacy and in an alternative to HST after more than one year of menopause. The usefulness of phytoestrogens remains to be determined, particularly due to the wide individual variability of their effects on climacteric symptoms and the low level of proof provided by epidemiological or clinical studies conducted to study the prevention of osteoporosis and the risk of breast cancer. Most of the analyses present methodological biases. Currently, the most widely accepted notion is that there is a beneficial effect on cardiovascular risk. To date, SERMs have selective indications and cannot be prescribed for all women: raloxifen is used for the prevention and treatment of menopause-related osteoporosis. The relative risk of venous thromboembolism with SERMs (raloxifen and tamoxifen) is comparable to that observed with HST. HST or any other treatment given for menopause must be an individual decision balancing the benefits against the risks and taking into account the desires of the patient perfectly informed of the currently available evidence. Prescriptions should be part of an overall scheme including nutritional advise and physical exercise aimed at preserving quality of life and preventing age-related effects which largely depend on genetic predisposition and the psycho-affective environment.

Cardiovascular Diseases↗
PubMed2003

Docetaxel-ifosfamide combination chemotherapy in patients with metastatic hormone-refractory prostate cancer: a phase I pharmacokinetic study.

This phase I study was designed to evaluate the activity toxicity and pharmacokinetics of docetaxel combined with ifosfamide in the treatment of hormone-refractory prostate cancer. Ten patients received a median of 4.6 treatment cycles. Docetaxel was administered at a dose of 40 mg/m2 in a 1-hour infusion followed by ifosfamide 3,000 mg/m2 in a 24-hour infusion every 3 weeks. The optimal sequence of chemotherapeutic agents was investigated by reversing the order of administration in the second cycle and by collecting a total of six pharmacokinetic blood samples per cycle from all patients during the first and second cycles. The sequence of administration did not influence the pharmacokinetics of docetaxel. Prostate-specific antigen (PSA) responses were observed in four out of nine patients, with a PSA response rate of 44.4% (complete response + partial response). The treatment was well tolerated. No grade IV toxicities were recorded and grade III leucopenia resulted in dose-reductions in 6 cycles (13.3%). The pharmacokinetic parameters of docetaxel were similar in both sequences. Our recommendation for further phase II studies is ifosfamide followed by low-dose docetaxel. Further phase II efficacy studies are warranted.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2002

High-dose, single-agent irinotecan as first-line therapy in the treatment of metastatic colorectal cancer.

PURPOSE: The efficacy and safety of single-agent, high-dose irinotecan (CPT-11, Campto) 500 mg/m(2) every 3 weeks were investigated as first-line treatment for advanced colorectal cancer (CRC). PATIENTS AND METHODS: Patients were enrolled into the study to receive a first cycle of therapy with irinotecan at a dose of 350 mg/m(2) every 3 weeks, which could be escalated to 500 mg/m(2) for the second and subsequent cycles depending on toxicity. Efficacy, safety and pharmacokinetics were determined in the intent to treat (ITT) population and the high-dose population (i.e. patients who had received at least three cycles of irinotecan, the second and third at 500 mg/m(2)). RESULTS: Of 49 patients enrolled into the study (ITT population), 31 (63%) received at least three cycles of treatment with cycles 2 and 3 at an irinotecan dose of 500 mg/m(2) (the high-dose population). The response rates (RR) for the ITT and high-dose populations were 24.5% and 35.5%, respectively. The main grade 3/4 toxicities per cycle in the ITT and high-dose populations were neutropenia 22% and 17%, febrile neutropenia 5% and 3%, and diarrhoea 12% and 7%, respectively. The pharmacokinetics of irinotecan and its metabolite SN-38 were investigated in 31 patients in cycle 1 and 22 patients in cycle 2. Irinotecan clearance and SN-38 exposure were not sufficiently correlated with toxicity in cycle 1 to identify patients for dose increase in subsequent cycles. The exposure to irinotecan and SN-38 increased in proportion to dose from 350 to 500 mg/m(2). CONCLUSION: These results suggest that high-dose irinotecan can be safely administered as first-line monotherapy to approximately two-thirds of patients who present with advanced CRC following a selective first cycle.

Adenocarcinoma↗
PubMed2002

Randomized controlled study of the influence of two low estrogen dose oral contraceptives containing gestodene or desogestrel on carbohydrate metabolism.

This study compared the impact on carbohydrate metabolism of two combinedoral contraceptives (COCs). This open-label, single-center trial enrolled participants for a total of 15 cycles. Thirty-six women were randomized to receive either 20 microg ethinyl estradiol (EE) and 75 microg gestodene (GSD) or 20 microg ethinyl estradiol and 150 microg desogestrel (DSG) daily for 21 days out of 28. A glucose tolerance test was performed at baseline and cycles 6 and 13. The area under the curve (AUC) for glucose increased in both study groups. The change was statistically significant (p = 0.036) for the 20 EE/75 GSD group at cycle 6 versus baseline. Fasting blood glucose at cycle 13 was significantly (p < 0.01) higher for both treatment groups compared to baseline. No changes were found for fasting insulin and fasting C-peptide levels or for the AUCs of insulin or C-peptide. Both regimens were well tolerated. Gestodene and desogestrel in combination with 20-microg ethinyl estradiol induce similar changes in carbohydrate metabolism which are smaller than those described earlier for COCs containing higher estrogen doses or more androgenic progestins such as levonorgestrel.

Adult↗
PubMed2002

[Diabetes yesterday, today and tomorrow. Work of the International Federation of Diabetes].

Diabetes mellitus is a frequent disorder affecting individuals of all ages. In children, adolescents and young adults, but also sometimes in older people, Type 1 diabetes is the consequence of insulin deficiency, resulting from an autoimmune process destroying the insulin producing cells in the pancreatic islets of Langerhans. In the adults and older persons (but sometimes also in young individuals), Type 2 diabetes (non-insulin dependent diabetes) occurs in genetically predisposed individuals and is favoured by weight excess and sedentarity. This form of diabetes is undiagnosed in about 50% of those affected. This concise review surveys the history of diabetes, the current situation and the expected changes in terms of epidemiology, prevention and treatment. The role of the International Diabetes Federation (IDF) whose headquarters are located in Brussels, is briefly described, particularly in the scope of its fight against a disease currently affecting 180 millions people worldwide, a figure likely to reach 325 millions at the 2025 horizon.

Diabetes Mellitus↗
PubMed2001

Control of retinoic acid receptor heterodimerization by ligand-induced structural transitions. A novel mechanism of action for retinoid antagonists.

Heterodimerization of retinoic acid receptors (RARs) with 9-cis-retinoic receptors (RXRs) is a prerequisite for binding of RXR.RAR dimers to DNA and for retinoic acid-induced gene regulation. Whether retinoids control RXR/RAR solution interaction remains a debated question, and we have used in vitro and in vivo protein interaction assays to investigate the role of ligand in modulating RXR/RAR interaction in the absence of DNA. Two-hybrid assay in mammalian cells demonstrated that only RAR agonists were able to increase significantly RAR interaction with RXR, whereas RAR antagonists inhibited RXR binding to RAR. Quantitative glutathione S-transferase pull-down assays established that there was a strict correlation between agonist binding affinity for the RAR monomer and the affinity of RXR for liganded RAR, but RAR antagonists were inactive in inducing RXR recruitment to RAR in vitro. Alteration of coactivator- or corepressor-binding interfaces of RXR or RAR did not alter ligand-enhanced dimerization. In contrast, preventing the formation of a stable holoreceptor structure upon agonist binding strongly altered RXR.RAR dimerization. Finally, we observed that RAR interaction with RXR silenced RXR ligand-dependent activation function. We propose that ligand-controlled dimerization of RAR with RXR is an important step in the RXR.RAR activation process. This interaction is dependent upon adequate remodeling of the AF-2 structure and amenable to pharmacological inhibition by structurally modified retinoids.

Dimerization↗
PubMed2001

Phase I and pharmacokinetic study of two sequences of gemcitabine and docetaxel administered weekly to patients with advanced cancer.

PURPOSE: To determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and effect of drug sequence on toxicities and pharmacokinetics of the combination of gemcitabine and docetaxel. METHODS: A total of 34 patients with advanced cancers were treated with gemcitabine and docetaxel on days 1 and 8 of each 21-day cycle according to the following dose escalation schedule: level 1, 800 and 30 mg/m2, respectively; level 2, 800 and 40 mg/m2; level 3, 1,000 and 40 mg/m2; and level 4, 1,250 and 40 mg/m2. At each dose level, at least three patients were assigned to one of the two sequences of drug administration: gemcitabine-->docetaxel or docetaxel-->gemcitabine. Once the MTD had been reached, six additional patients, who had received no more than one chemotherapy regimen, were enrolled to dose levels 3 and 4 (gemcitabine-->docetaxel) to determine the MTD in minimally pretreated patients. RESULTS: Neutropenia was the most frequent DLT with an overall incidence of 23.5%. Grade 3/4 neutropenia occurred in 62% of patients (8/13) who had received two or more prior chemotherapy regimens, but not at all (0/15) in patients who had received no more than one prior chemotherapy regimens (P< 0.001). Additional DLTs included grade 4 diarrhea and grade 4 stomatitis in one patient each. The MTD was determined to be gemcitabine 800 mg/m2 and docetaxel 40 mg/m2 in patients who had received two or more prior chemotherapy regimens. However, minimally pretreated patients (no more than one prior chemotherapy regimen) were able to tolerate higher doses with an MTD of gemcitabine 1,250 mg/m2 and docetaxel 40 mg/m2. There were no significant differences in toxicities or pharmacokinetics between the two sequences of administration. Partial and minor responses were observed in 23.5% of patients: non-small-cell lung (two of eight), gastric (two of three), head and neck (one of two), bladder (two of four) and hepatocellular cancer (one of one). CONCLUSIONS: The combination of gemcitabine and docetaxel administered on days 1 and 8 every 21 days was feasible and well tolerated in patients with advanced malignancies. The sequence of administration had no significant effect on the toxicity or pharmacokinetics of either drug. Minimally pretreated patients tolerated higher doses of this combination without significant toxicities. This schedule and combination demonstrated activity in a variety of solid tumors, and merits further evaluation.

Adult↗
PubMed2001

Murine prolactin-like protein E synergizes with human thrombopoietin to stimulate expansion of human megakaryocytes and their precursors.

The aim of this study was to determine the effect of promegakaryocytopoietic murine hormone prolactin-like protein E (PLP-E) on human megakaryocytopoiesis. Human bone marrow CD34+ cells, cultured in serum-free medium with combinations of thrombopoietin (TPO), stem cell factor (SCF), Flt-3 ligand (Flt-3L), and PLP-E, were analyzed via microscopy, flow cytometry, and clonogenic assay. Unlike the situation with mouse cells, PLP-E alone did not promote human megakaryocyte (MK) differentiation, but instead synergizes with TPO to increase colony-forming unit megakaryocyte (CFU-MK), burst-forming unit erythroid (BFU-E), and and colony-forming unit granulocyte erythroid macrophage mixed (CFU-GEMM) expansion, as well as total MK production. These effects can be attributed to an increase in colony frequency, combined with a significantly greater total cell expansion induced by adding PLP-E along with TPO. The number of cells in each CFU-MK colony is an indication of the maturity of the progenitor population, with larger colonies deriving from a more immature progenitor cell. PLP-E significantly expanded immature, intermediate, and mature CFU-MK subsets at 3 days of culture, as well as the intermediate and mature subsets at day 6. PLP-E combined with TPO induced significant expansion of all CFU-MK subsets at all time points. PLP-E further increased the effect of SCF and Flt-3L on TPO-induced total cell and CFU-MK expansion.PLP-E may act as a survival factor for primitive human megakaryocytic and erythroid progenitors. It appears to preserve the highly proliferative immature fraction of the progenitor compartment but by itself does not promote total cell proliferation or human MK production. PLP-E may prove useful in combination with TPO and other cytokines for ex vivo expansion of hematopoietic progenitors to be used in a clinical setting.

Animals↗
PubMed2001

Direct evidence to support the role of antigen-specific CD8(+) T cells in melanoma-associated vitiligo.

Vitiligo is a cutaneous pigmentary disorder characterized by the loss of melanocytes. An autoimmune mechanism is strongly suspected to be involved in this affection given that it is frequently associated with autoimmune hormonal disorders, and because antibodies directed against melanocytic antigens are found in the serum of patients with vitiligo. We examined the role of cellular immunity in melanoma-associated vitiligo by expanding infiltrating lymphocytes from fresh biopsy specimens of vitiligo patches in melanoma patients. The vitiligo-infiltrating lymphocytes were almost exclusively T lymphocytes, and most were CD8(+). Following in vitro expansion, vitiligo-infiltrating lymphocytes remained predominantly CD8(+) and expressed the cutaneous homing receptor CLA. Furthermore, vitiligo-infiltrating lymphocytes had a clonal or oligoclonal T cell receptor profile, possibly reflecting specific antigenic stimulation. Finally, vitiligo- infiltrating lymphocytes specifically recognized differentiation antigens shared by normal melanocytes and melanoma cells. This direct demonstration of CD8(+) T cell involvement in vitiligo suggests that, in melanoma patients, vitiligo may be a visible effect of a spontaneous antitumoral immune response.

Adult↗
PubMed2001

Interleukin-2 inhibits glucocorticoid receptor transcriptional activity through a mechanism involving STAT5 (signal transducer and activator of transcription 5) but not AP-1.

Cytokines and glucocorticoids (GCs) signaling pathways interfere with each other in the regulation of apoptosis and gene expression in the immune system. Interleukin-2 (IL-2), through the Janus kinase/signal transducers and activators of transcription (Jak/STAT) and mitogen-activated protein kinase (MAPK) pathways, activates STAT5 and activated protein-1 (AP-1) transcription factors, respectively, which are known to repress glucocorticoid receptor (GR) activity, at least in part, through protein-protein interactions. In this work, we have analyzed the mechanisms whereby IL-2 down-regulates the GC-induced transactivation of the mouse mammary tumor virus long terminal repeat (MMTV-LTR) in murine CTLL-2 T lymphocytes. Mutagenesis studies revealed that the MMTV-LTR STAT5 binding site (-923/-914) was not required for IL-2-mediated inhibition but identified both glucocorticoid response elements (GREs) and the -104/+1 region as critical elements for this negative response. The DNA binding activities of transcription factors required for GC-mediated activation of the MMTV-LTR promoter and that bind to the -104/+1 region (nuclear factor-1, Oct-1) were not affected by IL-2 treatment. Overexpression of wild-type STAT5B enhanced the effect of IL-2 on MMTV-LTR activity, and a dominant negative form of STAT5B (Y699F) abolished the IL-2-mediated MMTV-LTR inhibition, whereas AP-1 activation had no effect in this system. Direct interaction between liganded GR and STAT5 was observed in CTLL-2 cells in a STAT5 phosphorylation-independent manner. Overexpression of nuclear coactivators CBP (CREB-binding protein) or SRC-1a (steroid receptor coactivator 1a) did not blunt IL-2 inhibitory effects. We suggest that the STAT5-repressive activity on the GC-dependent transcription may involve direct interaction of STAT5 with GR, is dependent on the promoter context and STAT5 activation level, and occurs independently of coactivators levels in T cells.

Animals↗