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Biomedical subjects

D Picard

Publications and source records attributed to D Picard.

At least 19 recordsLinked to original sources
PubMed2006

[Cutaneous vasculitis with necrotic ulcers in rheumatoid arthritis: treatment with anti-TNFalpha].

INTRODUCTION: Anti-TNFalpha has occasionally been used in the treatment of recalcitrant forms of systemic vasculitis such as Behçet's disease, Wegener's granulomatosis and Churg-Strauss syndrome. We report on the outcome of treatment in rheumatoid arthritis patients with cutaneous vasculitis lesions on anti-TNFalpha. OBSERVATIONS: Two patients with rheumatoid arthritis present for several years had necrotic ulcers of the lower limbs due to cutaneous vasculitis. After the failure of various immunosuppressive drugs (cyclophosphamide, azathioprine, methotrexate), the two patients were treated with anti-TNFalpha: infliximab in the first case and adalimumab in the second. Cutaneous ulcers healed within two to four months of the start of anti-TNFalpha treatment. Despite ongoing anti-TNFalpha treatment, these cutaneous ulcers relapsed four to six months after complete healing. CONCLUSION: Initially spectacular healing of cutaneous vasculitis ulcers under anti-TNF alpha treatment followed by relapse after several months of treatment is suggestive of an escape mechanism.

Adalimumab↗
PubMed2004

Inbreeding and population structure of the potato cyst nematode (Globodera pallida) in its native area (Peru).

The dispersal abilities and the population genetic structure of nematodes living in the soil are poorly known. In the present study, we have pursued these issues in the potato cyst nematode Globodera pallida, which parasitizes potato roots and is indigenous to South America. A hierarchical sampling regime was conducted in Peru to investigate gene flow on regional, field and plant scales. Multilocus genotypes of single individuals were obtained using eight polymorphic microsatellites markers. Large heterozygote deficiencies were observed at most loci. The limited active dispersal of larvae from their cyst, which favours mating between (half) siblings, could be responsible for this pattern. Within fields, as well as among fields within regions (even 35 km apart), low F(ST) values suggest extensive gene flow. Among fields within regions, only 1.5-4.4% genetic variability was observed. Passive dispersal of cysts by natural means (wind, running water, or wild animals) or by anthropogenic means (tillage, movement of infected seed tubers) is probably responsible for the results observed. Among regions, high F(ST) values were observed. Thus long-range dispersal (more than 320 km apart) is probably limited by major biogeographical barriers such as the mountains found in the Andean Cordillera. These results provide useful information for the management of resistant varieties, to slow down the emergence and spread of resistance-breaking pathotypes.

Analysis of Variance↗
PubMed2004

Ability of peripheral DXA measurement to diagnose osteoporosis as assessed by central DXA measurement.

In order to evaluate the utility of peripheral measurement of bone mineral density (BMD) in the diagnosis of osteoporosis, we measured BMD at the spine and femoral neck with central dual-energy X-ray absorptiometry (DXA), at phalanx with AccuDXA (Schick) as well as proximal and distal forearm with pDXA (Norland) in 835 women ranging in age from 20 to 85 yr. In receiver operating characteristic (ROC) curves, where a positive case was defined as a T-score < or = -2.5 either on spine or femoral neck, the areas under the curve were not significantly different between sites. At a T-score of -2.5 as determined by each peripheral apparatus, sensitivity and specificity were, respectively, 0.39 and 0.95 for phalanx and 0.75 and 0.85 for proximal forearm whereas they were 0.42 and 0.96 for distal forearm. Using optimal absolute BMD cutoff values improved the results. Sensitivity and specificity were, respectively, 0.79 and 0.83 for phalanx at an absolute BMD value of 0.436 and 0.84 and 0.79 for proximal forearm at a value of 0.703, whereas they were 0.90 and 0.75 for distal forearm at a value of 0.208. Combining the two forearm measurements improves the results slightly. At cutoff values of 0.641 and 0.252, respectively for proximal and distal forearms, sensitivity was 0.83 and specificity was 0.84. Therefore, a peripheral measurement of BMD together with a good clinical evaluation of the osteoporosis risk profile of the patient, can be an interesting tool for the diagnosis of osteoporosis in areas where central DXA is not available.

Absorptiometry, Photon↗
PubMed2003

[Assessment off-label prescribing in Dermatology].

INTRODUCTION: The official policy of the French National Health Insurance system is to deny reimbursement for drugs prescribed for off-label indications. The objectives of this study were 1) to quantify the use of off-label prescriptions by physicians from a hospital department of dermatology in France; 2) to characterize these off-label prescriptions; 3) to assess data from the literature on the appropriateness of these off-label prescriptions. PATIENTS AND METHODS: For each patient consulting between February 1 and April 1, 2001, the symptom or the disease that was treated and the type of prescription were recorded on standard forms. RESULTS: Eighty six percent of prescriptions were labelled, 14 p. 100 were off-labelled. Inflammatory and hypersensitivity dermatoses were the most frequent indications of off-label prescriptions (26 p. 100). Treatments which most frequently corresponded to off-label prescriptions were topical corticosteroids and methotrexate. Examination of the literature showed that 70 p. 100 of the off-label prescriptions were not based on strong data from evidence-based-medicine. Many off-label prescriptions were made by the most graduate physicians. DISCUSSION: This study showed a great number of off-label prescriptions in dermatology. These prescriptions were often related to rare diseases that were managed by senior dermatologists. These off-label prescriptions were rarely in accordance with data from evidence-based-medicine.

Decision Making↗
PubMed2002

Heat-shock protein 90, a chaperone for folding and regulation.

Heat-shock protein 90 (Hsp90) is an abundant and highly conserved molecular chaperone that is essential for viability in eukaryotes. Hsp90 fulfills a housekeeping function in contributing to the folding, maintenance of structural integrity and proper regulation of a subset of cytosolic proteins. A remarkable proportion of its substrates are proteins involved in cell cycle control and signal transduction. Hsp90 acts with a cohort of Hsp90 co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function. The large conformational flexibility of Hsp90 and a multitude of dynamic co-chaperone complexes contribute to generating functional diversity, and allow Hsp90 to assist a wide range of substrates.

Amino Acid Sequence↗
PubMed2001

The direct proliferative stimulus of dehydroepiandrosterone on MCF7 breast cancer cells is potentiated by overexpression of aromatase.

In women after menopause aromatization of adrenal androgens represents the main source of estrogens, which may promote the development of hormone-dependent breast tumor. Several studies have attempted to determine the cell type within carcinomas that is responsible for 'in situ' estrogen biosynthesis and whether the amount produced may sustain relevant biological effects. Here we show P450arom mRNA and protein expression together with immunocytochemical localization of aromatase in the epithelial MCF7 breast cancer cell line. Moreover, we demonstrate that the enhanced aromatization of dehydroepiandrosterone in aromatase transfected MCF7 cells confers biological advantages such as proliferative stimulation similar to that induced by estradiol. Our results suggest that aromatase inhibitors may be particularly effective in the treatment of hormone-dependent breast cancer disease in postmenopausal women.

Aromatase↗
PubMed2001

The Hsp90 chaperone complex is both a facilitator and a repressor of the dsRNA-dependent kinase PKR.

PKR, a member of the eukaryotic initiation-factor 2alpha (eIF-2alpha) kinase family, mediates the host antiviral response and is implicated in tumor suppression and apoptosis. Here we show that PKR is regulated by the heat shock protein 90 (Hsp90) molecular chaperone complex. Mammalian PKR expressed in budding yeast depends on several components of the Hsp90 complex for accumulation and activity. In mammalian cells, inhibition of Hsp90 function with geldanamycin (GA) during de novo synthesis of PKR also interferes with its accumulation and activity. Hsp90 and its co-chaperone p23 bind to PKR through its N-terminal double-stranded (ds) RNA binding region as well as through its kinase domain. Both dsRNA and GA induce the rapid dissociation of Hsp90 and p23 from mature PKR, activate PKR both in vivo and in vitro and within minutes trigger the phosphorylation of the PKR substrate eIF-2alpha. A short-term exposure of cells to the Hsp90 inhibitors GA or radicicol not only derepresses PKR, but also activates the Raf-MAPK pathway. This suggests that the Hsp90 complex may more generally assist the regulatory domains of kinases and other Hsp90 substrates.

Dimerization↗
PubMed2001

International prospective evaluation of scintimammography with technetium-99m sestamibi: interim results.

OBJECTIVE: The purpose of this study is to evaluate the validity and reliability of scintimammography with technetium-99m (99mTc)-labeled sestamibi as an adjunct radiodiagnostic agent in the diagnosis of breast cancer. METHODS: This is a multicenter prospective cohort clinical trial that was initiated in June 1999 and will terminate May 2001. All patients with a physical or mammographic finding visiting any of the participating clinics are enrolled in the study. Patients who are younger than 18 years, pregnant, not willing to sign the consent form, or who have undergone an invasive procedure on the breast 30 days or less before scintimammography are excluded. At the time of the first interim report, 633 patients had been recruited from six Canadian centers. To date complete data have been collected for 530 patients. RESULTS: The mean (SD) age of the patients is 56 (12) years with a range between 24 and 85. There were 122 (23%) of the women in the sample who were postmenopausal and 36 (7%) who were perimenopausal. Breast density was graded as dense for 127 (24%), normal for 260 (50%), and fatty for 138 (26%). Of the 530 women in the study 156 (29%) had a palpable mass at physical examination. The mammographic results were classified as 76 (14%) breast imaging reporting and data system (BIRADS) 5, 60 (11%) BIRADS 4, 70 (13%) BIRADS 3 and the remaining BIRADS 2 or 1. The scintimammography results were positive for 118 (23%) of the patients and negative for 412 (78%). The histopathology showed malignant breast disease for 66 (12.5%) of the patients in the sample. Sensitivity and specificity of scintimammography for the detection of breast cancer was estimated 90.9% and 87.5%, respectively. A positive predictive value (PPV) of 50.8% with a negative predictive value of 98.5% and an accuracy of 87.5% were calculated. The PPV is interpreted as the posttest probability of disease given a positive test result. In this sample the pretest probability of disease would be best estimated by the prevalence of disease, which is equal to 12.5%. A positive scintimammography result would change the estimated probability to 51%, which is equivalent to a 400% change from the pretest value. Therefore a positive scintimammography result significantly increases our ability to predict the presence of malignant disease in this population. CONCLUSION: The interim results of the present study suggest that scintimammography with 99mTc-sestamibi is accurate and potentially useful as an adjunct to mammography for the detection of breast cancer.

Adult↗
PubMed2001

Genetic variability among cercariae of the Schistosomatidae (Trematoda: Digenea) causing swimmer's itch in Europe.

Ribosomal DNA sequences of the internal transcribed spacer 1 (ITS1) were obtained from schistosome cercariae responsible for swimmer's itch in Europe. Two types of ITS1 (1100 and 1400), which differ by the number of repeated patterns were found among cercariae shedded by Lymnaea ovata and L. auricularia (Lymnaeidae). A phylogenetic analysis of the ITS1 region showed that sequences of each type form two well-defined clades. An adult of Trichobilharzia regenti isolated from the nasal vessels of Anas platyrhynchos (Anatidae) was found to correspond to the cercaria type 1400. The sequencing of several ITS1 clones from a single cercaria of each type, as well as a specific PCR-based test suggested that both ITS1 types do not co-occur within a single individual.

Animals↗
PubMed2001

Hsp104 interacts with Hsp90 cochaperones in respiring yeast.

The highly abundant molecular chaperone Hsp90 functions with assistance from auxiliary factors, collectively referred to as Hsp90 cochaperones, and the Hsp70 system. Hsp104, a molecular chaperone required for stress tolerance and for maintenance of [psi(+)] prions in the budding yeast Saccharomyces cerevisiae, appears to collaborate only with the Hsp70 system. We now report that several cochaperones previously thought to be dedicated to Hsp90 are shared with Hsp104. We show that the Hsp90 cochaperones Sti1, Cpr7, and Cns1, which utilize tetratricopeptide repeat (TPR) domains to interact with a common surface on Hsp90, form complexes with Hsp104 in vivo and that Sti1 and Cpr7 interact with Hsp104 directly in vitro. The interaction is Hsp90 independent, as further emphasized by the fact that two distinct TPR domains of Sti1 are required for binding Hsp90 and Hsp104. In a striking parallel to the sequence requirements of Hsp90 for binding TPR proteins, binding of Sti1 to Hsp104 requires a related acidic sequence at the C-terminal tail of Hsp104. While Hsp90 efficiently sequesters the cochaperones during fermentative growth, respiratory conditions induce the interaction of a fraction of Hsp90 cochaperones with Hsp104. This suggests that cochaperone sharing may favor adaptation to altered metabolic conditions.

Amino Acid Sequence↗
PubMed2001

Normal parathyroid function with decreased bone mineral density in treated celiac disease.

Decreased bone mineral density (BMD) has been reported in patients with celiac disease in association with secondary hyperparathyroidism. The present study investigated whether basal parathyroid hormone (PTH) remained elevated and whether abnormalities of parathyroid function were still present in celiac disease patients treated with a gluten-free diet. Basal seric measurements of calcium and phosphate homeostasis and BMD were obtained in 17 biopsy-proven patients under treatment for a mean period of 5.7+/-3.7 years (range 1.1 to 15.9). In addition, parathyroid function was studied with calcium chloride and sodium citrate infusions in seven patients. Basal measurements of patients were compared with those of 26 normal individuals, while parathyroid function results were compared with those of seven sex- and age-matched controls. Basal results were similar in patients and controls except for intact PTH (I-PTH) (3.77+/-0.88 pmol/L versus 2.28+/-0.63 pmol/L, P<0.001), which was higher in the former group but still within normal limits. Mean 25-hydroxy vitamin D and 1,25-dihydroxy vitamin D values were normal in patients. Parathyroid function results were also found to be similar in both groups. Compared with a reference population of the same age (Z score), patients had significantly lower BMDs of the hip (-0.60+/-0.96 SDs, P<0.05) and lumbar spine (-0.76+/-1.15 SDs, P<0.05). T scores were also decreased for the hip (-1.3+/-0.9 SDs, P<0.0001) and lumbar spine (-1.4+/-1.35 SDs, P<0.0001), with two to three patients being osteoporotic (T score less than -2.5 SDs) and seven to eight osteopenic (T score less than -1 SDs but greater than or equal to -2.5 SDs) in at least one site. Height and weight were the only important determinants of BMD values by multivariate or logistical regression analysis in these patients. The results show higher basal I-PTH values with normal parathyroid function in treated celiac disease. Height and weight values are, but I-PTH values are not, an important determinant of the actual bone mass of patients. Normal parathyroid function in treated patients suggests a lack of previous severe secondary hyperparathyroidism and/or complete adaptation to prior changes in parathyroid function.

Absorptiometry, Photon↗
PubMed2001

Estrogen receptor alpha mediates the proliferative but not the cytotoxic dose-dependent effects of two major phytoestrogens on human breast cancer cells.

Phytoestrogens are a chemically diverse group of compounds made by plants that can have estrogenic effects in animals. Both tumorigenic and antitumorigenic effects have been reported. Although estrogens stimulate the growth of many breast tumors, there is a negative correlation between the incidence of breast cancer and the phytoestrogen-rich diet of certain Asian populations. To begin to resolve this paradox, we have analyzed the estrogenic properties of genistein and quercetin, two flavonoid phytoestrogens particularly abundant in soybeans. Trans-activation experiments with a transfected reporter gene for nuclear estrogen receptors (ER) show strong activation of the endogenous ER alpha by both phytoestrogens in two MCF7 human breast cancer cell lines. This is supported by the observation that the two phytoestrogens induce the down-regulation of ER alpha mRNA and protein levels. Using chimeric proteins consisting of the hormone binding domains of ER alpha and ER beta fused to the Gal4 DNA binding domain, we have established that genistein and quercetin are full estrogenic agonists of both ER isoforms. Ligand binding experiments with purified ER alpha and ER beta confirm that the two phytoestrogens are ER ligands. At concentrations that are sufficient to obtain substantial transcriptional activity, they stimulate the proliferation of two ER alpha-dependent breast cancer cell lines. At high concentrations, such as those reached with a soy-rich diet, genistein and quercetin are strong cytotoxic agents that even kill ER-independent HeLa cells. Thus, the mode of action of phytoestrogens and the balance between being risk or chemopreventive factors for breast cancer may depend on the dietary load.

Breast Neoplasms↗
PubMed2000

Estradiol decreases IGF-1 and IGF-1 receptor expression in rat aortic smooth muscle cells. Mechanisms for its atheroprotective effects.

Insulin-like growth factor (IGF-1) is a potent mitogen for vascular smooth muscle cells. Both IGF-1 and its receptor have been shown to be highly expressed in atherosclerotic lesions. Here we investigated whether part of the vasculoprotective properties of E(2) may be mediated by its negative regulation of the IGF-1 system. HeLa cells, which do not contain endogenous estrogen receptors (ER), were transiently transfected with IGF-1R promoter constructs with or without a plasmid encoding human ERalpha or ERbeta and treated with 100 nm 17beta-estradiol (E(2)) for 24 h. E(2) treatment decreased basal luciferase activity by 51%, and this effect was dependent on co-expression of ERalpha, whereas no repression was observed with ERbeta. A mutation within the DNA binding domain of the ERalpha abolished the repressor function of the ER receptor. Similarly, E(2) decreased IGF-1R transcription by 21% in rat aortic smooth muscle cells (RASMC), which express endogenous ER. This effect was specific for E(2), because it was inhibited by an antiestrogen and because progesterone did not have any effect on IGF-1R expression in HeLa or RASMC transfected with progesterone receptor. Accordingly, E(2) decreased IGF-1R and IGF-1 mRNA in RASMC by 47% and 33%. Western blot analysis and radioligand binding studies showed that E(2) also dose-dependently decreased IGF-1R protein expression in RASMC by 40% and 30%, respectively, and that IGF-1 protein was reduced by 43%. Repression of IGF-1R promoter activity by a combination of ERalpha and E(2) did not appear to be mediated via direct binding of ER to the IGF-1R promoter but rather by inhibition of SP1 binding to the IGF-1R promoter. Thus, E(2) down-regulates IGF-1R and IGF-1 expression in vascular smooth muscle cells. This may have important implications for the understanding of the beneficial effects of estrogen in the cardiovascular system.

Animals↗
PubMed2000

The molecular chaperone Cdc37 is required for Ste11 function and pheromone-induced cell cycle arrest.

The molecular chaperone Cdc37 is thought to act in part as a targeting subunit of the heat-shock protein 90 (Hsp90) chaperone complex. We demonstrate here that Cdc37 is required for activity of the kinase Ste11 in budding yeast. A cdc37 mutant strain is defective in Ste11-mediated pheromone signaling and in accumulation and functional maturation of the constitutively active Ste11 version Ste11DeltaN. Moreover, Cdc37, Ste11DeltaN and Hsp90 coprecipitate pairwise. Thus, Hsp90 and Cdc37 may transiently associate with Ste11 to promote proper folding and/or association with additional regulatory factors. Our results establish Ste11 as the first endogenous Cdc37 client protein in yeast.

Alleles↗
PubMed2000

Longitudinal study of bone density and its determinants in women in peri- or early menopause.

The evolution of bone mass across menopause as well as the factors related to bone loss were studied in 141 women already assessed 10 years ago while in premenopause. Bone density of the lumbar spine was measured by dual photon absorptiometry. Nutrient intakes, lifestyle habits, data on menopause, and hormone replacement therapy were obtained by questionnaires. Present bone density was related significantly to past and current calcium intake, current vitamin D intake, and leisure physical activity level, as well as bone density measured in premenopause. Average bone loss was related to time elapsed without estrogens, age at menopause and present age, as well as serum levels of osteocalcin and alkaline phosphatase (ALP). Bone loss was inversely related to calcium and vitamin D intakes and to serum 25-OH vitamin D (25OHD) levels. By multiple regression analyses, only bone density in premenopause, time without estrogens, weight, vitamin D intake, and serum ALP levels remained as independent predictors of present bone mass or bone loss. This study emphasizes the importance of building a good bone mass before menopause, of having adequate vitamin D intake, and of beginning estrogen replacement therapy as soon as possible to minimize bone loss in the first years of menopause.

Adult↗
PubMed1999

Adrenal androgens stimulate the proliferation of breast cancer cells as direct activators of estrogen receptor alpha.

Estrogens stimulate the proliferation of many breast tumors and cell lines derived from them. Antiestrogens have therefore become a powerful therapeutic agent to treat breast tumors that express estrogen receptor (ER) alpha. In addition, aromatase inhibitors are now used in postmenopausal women to block the in situ conversion of adrenal androgens to estrogens. This approach can only be successful if ER-alpha in a particular tumor is not directly stimulated by adrenal androgens. We have examined this possibility using several different cell lines as model systems: (a) wild-type MCF7 cells, an ER-alpha-dependent human breast cancer cell line; (b) MCF7SH cells, an estrogen-independent MCF7 variant; (c) Ishikawa cells, an ER-alpha-containing human uterine cell line; (d) ER-negative HeLa cells; and (e) budding yeast. Transactivation assays with transfected ER-alpha reporter genes reveal a direct activation of ER-alpha by dehydroepiandrosterone (DHEA), 5alpha-androstene-3beta,17beta-diol, testosterone, and the two nonaromatizable androgens, dihydrotestosterone and 5alpha-androstane-3beta,17beta-diol. The involvement of other steroid receptors could be ruled out with specific antihormones. Moreover, the same set of ligands stimulates the proliferation of the two breast cancer cell lines. At subsaturating and physiologically relevant concentrations of DHEA, DHEA stimulates the proliferation of MCF7SH cells, which correlates with a substantial, albeit submaximal, transcriptional response. Thus, adrenal androgens must also be considered as risk factors in postmenopausal women.

Androgens↗