Monoculture-based consumer-resource models predict species dominance in mixed batch cultures of dinoflagellates.

Global change will disturb the frequency, scale and distribution of harmful algal blooms (HABs), but we are unable to predict future HABs due to our limited understanding of how physicochemical changes in the environment affect interspecific competition between dinoflagellates. Trait-based mechanistic modelling is an important tool to unravel and quantify various direct and indirect interactions between species. The present study explores whether MacArthur's consumer-resource model can be used as a viable base model to predict dinoflagellate growth in closed multispecies systems. To this end, two batch culture experiments (294 cultures in total) with monocultures and multispecies cultures of Alexandrium minutum, Prorocentrum lima, P. micans, Protoceratium reticulatum and Scrippsiella trochoidea were performed. Despite changes to the relative (different nitrate concentrations) and absolute nutrient availability (dilutions of L1 medium), P. micans outcompeted all other species in mixed cultures. Consumer-resource modelling parameterized using monoculture growth correctly predicted this species dominance (R² between 0.80 and 0.95). Parameter estimates revealed that P. micans had a faster uptake of nitrogen when compared to its competitors, but did not differ in resource efficiency and natural mortality rate. Yet, while the model accurately predicted community dynamics during the growth phase, it was not able to predict their dynamics beyond the point of quiescence. Consumer-resource modelling was shown to differentiate the roles of resource assimilation, resource efficiency, and natural mortality rates in batch culture experiments with minimal data requirements beyond common measurements. The results suggest that consumer-resource models provide a promising basis for trait-based modelling of interspecific competition between (harmful) algae.

Endocrine activity in an urban river system and the biodegradation of estrogen-like endocrine disrupting chemicals through a bio-analytical approach using DRE- and ERE-CALUX bioassays.

The Zenne River, crossing the Brussels region (Belgium) is an extremely urbanized river impacted by both domestic and industrial effluents. The objective of this study was to monitor the occurrence and activity of Endocrine Active Substances (EAS) in river water and sediments in the framework of the Environmental Quality Standards Directive (2008/105/EC and 2013/39/EU). Activities were determined using Estrogen and Dioxin Responsive Elements (ERE and DRE) Chemical Activated Luciferase Gene Expression (CALUX) bioassays. A potential contamination source of estrogen active compounds was identified in the river at an industrial area downstream from Brussels with a peak value of 938 pg E2 eq./L water (above the EQS of 0.4 ng/L) and 195 pg E2 eq./g sediment. Estrogens are more abundantly present in the sediments than in the dissolved phase. Principal Component Analysis (PCA) showed high correlations between Suspended Particulate Matter (SPM), Particulate (POC) and Dissolved Organic Carbon (DOC) and estrogenic EAS. The dioxin fractions comply with previous data and all were above the United States Environmental Protection Agency (US EPA) low-level risk, with one (42 pg TCDD eq./g sediment) exceeding the high-level risk value for mammals. The self-purifying ability of the Zenne River regarding estrogens was examined with an in vitro biodegradation experiment using the bacterial community naturally present in the river. Hill coefficient and EC50 values (Effective Concentration at 50%) revealed a process of biodegradation in particulate and dissolved phase. The estrogenic activity was decreased by 80%, demonstrating the ability of self-purification of estrogenic compounds in the Zenne River.

Arsenic speciation in the River Zenne, Belgium.

Arsenic species have been assessed in the Zenne River, a sewage contaminated tributary of the Scheldt estuary, in winter 2003. The highest total dissolved As concentrations were found in the middle part of the river with values up to 3.6 microg L(-1). Particulate As concentrations increase towards the mouth of the River with highest levels of 2 microg L(-1). A very good correlation between the % of dissolved As and % of dissolved Fe was observed. They both linearly decrease with the amount of dissolved oxygen. In the middle part of the Zenne River where the oxygen levels were lowest, even below 1 mg L(-1), As(III) was the dominant species. In the other parts (upstream and downstream) of the river, As(V) was dominant. A linear relation between the measured redox values and those calculated via the As(III)/As(V) couple exists, but the range of measured Eh values is much larger than the calculated ones. No methylated dissolved As species were found during our survey.

Pharmacodynamics of follicle stimulating hormone (FSH) in postmenopausal women during pulsed estrogen therapy: Evidence that FSH release and synthesis are controlled by distinct pathways.

17 beta-Estradiol (E2) exerts negative feedback effects at the hypothalamo-pituitary level on serum FSH. This study investigated the effects of repeated daily administration of intranasal E2 (S21400) on the pharmacokinetics (PK) of E2 and estrone (E1) and the pharmacodynamics (PD) of FSH and assessed the PK/PD relationship between E2 and FSH using population model-dependent analysis. Postmenopausal volunteers (n = 24) received according to a balanced cross-over design, two 28-d treatments separated by a 2-month wash-out period: 300 microg E2, either alone or combined with oral dydrogesterone (20 mg/d) during the last 14 d of one of the treatments. Absorption of E2 was rapid, with maximal plasma concentrations at 10-30 min, returning to postmenopausal levels within 12 h. Over the 24-h period, FSH levels showed a U curve, with a minimum around 8 h after E2 administration. Moreover, over the treatment period, FSH basal values decreased by 17% between d 1 and 14 and an additional 5% between d 14 and 28. A PK/PD model described these short- and mid-term effects, possibly reflecting separate regulation mechanisms by E2 on FSH release and biosynthesis, respectively. The administration of progestin had no influence on E1, E2, and FSH model parameters. This study suggests that daily transient tissue exposure to E2 after pulsed estrogen therapy elicits short- and mid-term effects on the gonadotropin axis.

Community-acquired pneumonia. Importance of initial noninvasive bacteriologic and radiographic investigations.

During a one-year epidemiologic survey of acute community-acquired pneumonia, we prospectively investigated in 116 adult nonimmunocompromised patients (a) the importance of initial noninvasive investigations (ie, blood culture and quantitative sputum culture) and the value of the initial radiologic type of pneumonia in diagnosing of the etiologic agent, and (b) the management of pneumonia. Quantitative sputum culture or blood culture (or both) permitted bacteriologic diagnosis in 44 percent of the cases. The radiologic types found were segmental or alveolar densities in 75 patients (65 percent), patchy alveolar densities in 11 (9 percent), mixed opacities in 26 (22 percent), and interstitial infiltrates in four (3 percent). We observed that (a) the prognosis was identical whether a bacteriologic diagnosis was made or not, (b) the Gram stain, an inexpensive procedure, was as contributive for bacteriologic diagnosis as quantitative sputum culture, diagnosis as (c) blood cultures were poorly contributive in patients without severe infections, and (d) alveolar densities were associated with a bacterial infection in 90 percent of the cases of known etiology. On the basis of these results, a pragmatic strategy of initial management of community-acquired pneumonia is proposed.

GR38032F, a 5HT3 receptor antagonist, in the prophylaxis of acute cisplatin-induced nausea and vomiting.

A total of 28 patients receiving cancer chemotherapy with cisplatin-containing regimens (70-120 mg/m2) participated in an evaluation of the efficacy and safety of GR38032F for the prevention of acute nausea and vomiting. GR38032F, a 5HT3 receptor antagonist, was given 30 min prior to cisplatin as an 8-mg loading dose by i.v. infusion over 15 min, followed by continuous infusion at a rate of 1 mg/h for 24 h. Efficacy was assessed by measurement of the number of episodes of retching and vomiting occurring in the 24 h after cisplatin administration and by an assessment of nausea during the same period. In all, 26 patients were evaluable for efficacy: overall, complete control was achieved in 12 patients (46%), major control (1-2 emetic episodes), in 6 (23%); minor control (3-5 episodes), in 1 (4%); control could not be achieved (failure; greater than 5 episodes) in 7 patients (27%). GR3832F was the tolerated, with no significant drug-related adverse events. These encouraging results should be confirmed in comparative trials.

Effect of a macrolide (spiramycin) on the pharmacokinetics of L-dopa and carbidopa in healthy volunteers.

In one well-equilibrated parkinsonian patient treated with combined L-dopa and carbidopa (Sinemet), we have observed changes in treatment efficacy while receiving spiramycin (Rovamycine) for an intercurrent respiratory infection. A preliminary study of the pharmacokinetics of L-dopa and its main metabolites 3-O-methyldopa (3-OMD) and dihydroxyphenylacetic acid (dopac) in two parkinsonian patients treated with Sinemet has revealed a marked decrease in the AUC0-360 of these two metabolites after a 3-day course of Rovamycine. In order to confirm this interaction, we have studied the modifications of the pharmacokinetics of L-dopa, 3-OMD, dopac, and carbidopa in eight male healthy volunteers after a single dose of Sinemet 250 (L-dopa, 250 mg and carbidopa, 25 mg) before and after a 3-day course of Rovamycine. Our study confirms this interaction. After spiramycin, we observed a marked reduction in AUC0-360 for L-dopa (p less than 0.001), 3-OMD (p less than 0.001), and carbidopa (p less than 0.001), and an increase in AUC0-360 for dopac (p less than 0.01). The L-dopa elimination half-life was increased (p less than 0.012); differences in peak plasma concentrations did not attain statistical significance. We think that these modifications in L-dopa pharmacokinetics after spiramycin are due to nonabsorption of carbidopa secondary to modified gastrointestinal motility.

Plasma estradiol concentrations and pharmacokinetics following transdermal application of Menorest 50 or Systen (Evorel) 50.

OBJECTIVES: In order to compare the pharmacokinetics of two transdermal estrogen replacement therapy (ERT) systems designed to release 50 micrograms 17 beta-estradiol/day, two studies were performed in healthy postmenopausal volunteers. METHODS: Both studies had a cross-over design and incorporated a 1-week wash-out period between treatments. In the first study, Menorest 50 and Systen 50 (Evorel 50) were compared over four days of application in 30 women. In the second, 13 women wore each of the two systems for a total of 12 days each (three patches each for 4 days), and comparison was made during the third patch period (steady state, between days 8 and 12). Plasma 17 beta-estradiol levels were assayed using specific direct radioimmunoassays, and pharmacokinetic parameters were calculated by standard methods. All the samples of the first study were re-analysed using a different radioimmunoassay and the results of both assays were compared. RESULTS: In both studies, plasma 17 beta-estradiol levels rose at a comparable rate and reached similar peak levels with each of the two formulations. Levels then remained relatively constant throughout both evaluation periods with Menorest 50, but began to decline after 12 hours in the first study and after 30 h under steady state conditions in the second study with Systen 50. The difference between the two products was statistically significant in both studies. Analysis of pharmacokinetic parameters confirmed the greater bioavailability of Menorest 50. In addition, 17 beta-estradiol levels remained within the suggested therapeutic ranges for relief of acute symptoms and protection against osteoporosis for longer periods of time with Menorest 50 than with Systen 50. CONCLUSION: Since the acute efficacy, long-term protective effects, side effects and risks associated with ERT may depend on critical threshold plasma levels, much attention should be paid to the pharmacokinetic profiles of different formulations. The comparison of these two different radioimmunoassays demonstrates the comparability of their results.

Recovery of acetylsalicylic acid and indalpine (LM 5008) after buccal partitioning.

The recoveries were compared of acetylsalicylic acid (ASA) and indalpine (1) after buccal absorption in three trained human volunteers. Recovery of the poorly lipid soluble ASA was less than 1% at pH 5 or 8, while that of the lipid soluble I was 19% and 13% at pH 5 and 8 respectively. This difference in recovery may represent a difference in their storage within the buccal mucosa dependent on their different lipid solubilities.

Pulsed estrogen therapy: pharmacokinetics of intranasal 17-beta-estradiol (S21400) in postmenopausal women and comparison with oral and transdermal formulations.

Pharmacokinetics of estradiol and estrone were assessed in postmenopausal women receiving S21400, a novel 17beta-estradiol formulation administered by nasal route; the results were compared with those obtained with oral and transdermal routes. Thirty six women received three treatments: a specified dose of 17beta-estradiol (100, 300 or 450 microg) given once and as 2 doses, 12 h apart, using three parallel dose groups in a randomised, crossover study. Thereafter, a reservoir patch (50 microg/day of 17beta-estradiol) or a tablet of 2 mg micronised 17beta-estradiol were randomly administered. Plasma concentrations of estradiol and estrone were measured by radioimmunoassays. Following intranasal dosing, estradiol was rapidly absorbed with plasma concentrations reaching maximal values (approximately 1400 pg/ml with a single 300 microg dose) after 10-30 min and returning within 12 h to levels of untreated postmenopausal women. Systemic exposure to estradiol was dose proportional and independent of the treatment regimen. Moreover, the dose of 300 microg gave an estimated 24 h systemic exposure to exogenous estradiol close to that of the 50 microg/day reservoir patch or the 2 mg tablet. The mean estrone to estradiol ratio was similar and 4-fold lower than those with the patch and the tablet, respectively. In conclusion, by this new route for estrogen replacement therapy, the nasal route, the pharmacokinetics of estradiol as S21400 were linear and displayed a 'pulsed' kinetic profile, different from those obtained with the usual routes of administration.

[Diffusion of minocycline in pulmonary tissue]. / Diffusion de la minocycline dans le tissu pulmonaire.

The penetration of minocycline into lung tissue was evaluated in 14 patients about to undergo excision of the lung for cancer. The patients received minocycline orally in doses of 100 mg twice a day for 3 days, the 100 mg in the morning of the operation day. Minocycline concentrations were measured in plasma samples taken before surgery and in the lung tissue resected. The mean tissue/plasma concentration ration was 3.17 +/- 0.41 (range: 1.5 to 7.48). The same ratios were obtained in peritumoral and tumoral tissues. These results indicate that minocycline penetrates well into tissues.

[Metastatic colorectal cancer: new therapeutics]. / Cancer colorectal métastatique: nouveautés thérapeutiques.

NEED FOR NEW CHEMOTHERAPEUTIC AGENTS: The use of 5-FU in combination with leucoverin (LV) in the treatment of advanced colorectal cancer has consistently provided antitumoral response. The antitumoral activity of the 5-FU/LV combination is associated with inhibition of thymidylate synthetase, an essential enzyme in pyrimidine de novo biosynthesis of thymidilates as precursors of DNA synthesis. However, dose-limiting toxicities and the limited impact on survival point to the need to develop new drugs and approaches to improve therapeutic efficacy and survival. CLINICAL RESULTS: In advanced colorecal cancer, clinical results have confirmed the therapeutic efficacy of direct and indirect thymidylate synthetase inhibitors. Promising new agents: 5-FU prodrugs and inhibitors of dihydropyrimidine dehydrogenase (DPD) are promising chemotherapeutic agents with good oral bioavailability which can be combined with other drugs (leucoverin) with acceptable toxicity. Oxaliplatin and topoisomerase inhibitors such as irinotecan (CPT-11) have demonstrated activity in previously treated and newly diagnosed patients. COMBINATIONS: The best combination between DNA interaction drugs based on potentiation of DNA damage induced by thymidylate synthetase inhibitors and inhibition of DNA repair by DNA interactions remains to be evaluated.

[Non-cancer uses of methotrexate]. / Les utilisations non cancérologiques du méthotrexate.

Methotrexate, used for nearly 40 years as an antimetabolite for cancer therapy, also has indications in dermatology, rheumatology and pneumology. When given at low dosage, it has an antiinflammatory effect although the mechanism is not totally understood. Numerous therapeutic trials have been performed in chronic inflammatory diseases such as rheumatoid arthritis in the adult, juvenile polyarthritis and corticosteroid-dependent asthma. Methotrexate is effective in severe resistant forms of rheumatoid arthritis and is used either alone or in combination with other drugs as first intention therapy because of the good tolerance, patient compliance and ease of use. The beneficial effect in severe corticosteroid-dependent asthma remains to be demonstrated. It has also been used in severe forms of psoriasis and may be useful in other diseases with an autoimmune component. Other less common indications including Crohn's disease, ectopic pregnancy and pregnancy termination require confirmation. Tolerance and compliance are generally good, even for prolonged treatments and undesirable effects are almost always reversible at withdrawal.

[Anticancer chemotherapy. Prevention of complications]. / Chimiothérapie anticancéreuse. Prévention des complications.

OPTIMAL CHEMOTHERAPY DOSE: The goal of cancer chemotherapy is to eradicate the malignant disease while minimizing severe toxic effects. There is an optimal chemotherapy dose intensity above which palliation is adversely affected by toxicity; below this level the effect is also adverse because of a low rate of tumor response. METHODS FOR REDUCING TOXICITY: There are several methods by which one can reduce the toxicity of cancer chemotherapy, such as the application of rationally designed dosage schedules, alternative routes of administration, biochemical modulation, and the development of drug camers and analogs. Growth factors, interleukins can accelerate the recovery of the hematopoietic cell population after chemotherapy. CHEMOPROTECTORS: Chemoprotectors achieve selective protection of normal tissues. These include mercaptoethanesulfonate (Mesna) for oxazophosphorouros, the cardioprotectant iron chelator, cardioxane, the nucleophilic tripeptide glutathione, and perhaps aminothiolaminofostine. QUALITY OF LIFE: Considerable effort has been made to reduce the negative effect of chemotherapy-induced nausea and vomiting on the quality of life of cancer patients. 5 HT3 receptor antagonist plus dexamethasone led to a significantly higher rate of control of emetic episodes after chemotherapy.

[Biosphonates in oncology]. / Les bisphosphonates en cancérologie.

MECHANISM OF ACTION: Tumor-induced osteolysis or lytic bone disease is mediated by osteoclast activation. Bisphosphonates inhibit bone resorption by reducing osteoclastic activity. INDICATIONS: Bisphosphonates were shown to be effective in treating cancer-related hypercalcemia. Recent large randomized clinical trials have shown the efficacy of bisphosphonates in reducing bone pain, pathological fractures and spinal cord compression for patients with multiple myeloma and breast cancer metastatic to bone. The potential survival benefit from pamidronate in patients with advanced myeloma warrants further study. FUTURE: Future clinical trials will use more potent bisphosphonates (zoledronate, ibandronate) with the ultimate goal of trying to prevent bone metastases.

[From serum pharmacokinetics to extravascular pharmacokinetics of antibiotics. Importance of protein binding]. / De la pharmacocinétique sérique à la pharmacocinétique extravasculaire des antibiotiques. Importance de la liaison aux protéines.

Serum and urinary concentrations of antibiotics are not predictive of their extravascular distribution. Data from an animal model giving access to an extravascular fluid have demonstrated the effects of protein binding on the extravascular diffusion of cephalosporins. A high percentage of protein binding delays extravascular distribution and facilitates accumulation from repeated doses. Moreover, strongly bound drugs may reduce the number of protein-bound cephalosporin molecules by competing for binding sites and interfere with the extravascular distribution of these antibiotics without modifying their serum levels.

[Gastric volvulus associated with Zenker's diverticulum: a rare cause of recurrent pneumopathy]. / Volvulus gastrique associé à un diverticule de Zenker: une cause rare de pneumopathie récidivante.

We report on a case of a patient with recurrent pneumonia related to a pharygo-esophageal (Zenker's) diverticulum associated with a chronic thoracic gastric volvulus. Mechanism, diagnosis and treatment of this rare disease are discussed.

[Comparative serum pharmacokinetics of prednisone and prednisolone methylsulfobenzoate after oral administration]. / Pharmacocinétique sérique comparée de la prednisone et du méthylsulfobenzoate de prednisolone après administration orale.

Pharmacokinetic values of prednisone and prednisolone were measured in the serum of 6 healthy volunteers after oral administration of either prednisolone methylsulfobenzoate 30 mg or prednisone 30 mg. Peak serum concentrations of prednisolone obtained after dosing with prednisone occurred earlier and were higher (473 +/- 106 ng/ml) than those obtained after dosing with prednisolone methylsulfobenzoate (232 +/- 70 ng/ml; P less than 0.01). Similarly, areas under the 0-8 h concentration curves were significantly greater after dosing with prednisone than after dosing with prednisolone methylsulfobenzoate (prednisolone: P less than 0.001; prednisone: P less than 0.02). The differences may be due to prednisolone methylsulfobenzoate not being absorbed as well as prednisone. These kinetic data may warrant a reappraisal of the therapeutic equivalence of the two drugs taken for granted in France.

[Pharmacokinetic interaction of cefixime and 2 antacids. Preliminary results]. / Etude de l'interaction pharmacocinétique entre le céfixime et deux antiacides. Résultats préliminaires.

A crossover study was undertaken in 8 healthy volunteers to evaluate the pharmacokinetics of cefixime administered orally alone or combined with an antacid. Each subject received successively: cefixime alone, Maalox followed 30 min later by cefixime, then Maalox followed 4 hours later by cefixime and finally Alka-Seltzer followed 30 min later by cefixime. Sixteen blood samples were drawn from 0 to 24 hours after oral administration, and plasma cefixime parameters were determined, using a HPLC assay. Four parameters were used to detect a possible interaction: Cmax, Tmax, AUCO-N and AUCO-alpha. No significant difference was observed between the four parameters. Thus, poor absorption of cefixime when combined with an antacid can be ruled out.

[Is systematic syphilis serology still useful in a department of internal medicine? A one-year prospective study using a diagnostic and therapeutic decision algorithm]. / La sérologie syphilitique systématique a-t-elle encore un intérêt dans un service de médecine interne? Etude prospective sur un an à l'aide d'un algorithme de décision diagnostique et thérapeutique.

During one year syphilis serology was systematically studied, using the TPHA and VDRL tests, in each of the 1,279 patients hospitalized in an Internal Medicine department. In all cases diagnosis and treatment were analyzed by means of a decision algorithm. Only 37 patients were found to have one or both serological tests positive. No evolutive syphilis was observed, and none of these positive tests was contributive to the diagnosis of another disease. Only 14 patients received a specific antibiotic treatment on the grounds that their positive test confirmed a late asymptomatic syphilis. We conclude that systematic syphilis serological tests are not useful in an Internal Medicine department, except in some patients epidemiologically at high risk of syphilis.