Effects of the combined artesunate and mefloquine antimalarial drugs on rat embryos.

Artemisinins combination therapy (ACT) is the first choice therapy for falciparum malaria. Data on the safety of ACTs in pregnancy are limited and controversial and the use is not recommended on the first trimester. To evaluate the effects of isolated and combined artesunate (AS)/mefloquine (MQ) on embryo rats, pregnant rats were treated orally with AS (15 and 40 mg/kg body weight (bwt)/day), MQ (30 and 80 mg/kg bwt/day) and AS/MQ (15/30 and 40/80 mg/kg bwt/day) on days 9-11 post coitum (pc). The dams were euthanized on day 12 pc and gestational and embryos histological parameters were evaluated. Embryolethality and histopathological anomalies were significant when AS was given alone or combined with MQ. Combination of AS and MQ did not enhance their toxicity compared to their separate administrations; on the other side, there was a reduction in the toxic effects of the AS when combined with MQ. Isolated MQ did not induce developmental toxicity.

Computed tomography assessment of positive end-expiratory pressure-induced alveolar recruitment in patients with acute respiratory distress syndrome.

Computed tomography (CT) assessment of positive end-expiratory pressure (PEEP)-induced alveolar recruitment is classically achieved by quantifying the decrease in nonaerated lung parenchyma on a single juxtadiaphragmatic section (Gattinoni's method). This approach ignores the alveolar recruitment occurring in poorly aerated lung areas and may not reflect the alveolar recruitment of the entire lung. This study describes a new CT method in which PEEP-induced alveolar recruitment is computed as the volume of gas penetrating in poorly and nonaerated lung regions following PEEP. In 16 patients with acute respiratory distress syndrome a thoracic spiral CT scan was performed in ZEEP and PEEP 15 cm H(2)O. According to the new method, PEEP induced a 119% increase in functional residual capacity (FRC). PEEP-induced alveolar recruitment was 499 +/- 279 ml whereas distension and overdistension of previously aerated lung areas were 395 +/- 382 ml and 28 +/- 6 ml, respectively. The alveolar recruitment according to Gattinoni's method was 26 +/- 24 g and no correlation was found between both methods. A significant correlation was found between PEEP-induced alveolar recruitment and increase in Pa(O(2)) only when recruitment was assessed by the new method (Rho = 0.76, p = 0.003), suggesting that it may be more accurate than Gattinoni's method.

Regional distribution of gas and tissue in acute respiratory distress syndrome. III. Consequences for the effects of positive end-expiratory pressure. CT Scan ARDS Study Group. Adult Respiratory Distress Syndrome.

OBJECTIVE: To determine whether differences in lung morphology assessed by computed tomography (CT) affect the response to positive end-expiratory pressure (PEEP). DESIGN: Prospective study over a 53-month period. SETTING: Fourteen-bed surgical intensive care unit of a university hospital. PATIENTS AND PARTICIPANTS: Seventy-one consecutive patients with early adult respiratory distress syndrome (ARDS). MEASUREMENTS AND RESULTS: Fast spiral thoracic CT was performed at zero end-expiratory pressure (ZEEP) and after implementation of PEEP 10 cmH2O. Hemodynamic and respiratory parameters were measured in both conditions. PEEP-induced overdistension and alveolar recruitment were quantified by specifically designed software (Lungview). Overdistension occurred only in the upper lobes and was significantly correlated with the volume of lung, characterized by a CT attenuation ranging between -900 and -800 HU in ZEEP conditions. Cardiorespiratory effects of PEEP were similar in patients with primary and secondary ARDS. PEEP-induced alveolar recruitment of the lower lobes was significantly correlated with their lung volume (gas + tissue) at functional residual capacity. PEEP-induced alveolar recruitment was greater in the lower lobes with "inflammatory atelectasis" than in the lower lobes with "mechanical atelectasis." Lung morphology as assessed by CT markedly influenced the effects of PEEP: in patients with diffuse CT attenuations PEEP induced a marked alveolar recruitment without overdistension, whereas in patients with lobar CT attenuations PEEP induced a mild alveolar recruitment associated with overdistension of previously aerated lung areas. These results can be explained by the uneven distribution of regional compliance characterizing patients with lobar CT attenuations (compliant upper lobes and stiff lower lobes) contrasting with a more even distribution of regional compliances observed in patients with diffuse CT attenuations. CONCLUSIONS: In patients with ARDS, the cardiorespiratory effects of PEEP are affected by lung morphology rather than by the cause of the lung injury (primary versus secondary ARDS). The regional distribution of the loss of aeration and the type of atelectasis -- "mechanical" with a massive loss of lung volume, or "inflammatory" with a preservation of lung volume-- characterizing the lower lobes are the main determinants of the cardiorespiratory effects of PEEP.

Heterotrimeric collagen peptides as fluorogenic collagenase substrates: synthesis, conformational properties, and enzymatic digestion.

The collagenase cleavage site of collagen type I, i.e., the sequence portions 772-784 (P(4)-P(9)') and 772-785 (P(4)-P(10)') of the two alpha1-chains and the sequence portion 772-784 (P(4)-P(9)') of the alpha2-chain, were assembled in an alpha1alpha2alpha1' register by C-terminal cross-linking of these peptides with an artificial cystine knot. The triple-helical conformation of the construct was stabilized by N-terminal extensions with (Gly-Pro-Hyp)(5) repeats. The gaps in the sequence alignment were filled up, and the alpha1-chain was dansylated and the alpha1'-chain was acylated with a tryptophan residue to place in spatial proximity the two chromophores for an efficient fluorescence resonance energy transfer. Although the incorporation of the two N-terminal chromophores leads to partial destabilization of the overall triple-helical fold, the heterotrimer behaved as a collagen-like substrate of the matrix metalloproteinases MMP-1 and MMP-13. Cleavage of the fluorogenic heterotrimer leads to a 6-fold increase in fluorescence intensity, thus making it a useful fluorogenic substrate for interstitial collagenases. With this folded heterotrimeric collagen molecule it was shown that fluorescence resonance energy transfer, as applied so far only for the design of linear fluorogenic enzyme substrates, can also be exploited in conformation dependency.

Decreased soluble adhesion molecule L-selectin plasma concentrations after major trauma.

BACKGROUND: Binding of the leukocyte glycoprotein L-selectin to ligands expressed by activated endothelium directs leukocyte recruitment to areas of acute inflammation. Sequestration by activated microvascular endothelium has been proposed to explain the low plasma concentrations of soluble L-selectin (sCD62L) observed early in patients with acute respiratory distress syndrome. We hypothesized that inflammatory endothelial activation may occur in trauma patients, leading to decreased sCD62L plasma concentrations. METHODS: This study was a prospective analysis of sCD62L plasma concentrations in patients with isolated head injuries and multiple trauma patients without head injuries admitted to two tertiary-level intensive care units. sCD62L plasma concentrations were determined in 18 consecutive adult patients with isolated moderate and severe head injuries and in 13 multiple trauma patients without head injuries immediately upon admission to the intensive care unit and then daily for up to 10 days after trauma. RESULTS: Compared with healthy adult controls (n=22), patient sCD62L plasma concentrations were significantly decreased upon admission (5.7+/-1.6 vs. 11.0+/-1.7 pmol/mL; p < 0.001). In all patients, sCD62L concentrations remained depressed throughout the study period. sCD62L concentrations did not differ significantly between patients with isolated head injuries and multiple trauma patients without head injuries, although repeated-measures analysis of variance showed significantly more depressed sCD62L concentrations associated with severe (n=14) compared with moderate head injuries (n=4) during the study period (p < 0.05). CONCLUSION: Patients with major trauma present with a significant reduction of sCD62L plasma concentrations within the first 12 hours after trauma and during subsequent intensive care. This finding suggests widespread microvascular endothelial activation after trauma, which may be associated with increased neutrophil extravasation.

Non-peptidic cysteine derivatives as inhibitors of matrix metalloproteinases.

By exploiting the thiol function of L-cysteine as a chelating group of the active-site zinc atom of matrix metalloproteinases (MMPs), N- and C-terminal derivatization of this amino acid with aliphatic and aromatic groups allowed us to explore the selectivity of the S and/or S' binding subsites of human neutrophil collagenase (MMP8) and stromelysin (MMP3). With N-benzyloxycarbonyl-L-cysteine-(2-phenyl)ethylamide a submicromolar inhibitor of MMP8 was discovered.

Identification and quantitation of corrinoid precursors of cobalamin from Pseudomonas denitrificans by high-performance liquid chromatography.

After initial pretreatment for removal of interfering substances, corrinoid precursors of cobalamin from cultures of Pseudomonas denitrificans were separated by HPLC with a gradient elution system. In this system, all the following compounds are separated in their dicyano form, and retention times are given: cobyrinic acid; cobyrinic acid a-amide; cobyrinic acid c-amide; cobyrinic acid g-amide; cobyrinic acid a,g-diamide; cobyrinic acid c,g-diamide; cobyrinic acid a,c-diamide; cobyrinic acid a,c,g-triamide; cobyrinic acid triamide, tetraamide, and pentaamide isolated from P. denitrificans; cobyric acid; cobinamide; cobinamide phosphate; GDP-cobinamide; cyanocobalamin 5'-phosphate; and cyanocobalamin. Application of this HPLC method to culture samples of P. denitrificans revealed that in this microorganism the level of cobyrinic acid and cobyrinic acid monoamide is far lower than that of all other corrinoid precursors of cobalamin and suggested that (i) the (R)-1-amino-2-propanol group is incorporated only after completion of all the other amidations and (ii) the amidations follow only one sequence. The usefulness of this HPLC method was further demonstrated by identifying the 57Co-labeled corrinoid precursors of cobalamin accumulated by cobalamin-deficient mutants of Agrobacterium tumefaciens. A TLC system that separates the different corrinoid intermediates (in their dicyano form) and cyanocobalamin is also described.

Ro 22-5417, a new clavam antibiotic from Streptomyces clavuligerus. III. Absolute stereochemistry.

The complete stereostructure of the new antibiotic Ro 22-5417 has been established as 3-[(3S,5S)-7-oxo-1-aza-4-oxabicyclo[3.2.O]hept-3-yl]-L-alanine. This result together with the synthesis of an (3R,5R)-L-analog allowed us to postulate that clavams require the R-configuration at the ring juncture for beta-lactamase inhibitory activity, while the opposite S-stereochemistry is essential for antifungal activity.

[Adjustment of nitrogen fertilization to the needs of plants and limitations posed by the risk of nitrate accumulation and pollution of the soil and subsoil]. / Adaptation de la fertilisation azotée aux besoins des plantes et limitation du risque d'accumulation et de pollution du sol et du sous-sol par les nitrates.

In chalky Champagne, nitrogen balance is study to adjust availability to plant response. For this, it is necessary to know some parameters whose measurement is obtained progressively; plants exportation, nitrogen transformations in terms of transport processes in soil system, kinetic of mineralization of soil organic nitrogen, plants residus and agricultural waste waters. Lysimeters with rotation of Champagne (wheat, sugarbeet, potatoes...) are used to measure losses of nitrogen and follow transport of nitrates by mean of soil solution captors. Comparisons with field results, lysimeters results and laboratory experimentations are used to adjust an experimental model. Two examples show: 1) Nitrogen fertilizer requirement for wheat. 2) Possibility of maximum application for agricultural waste waters.

Contact allergy to Frullania and Laurus Nobilis: cross-sensitization and chemical structure of the allergens.

Cross-sensitization between two plant allergens, Frullania and Laurus Nobilis (L.), has been demonstrated in Strabourg. A review of the haptens isolated from Frullania outlines the importance of the purification of allergen to ascertain the nature of the causative agent. New results on laurel oil point to the possibility of a common denominator (the a-methylene gamga-butyrolactone moiety) between this plant and Frullania; former results are re-interpreted and analyzed. In conclusion, the importance of physico-chemical methods used to purify and isolate haptens, and help in their definition, is stressed.