wnt10a is required for zebrafish median fin fold maintenance and adult unpaired fin metamorphosis.

BACKGROUND: Mutations of human WNT10A are associated with odonto-ectodermal dysplasia syndromes. Here, we present analyses of wnt10a loss-of-function mutants in the zebrafish. RESULTS: wnt10a mutant zebrafish embryos display impaired tooth development and a collapsing median fin fold (MFF). Rescue experiments show that wnt10a is essential for MFF maintenance both during embryogenesis and later metamorphosis. The MFF collapse could not be attributed to increased cell death or altered proliferation rates of MFF cell types. Rather, wnt10a mutants show reduced expression levels of dlx2a in distal-most MFF cells, followed by compromised expression of col1a1a and other extracellular matrix proteins encoding genes. Transmission electron microscopy analysis shows that although dermal MFF compartments of wnt10a mutants initially are of normal morphology, with regular collagenous actinotrichia, positioning of actinotrichia within the cleft of distal MFF cells becomes compromised, coinciding with actinotrichia shrinkage and MFF collapse. CONCLUSIONS: MFF collapse of wnt10a mutant zebrafish is likely caused by the loss of distal properties in the developing MFF, strikingly similar to the proposed molecular pathomechanisms underlying the teeth defects caused by the loss of Wnt10 in fish and mammals. In addition, it points to thus fur unknown mechanisms controlling the linear growth and stability of actinotrichia and their collagen fibrils.

Correlation of p53 mutations with resistance to platinum-based chemotherapy and shortened survival in ovarian cancer.

PURPOSE: The p53 tumor suppressor gene plays a central role in cell cycle regulation and induction of apoptosis. We analyzed p53 alterations and their impact on response to chemotherapy and clinical outcome in ovarian cancer patients. EXPERIMENTAL DESIGN: One hundred seventy-eight ovarian carcinomas, snap frozen and stored at -80 degrees C, were analyzed for mutations of the p53 gene (exons 2-11) by single-strand conformation polymorphism and DNA sequencing and for p53 overexpression by immunohistochemistry (monoclonal antibody DO7). RESULTS: p53 mutations were found in 56% (99 of 178) of the tumors, and 62% of these were located in evolutionary highly conserved domains of the gene. Time to progression and overall survival were significantly shortened in patients with p53 mutations compared with wild-type p53 (P = 0.029 and P = 0.014) and patients with mutations in highly conserved domains as opposed to nonconserved domains or wild-type p53 (P = 0.010 and P = 0.007). p53 protein overexpression (>10% positively stained nuclei) was found in 62% (110 of 178). Time to progression and overall survival were shorter in cases with p53 overexpression (cutpoint, 10%: P = 0.071 and P = 0.056) but only marginally significant. Resistance to adjuvant cisplatin or carboplatin chemotherapy was significantly more frequent in patients with p53 overexpression (P = 0.001) or p53 missense mutations (P = 0.008) than patients with normal p53. CONCLUSIONS: p53 alterations correlate significantly with resistance to platinum-based chemotherapy, early relapse, and shortened overall survival in ovarian cancer patients in univariate analysis. In multivariable analysis though, p53 was not an independent prognostic factor.

Dose-response comparisons of five lung surfactant factor (LSF) preparations in an animal model of adult respiratory distress syndrome (ARDS).

1. We have examined the effects of five different lung surfactant factor (LSF) preparations in the rat lung lavage model. In this model repetitive lung lavage leads to lung injury with some similarities to adult respiratory distress syndrome with poor gas exchange and protein leakage into the alveolar spaces. These pathological sequelae can be reversed by LSF instillation soon after lavage. 2. The tested LSF preparations were: two bovine: Survanta and Alveofact: two synthetic: Exosurf and a protein-free phospholipid based LSF (PL-LSF) and one Recombinant LSF at doses of 25, 50 and 100 mg kg-1 body weight and an untreated control group. 3. Tracheotomized rats (10-12 per dose) were pressure-controlled ventilated (Siemens Servo Ventilator 900C) with 100% oxygen at a respiratory rate of 30 breaths min-1, inspiration expiration ratio of 1:2, peak inspiratory pressure (PIP) of 28 cmH2O at positive end-expiratory pressure (PEEP) of 8 cmH2O. Two hours after LSF administration, PEEP and in parallel PIP was reduced from 8 to 6 (1st reduction), from 6 to 3 (2nd reduction) and from 3 to 0 cmH2O (3rd reduction). 4. Partial arterial oxygen pressure (PaO2, mmHg) at 5 min and 120 min after LSF administration and during the 2nd PEEP reduction (PaO2(PEEP23/3)) were used for statistical comparison. All LSF preparations caused a dose-dependent increase for the PaO2(120'), whereas during the 2nd PEEP reduction only bovine and recombinant LSF exhibited dose-dependency. Exosurf did not increase PaO2 after administration of the highest dose. At the highest dose Exosurf exerted no further improvement but rather a tendency to relapse. The bovine and the Recombinant LSF are superior to both synthetic LSFpreparations.5. In this animal model and under the described specific ventilatory settings, even between bovine LSFpreparations there are detectable differences that are pronounced when compared to synthetic LSFwithout any surfactant proteins. We conclude that the difference between bovine and synthetic LSFpreparations can be overcome by addition of the surfactant protein C.

The initial steps of tumor progression in melanocytic lineage: a histochemical approach.

Antigen expression was studied by immunohistochemistry in 133 human melanocytic skin lesions to gain insight into the initial steps of tumor development, i.e. in particular the change from melanocytes to benign nevi. We refer to the proposed progression model of Clark and co-workers. The following types of antigens were investigated: (i) intermediate filament antigens (vimentin), (ii) melanoma-associated antigens (HMB-45, NKI/C3, MA-930, LS59), (iii) proliferation-associated antigens (S-100, Ki67, Ro/SSA, calmodulin), (iv) progression-associated antigens (HLA-DR, ICAM-1), and (v) basal membrane antigens (bullous pemphigoid antigen, laminin, fibronectin, collagen type IV). The intensity of expression and the topography of immunoreactive pigment cells were compared with the stage of tumor progression. Special attention was paid to the early steps of this process, i.e. the disturbance of the epidermal melanin unit and the development of melanocytic ("nevocellular")nevi. A dramatic shift of antigen expression (antigen types [i] to [v]) was noted in benign nevi compared with melanocytes. Nevi with cellular atypia disclosed a tendency towards an increased percentage of tumor cells reactive for melanoma- and progression-related antigens (types [ii] and [iv]). However, there was no clear cut level of distinction of antigen expression (types [i] to [v]) between benign and primary malignant melanocytic tumors. So-called dysplastic nevi resembled benign tumors or melanocytes rather than malignant melanoma. Metastatic melanoma of skin showed a relatively high number of Ki67-positive, cycling melanoma cells. The results have a bearing on the concepts of melanocytic nevus ontogenesis and "maturation". It appears that melanocytes lose maturity on their way down to the dermis in contrast to traditional concepts (Abtropfung); this might be of importance for our understanding of melanoma development in association with melanocytic nevi. Our findings are discussed with regard to Clark's model of tumor progression.

Lack of effect of diacetyl-splenopentin (Berlopentin) on the pharmacokinetics of caffeine.

The influence of Berlopentin on caffeine clearance was measured after a 6 week i.v. treatment or a 4 week s.c. administration within a phase I trial. It was demonstrated that therapy with Berlopentin did not affect significantly caffeine elimination. Thus, clearance of drugs which are biotransformed by hepatic microsomal oxidation are unlikely to be affected by the coadministration of Berlopentin.

[Total knee replacement for primary treatment of intra-articular tibial head fractures in elderly patients]. / Kniegelenkendoprothese zur primären Therapie der intraartikulären Tibiakopffraktur im höheren Alter.

Intra-articular fractures of the tibial head pose a huge challenge for the surgeon. An increase of these fractures, especially in the elderly, has been observed in recent years. The cause of injury in the elderly is in most cases a slight trauma. The mechanism of dislocation plays only a subordinated role. These are serious injuries of the bone, which are accompanied by soft tissue lesions. Furthermore, there are some factors, which could have a negative effect on the treatment, such as osteoporosis, diseases of the vascular system, osteoarthrosis, limited coordination, and insufficient autologous cancellous bone. Every surgeon is aware of secondary, clinically relevant deficits after operative treatment of the tibial head in the elderly. We treated two elderly patients with different additional findings by total knee replacement.

Interaction with histamine H1-receptors and bronchospasmolytic effects of urapidil.

The antihypertensive drug, urapidil, competitively antagonized the histamine-induced contractions in guinea pig isolated tracheal and ileal preparations. Its affinity to histamine H1-receptors was 3-fold higher than that of histamine but 10- and 30-fold weaker than that of diphenhydramine and indoramin, respectively. Urapidil did not inhibit contractions induced by muscarinic agonists in both organs. Investigations in spontaneously breathing guinea pigs showed a greater efficacy of urapidil than that of diphenhydramine in protecting the animals against histamine-induced bronchospasms, whereas acetylcholine-induced spasms were only moderately inhibited. Theophylline, at a 100-fold higher dosage than urapidil, protected the animals against both histamine and acetylcholine challenges. This experimentally observed effect of urapidil supports clinical trials in hypertensive patients suffering also from obstructive lung disease and/or allergic illness.

[Methods for simultaneous recording of pharmacodynamic and toxic effects on interior sensitive receptors, respiration and cardiac-circulatory system of guinea pigs (author's transl)]. / Methode zur simultanen Registrierung von pharmakodynamischen bzw. toxischen Effekten auf innere sensible Rezepforen, auf die Atmung und auf das Herz-Kreislauf-System von Meerschweinchen.

A method for simultaneous, continuous registration of pharmacodynamic and toxic effects, resp., on pulmonary-stretch receptors, on respiration and on hemodynamics in guinea pigs is described. The following parameters are recorded synchronously by a multi-track recorder: 1. The afferences in the cervical n. vagus; its electrical integration is employed for measuring the total intensity and the ex- and the inhalation intensity, resp., of the afferences; 2. the pneumatogram for measuring the maximum velocity of air flow, duration of the breath phase and parts thereof (in-, and exhalation and postexpiratory pause), and the respiration rate; 3. the diastolic and systolic blood pressure during in- and exhalation and postexpiratory pause; 4. the electrocardiogram (ECG). The normal distribution of the initial values is examined and discussed. Further the initial values measured in three series of experiments are discussed and compared: mono-vagotomy/spontaneous respiration, bivagotomy/spontaneous respiration and artificial respiration/monovagotomy. The results are compared with some experimental and clinical findings from literature.

Influence of urapidil on alpha- and beta-adrenoreceptors in pithed rats.

The interaction of urapidil with pre- and postsynaptic alpha-adrenoreceptors and with postsynaptic beta-adrenoreceptors was studied in pithed normotensive rats and compared to the effects of clonidine, prazosin, and atenolol. I.v. injection of urapidil did not substantially change blood pressure, while clonidine raised blood pressure. Urapidil dose-dependently antagonized the pressor effects of the alpha 1-agonist L-phenylephrine (pDR2 6.8) and of the alpha 2-agonist azepexole (pDR2 5.2). Compared to urapidil, prazosin was a more potent antagonist of phenylephrine at postsynaptic vascular alpha 1-adrenoreceptors (pDR2 8.7) and of azepexole at alpha 2-adrenoreceptors (pDR2 5.6). Urapidil inhibited the tachycardia produced by discontinuous or continuous electrical stimulation of the thoracic spinal outflows (ID50 4.8 and 27.2 mumol/kg, respectively). In contrast to the inhibitory action of clonidine (ID50 0.039 and 0.023 mumol/kg, respectively), the inhibition by urapidil was not reversed by the selective alpha 2-antagonist rauwolscine (10 mumol/kg). Prazosin did not change stimulation-evoked tachycardia but atenolol caused pronounced inhibition (ID50 0.158 mumol/kg, discontinuous stimulation). Urapidil dose-dependently antagonized the tachycardic effect of isoprenaline at beta 1-adrenoreceptors (pDR2 5.1) but also exhibited intrinsic activity by increasing basal heart rate (maximum effect of urapidil was 30% of that of isoprenaline). Urapidil did not change the vasodilatory beta 2-adrenoreceptor-mediated effect of isoprenaline. The results suggest that urapidil is an antagonist at postsynaptic vascular alpha 1- and alpha 2-adrenoreceptors, with a greater potency against alpha 1-adrenoreceptors. An agonistic interaction of urapidil with presynaptic alpha 2-adrenoreceptors could not be demonstrated in pithed rats. Instead, the inhibition by urapidil of stimulation-evoked tachycardia could be accounted for by its beta 1-adrenoreceptor antagonistic effect.

Effects of early treatment with rSP-C surfactant on oxygenation and histology in rats with acute lung injury.

Surfactant treatment in patients with acute respiratory distress syndrome (ARDS) may be a promising treatment strategy. The aim of this study was to investigate whether addition of a recombinant surfactant protein C (rSP-C) to a plain phospholipid (PL) surfactant (PL surfactant) can result in activity comparable to commercially available surfactant preparations (Alveofact and bLES) which contain surfactant protein B and C. In this investigation dose-response comparisons of four surfactants were performed in an animal model of ARDS induced by total lung lavage. The surfactants were given shortly (;10 min) after the last lavage. The effects of surfactant treatment were compared with respect to improve oxygenation and to prevent histopathological changes, such as hyaline membrane formation. The surfactants were compared to lavaged, untreated controls. The surfactants were administered at doses of 25, 50 and 100 mg total amount of phospholipids/kg body weight. At 120 min after early treatment, all three doses of rSP-C surfactant showed statistically significant higher improvements in oxygenation than PL surfactant. This improvement was comparable to bLES and superior to Alveofact. The rSP-C surfactant showed the most prominent effect on preventing hyaline membrane formation. It was again superior to PL surfactant and comparable to bLES. It is concluded that addition of rSP-C enhances the activity of a pure PL surfactant. The rSP-C surfactant showed comparable or even superior activity to bovine-derived surfactant preparations containing both, SP-B and SP-C.

Comparative investigation of the effects of zardaverine and theophylline on pulmonary function in rats.

Zardaverine (Byk Gulden, Konstanz, Germany) is a new selective phosphodiesterase (PDE) III/IV inhibitor. The bronchodilating and bronchoprotective potency of zardaverine and the nonselective PDE inhibitor theophylline was compared by measuring typical spontaneous and forced respiratory function parameters in anesthetized female Wistar rats using whole-body plethysmography. Zardaverine (3, 10, 30 mumol/kg) and theophylline (30, 100, 300 mumol/kg), respectively, were given orally in 4% Methocel/0.9% saline solution 20 min before measurement. One week before treatment, control measurements were performed in the same animals after administration of the vehicle. When spontaneously breathing, the 30 mumol/kg zardaverine- (300 mumol/kg theophylline-) treated animals showed significant changes: a 23% (14% ns) decrease in lung resistance and a 43% (25%) increase in dynamic compliance. These changes can be interpreted as an indication of bronchodilation, since quasistatic lung compliance was unchanged. In the acetylcholine challenge test, treatment with only 10 mumol/kg zardaverine (but 300 mumol/kg theophylline) revealed significant changes compared to control measurement: a 37% (28%) lower resistance and 85% (44%) higher compliance. It has been determined that zardaverine is more than 30 times as potent as theophylline in inhibiting acetylcholine-induced bronchospasms, which is also supported by forced expiratory flow data.

Biotransformation of urapidil: metabolites in serum and urine and their biological activity in vitro and in vivo.

The biotransformation products of the antihypertensive drug urapidil were determined in the serum and urine of rat, dog and man. Comparison of the pattern of urapidil metabolism revealed that all species examined formed the same metabolites. However, quantitative differences were noted. The pattern of metabolites in serum was seen to parallel the excretion of urapidil and its metabolites in urine. The p-hydroxylated urapidil (M1) was found to be the predominant metabolite in man, the uracil-N-demethylated metabolite (M3) in dog, and M1 as well as the O-demethylated urapidil (M2) were found to be important in the rat. Furthermore, trace amounts of the urapidil-N-oxide (M5) are found in dog urine. As determined in the isolated rat vas deferens preparation, urapidil and the synthetized metabolites M1, M2, M3 and M5 are competitive antagonists of the effects of noradrenaline at postsynaptic alpha 1-adrenoceptors. Metabolites M2 and M3 exhibit alpha 1-adrenoceptor antagonism (pA2 values of 6.79 and 6.93 respectively) which are comparable to urapidil (pA2 = 7.02), whilst M1 and M5 are less potent antagonists giving pA2 values of 5.69 and 5.55 respectively. On i.v. or i.j. administration of urapidil, M1, M2, M3 or M5 to anaesthetized, normotensive rats, or orally to conscious spontaneously hypertensive rats, differences in cardiovascular responses were seen. Whilst M1 had little antihypertensive activity, M2 and M3 lowered blood pressure to a similar extent to that seen with urapidil. However, the duration of activity observed was shorter. Urapidil-N-oxide (M5) appeared to possess hypotensive activity comparable to urapidil, but examination of serum samples following the administration of M5 yielded mainly urapidil, suggesting that M5 exhibits its activity following reduction back to urapidil. In view of the serum levels attained and of the biological activity, the metabolites of urapidil do not appear to contribute significantly to the cardiovascular effects of urapidil in man or rat. However, in view of the serum levels and duration of M3 observed in dogs, this metabolite may make a significant contribution to the hypotensive activity of urapidil in this species.

An M1-selective muscarinic receptor antagonist telenzepine improves lung function in patients with chronic obstructive bronchitis.

The effect of an M1-selective muscarinic receptor antagonist telenzepine on lung function was investigated in 18 patients with chronic obstructive bronchitis in a double blind, placebo-controlled, randomized crossover study. FEV1, FEF50, PEF and FVC were measured every 0.5 h up to 2 h, then every 1 h up to 6 h after administration of a single, oral dose of 5 mg in the morning. Compared with placebo, telenzepine increased (time average over 6 hours; median and 68%-range): 1) FEV1 from 1.46 (0.81, 2.06) to 1.67 (1.06, 2.40) l, p less than 0.01; 2) PEF from 3.58 (2.33, 4.55) to 3.88 (3.10, 5.07) l/s, p less than 0.01; 3) FEF50 from 0.93 (0.45, 1.58) to 1.17 (0.67, 1.90) l/s, p less than 0.001. Whereas the median increase in FEV1 15 min after 2 puffs of salbutamol was 20% (range 15 to 74%), FEV1 improved by 32% (range -15 to 130%) at the time of maximum difference between placebo and telenzepine. The heart rate did not change. We conclude that in patients with chronic obstructive bronchitis substantial improvement of lung function parameters can be achieved by an M1-receptor antagonist. It is possible that with the dose administered direct actions on muscarinic receptors on the smooth muscle (M3) contribute to the observed bronchodilatation. The unchanged heart rate indicates little effect on cardiac M2-receptors.

Zardaverine: a cyclic AMP specific PDE III/IV inhibitor.

Zardaverine is shown to inhibit selectively two out of five isoenzyme classes of phosphodiesterases, namely PDE III from human platelets and PDE IV from human polymorphonuclear leucocytes (PMN) with IC50 values of 0.58 and 0.17 microM, respectively. Motapizone or rolipram, for comparison, are more selective recognizing either PDE III or PDE IV. On the cellular level, agonist induced aggregation of platelets or activated secretions of PMN and several proinflammatory cells are synergistically inhibited by zardaverine and adenylate cyclase activators such as prostaglandins or forskolin. Application of zardaverine and selective drugs show that the effects of PDE inhibitors in platelets are mediated by a PDE III isoenzyme, whereas by a PDE IV isoenzyme in neutrophils, eosinophils, basophils and mast cells. An antiinflammatory potential in vivo of zardaverine is demonstrated by the inhibition of bronchial cell infiltration following inhalative allergen challenge in sensitized guinea pigs. Zardaverine and dexamethasone prevent bronchial eosinophilia and neutrophilia with similar dosage of 30 microM/kg orally, suggesting that this PDE III/IV inhibitor may be useful for both, bronchorelaxation and reduction of inflammation in asthma therapy.

Modulation of luminol chemiluminescence of fMet-Leu-Phe-stimulated neutrophils by affecting dephosphorylation and the metabolism of phosphatidic acid.

This paper is addressed to study how PKC-mediated effects and phosphatidic acid interact together in activation of NADPH-oxidase in formyl-methionyl-leucyl-phenylalanine (fMet-Leu-Phe) stimulated neutrophils as detected by luminol chemiluminescence. The early luminescence response in fMet-Leu-Phe-stimulated cells (up to 5 min after stimulation) depends mainly on reactive oxygen species generated extracellularly, whereas all later events are caused by oxidation of luminol inside the cells. The two protein phosphatase inhibitors, okadaic acid and calyculin A, dramatically increased the late luminescence of cells. This enhancement was totally inhibited by the phospholipase D modulator butanol, while the protein kinase C (PKC) inhibitor bisindolylmaleimide I was insensitive. The early luminescence response of the cells was slightly inhibited by both protein phosphatase inhibitors and depended on protein kinase C as well as on phospholipase D activities. Propranolol, an inhibitor of phosphatidate phosphohydrolase, enhanced all parts of luminescence response of fMet-Leu-Phe-stimulated neutrophils at concentrations up to 2.5 x 10(-5) mol/L. While the late luminescence response of propranolol-treated cells was not inhibited by the PKC inhibitor bisindolylmaleimide I, the first response depended on protein kinase C. The inhibitor of diacylglycerol kinase R59949 enhanced the luminescence signal only during the first 4 min in fMet-Leu-Phe-stimulated cells. Only diacylglycerols derived from phospholipase C, such as 1-stearoyl-2-arachidonoyl-sn-glycerol, were able to initiate an oxidative burst in cells. Saturated diacylglycerols (e.g. 1,2-dipalmitoyl-sn-glycerol or 1,2-distearoyl-sn-glycerol) did not yield any luminol chemiluminescence, although they were incorporated into the plasma membrane, as evidenced by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. Our results demonstrate that phosphatidic acid produced by phospholipase D is responsible for NADPH-oxidase activity in fMet-Leu-Phe-stimulated neutrophils over the entire measuring time, whereas PKC-mediated processes are only involved during the first 5 min.

Randomized placebo-controlled study on the characteristics and duration of action of surfactant treatment in premature lambs.

In a placebo-controlled study, the characteristics and duration of action of a commercially available bovine lung surfactant factor (LSF; 50 mg/kg body weight) were investigated in premature lambs at 124-127 days gestational age. Exact mating of ewes was controlled by progesterone hormone analysis. To minimize unwanted effects of narcotics through transplacental transfer to the fetus, spinal anaesthesia of the ewes was performed. The physiological status 'in utero' was demonstrated by arterial blood gas analysis (partial arterial oxygen pressure (PaO2), partial arterial carbon dioxide pressure (PaCO2) and arterial blood pH) of the fetus before umbilical cord ligature. The values for blood gases, blood pressure and lung mechanics measured after onset of ventilation and before LSF treatment were indicative of fetal maturity. Immediately after LSF treatment, PaO2 increased significantly, then decreased for about 2 h and finally stabilized on a plateau until the end of the experiment. In contrast, arterial blood pH and PaCO2 values normalized more slowly and remained normal for a longer period in the LSF group, whereas both parameters did not normalize in the placebo group. Total dynamic lung compliance also showed a slow improvement and remained on a higher level for a longer period than PaO2. Using a low respiratory rate it was possible to ventilate at lower peak inspiratory pressures and this resulted in higher compliance values. In conclusion, the presented data suggest that artificial ventilation greatly influences lung mechanics. Due to a relatively short substance effect concerning PaO2 we assume that higher or repeated doses of LSF may be necessary to produce sustained improvements in clinical trials.

Comparison of a phospholipid-based protein-free surfactant and a natural bovine surfactant (SURVANTA) during pressure and volume-controlled ventilation in an improved rabbit fetus model.

During pressure- or volume-controlled ventilation different surfactant preparations were compared in an improved rabbit fetus model. Based on a self-designed software program, this model enables on-line registration of lung mechanics and heart rate in up to ten fetuses. Using a commercially available bovine lung surfactant (SURVANTA) as standard, we compared animals treated with a protein-free surfactant preparation containing only phospholipids, PL (dipalmitoylphosphatidylcholine:palmitoyloleoylphosphatidylglycerol++ +, DPPC:POPG 70:30) plus palmitic acid (PA) with an untreated ventilated control group. During pressure-controlled ventilation the insufflation pressure (IP) was decreased and increased stepwise with and without positive end-expiratory pressure (PEEP). SURVANTA was significantly more potent than PL plus PA and both differed significantly from the untreated controls. With additional PEEP the differences between SURVANTA and PL+PA disappeared but the differences to the controls were still present. We found that, with additional PEEP, active natural surfactants lead to ECG-irregularities, which indicates that PEEP influences pulmonary and cardiovascular function and compromises the benefits of surfactant therapy. Also during volume-controlled ventilation SURVANTA was superior to PL+PA and the untreated controls. In order to raise the level of activity of pure PL mixtures to that of natural bovine surfactants, we suggest that a surface active protein (probably SP-C) must be added to such mixtures.

Constituents of Veltheimia viridifolia; I. Homoisoflavanones of the bulbs.

The new homoisoflavanone R(-)-3-(4-hydroxybenzyl)-5-hydroxy-6, 7,8-trimethoxychroman-4-one (1) was isolated from the petroleum ether and the diethyl ether extracts of the bulbs of Veltheimia viridifolia (Hyacinthaceae) together with the known homoisoflavanone muscomin (2). The structures of the compounds were elucidated by means of 1H-NMR, 2D 1H-1H-COSY, 13C-NMR, HMQC, HMBC, mass, and CD spectra. Pharmacological testings of the new homoisoflavanone are reported.