Photoionization of 2-pyridone and 2-hydroxypyridine.

We studied the photoionization of 2-pyridone and its tautomer, 2-hydroxypyridine by means of VUV synchrotron radiation coupled to a velocity map imaging electron/ion coincidence spectrometer. The photoionization efficiency (PIE) spectrum is composed of steps. The state energies of the [2-pyridone](+) cation in the X[combining tilde] ground and A excited electronic states, as well as of the [2-hydroxypyridine](+) cation in the electronic ground state, are determined. The slow photoelectron spectra (SPES) are dominated by the 0(0)(0) transitions to the corresponding electronic states together with several weaker bands corresponding to the population of the pure or combination vibrational bands of the cations. These vibrationally-resolved spectra compare very well with state-of-the-art calculations. Close to the ionization thresholds, the photoionization of these molecules is found to be mainly dominated by a direct process whereas the indirect route (autoionization) may contribute at higher energies.

Resonant infrared multiphoton dissociation spectroscopy of gas-phase protonated peptides. Experiments and Car-Parrinello dynamics at 300 K.

The gas-phase structures of protonated peptides are studied by means of resonant infrared multiphoton dissociation spectroscopy (R-IRMPD) performed with a free electron laser. The peptide structures and protonation sites are obtained through comparison between experimental IR spectra and their prediction from quantum chemistry calculations. Two different analyses are conducted. It is first supposed that only well-defined conformations, sufficiently populated according to a Boltzmann distribution, contribute to the observed spectra. On the contrary, DFT-based Car-Parrinello molecular dynamics simulations show that at 300 K protonated peptides no longer possess well-defined structures, but rather dynamically explore the set of conformations considered in the first conventional approach.

Ab initio molecular dynamics of protonated dialanine and comparison to infrared multiphoton dissociation experiments.

Finite temperature Car-Parrinello molecular dynamics simulations are performed for the protonated dialanine peptide in vacuo, in relation to infrared multiphoton dissociation experiments. The simulations emphasize the flexibility of the different torsional angles at room temperature and the dynamical exchange between different conformers which were previously identified as stable at 0 K. A proton transfer occurring spontaneously at the N-terminal side is also observed and characterized. The theoretical infrared absorption spectrum is computed from the dipole time correlation function, and, in contrast to traditional static electronic structure calculations, it accounts directly for anharmonic and finite temperature effects. The comparison to the experimental infrared multiphoton dissociation spectrum turns out very good in terms of both band positions and band shapes. It does help the identification of a predominant conformer and the attribution of the different bands. The synergy shown between the experimental and theoretical approaches opens the door to the study of the vibrational properties of complex and floppy biomolecules in the gas phase at finite temperature.

Photoinduced processes in protonated tryptamine.

The electronic excited state dynamics of protonated tryptamine ions generated by an electrospray source have been studied by means of photoinduced dissociation technique on the femtosecond time scale. The result is that the initially excited state decays very quickly within 250 fs. The photoinduced dissociation channels observed can be sorted in two groups of fragments coming from two competing primary processes on the singlet electronic surface. The first one corresponds to a hydrogen-atom loss channel that creates a tryptamine radical cation. The radical cation subsequently fragments to smaller ions. The second process is internal conversion due to the H-atom recombination on the electronic ground state. Time-dependent density functional theory calculations show that an excited pisigma* state dissociative along the protonated amino N-H stretch crosses both the locally excited pipi* state and the electronic ground state S(0) and thus triggers the photofragmentation reactions. The two processes have equivalent quantum yields, approximately equal to 50% of the fragments coming from the H-atom loss reaction. The two primary reaction paths can clearly be distinguished by their femtosecond pump/probe dynamics recorded on the different fragmentation channels.

Ultrafast deactivation mechanisms of protonated aromatic amino acids following UV excitation.

Deactivation pathways of electronically excited states have been investigated in three protonated aromatic amino acids: tryptophan (Trp), tyrosine (Tyr) and phenylalanine (Phe). The protonated amino acids were generated by electrospray and excited with a 266 nm femtosecond laser, the subsequent decay of the excited states being monitored through fragmentation of the ions induced and/or enhanced by another femtosecond pulse at 800 nm. The excited state of TrpH+ decays in 380 fs and gives rise to two channels: hydrogen atom dissociation or internal conversion (IC). In TyrH, the decay is slowed down to 22.3 ps and the fragmentation efficiency of PheH+ is so low that the decay cannot be measured with the available laser. The variation of the excited state lifetime between TrpH+ and TyrH+ can be ascribed to energy differences between the dissociative pi sigma* state and the initially excited pi pi* state.

Control of bond-cleaving reactions of free protonated tryptophan ion by femtosecond laser pulses.

The excited-state dynamics of protonated tryptophan ions is investigated by photoinduced fragmentation in the gas phase. In contrast to the neutral molecule that decays on the nanosecond time scale, the protonated species exhibits an ultrafast decay with two time constants of about 400 fs and 15 ps. In addition, after UV excitation by a pump photon at 266 nm, specific photofragments, and in particular the NH3-loss channel, can be enhanced by the absorption of a probe photon at 800 nm. The bond-cleaving reactions can thus be controlled by a variation of the pump/probe delay.

Long-range electron binding to quadrupolar molecules.

An excess electron can be bound to a molecule in a very diffuse orbital as a result of the long-range contributions of the molecular electrostatic field. Following a systematic search, we report experimental evidence that quadrupole binding occurs for the trans-succinonitrile molecule (EA=20+/-2 meV), while the gauche-succinonitrile conformer supports a dipole-bound anion state (EA=108+/-10 meV). Theoretical calculations at the DFT/B3LYP level support these interpretations and give electron affinities of 20 and 138 meV, respectively.

Adjuvant endocrine treatment with medroxyprogesterone acetate or tamoxifen in stage I and II endometrial cancer--a multicentre, open, controlled, prospectively randomised trial.

Endometrial cancer is a hormone-dependent disease and therefore an adjuvant hormonal therapy might improve the outcome in the early stages of the disease. Between 1983 and 1989, we conducted a randomised trial of 388 patients who received either medroxyprogesterone acetate (MPA) (n=133) or tamoxifen (n=121) orally for 2 years, or were observed only (n=134) after surgical therapy. The aim was to evaluate whether an adjuvant treatment can improve disease-free and overall survival rates. After a median follow-up period of 56 months (range 3-199 months), we observed no differences in the disease-free and overall survival rates for the tamoxifen group compared with the control or the MPA group. Side-effects were more frequent and severe in the MPA-group than in the tamoxifen group. In patients with early endometrial cancer, adjuvant endocrine treatment did not significantly improve the outcome. However, tamoxifen did have some beneficial effects on coexisting morbidity.

Laser separation of geometrical isomers of weakly bound molecular complexes.

Molecular assemblies held together by weak intermolecular bonds exhibit a rich variety of geometries. Even a simple complex formed by only two molecules can adopt several conformations corresponding to different geometrical isomers. Isomers of small polar dimers can be isolated nondestructively by taking advantage of a selective and reversible ionization process, with the use of a mass spectrometry method that allows the determination and control of the geometrical configuration of neutral or negatively charged molecular complexes in supersonic beams. Here, the method is applied to isolated nucleic acid base pairs that can be selected in stacked or H-bonded configurations.

Adjuvant randomized trials of doxorubicin/cyclophosphamide versus doxorubicin/cyclophosphamide/tamoxifen and CMF chemotherapy versus tamoxifen in women with node-positive breast cancer.

PURPOSE: We report two randomized trials of adjuvant systemic therapy in 747 patients < or = 65 years of age with histologically proven node-positive breast cancer. PATIENTS AND METHODS: Patients were selected for the two trials on the basis of lymph node and hormone receptor status. The only stratification was based on the treating institution. In patients with a lower probability of recurrence (n = 276), a comparison between endocrine therapy (tamoxifen [Tam] 30 mg/d for 2 years) and chemotherapy (cyclophosphamide, methotrexate, and fluorouracil [CMF] intravenously [IV], six cycles every 4 weeks) was performed. In patients with a higher risk of recurrence (n = 471), a comparison between chemotherapy alone (doxorubicin plus cyclophosphamide [AC] i.v., eight cycles every 3 weeks) and the same chemotherapy plus Tam was made. RESULTS: Overall, we found that CMF and Tam are equally effective in a subgroup of patients with a relatively good prognosis (low-risk patients). However, in the subset of women < or = 49 years old, a significantly greater disease-free survival (DFS) rate (P = .01) and overall survival (OS) rate (P = .002) was observed following therapy with CMF compared with Tam. In patients > or = 50 years old, the opposite was found, and Tam appeared to be superior to CMF (DFS, P = .003; OSm P = .5). These results must be interpreted cautiously, since a post-hoc stratification of patients by age (< or = 49, > or = 50) was performed, and significantly more younger, low-risk patients were randomized to receive chemotherapy alone and more older patients to receive Tam alone. Among patients with a relatively poor prognosis (high-risk patients), a combination of AC plus Tam was equivalent to AC and, when women were analyzed by age, this was found to be true of patients < or = 49 years as well. However, the addition of Tam to AC in women age > or 50 years resulted in a statistically significantly higher DFS (P = .01) and a trend toward better OS compared with women who received AC alone. CONCLUSION: Further trials are required to analyze the role of combined simultaneous or sequential chemoendocrine adjuvant treatment or each single therapy alone in defined risk-adapted subsets of node-negative and node-positive patients.

[Prenatal diagnosis and treatment of auricular flutter. Apropos of a case and review of the literature]. / Diagnostic et traitement anténatal d'un flutter auriculaire. A propos d'un cas, revue de la littérature.

In newborns, atrial flutter is a rare, but severe condition. Late diagnosis was usual and based on fetal ECG. Now, fetal ultrasonography can differentiate in utero atrial flutter and other supra ventricular tachycardias; so it can be treated before development of cardiac failure. Among numerous and various available drugs, digoxin is universally recommended, but the delayed effect and the maternal serum levels to obtain effective fetal concentration of digoxin are not well known. Furthermore, endogenous "digoxin-like" substances have been found in maternal blood in late pregnancy; this finding raises the problem of the validity of monitoring the treatment only by serum digoxin levels. A case of atrial flutter, diagnosed in utero by ultrasonography and treated by digoxin before development of cardiac failure is reported. Neonatal echocardiography showed an aneurysm of the atrial septum, which needed simple monitoring. Its responsibility in the pathogenesis of the arrhythmia is unclear. Numerous cases of aneurysm of the atrial septum have been reported in healthy adults without atrial arrhythmias.

[Use of anti-digoxin antibodies in digitalis poisoning in an infant]. / Utilisation des anticorps anti-digoxine au cours d'une intoxication digitalique chez un nourrisson.

Digitalis poisoning is rare, always iatrogenic and potentially lethal in infants. We report one case of severe poisoning in which treatment with digoxin Fab antibody fragments was successful. Evolution of plasma digitoxin levels showed an initial rapid decrease (T 1/2:1 hour), then a slower decline (T 1/2:5.5 days). No undesirable side-effects were observed.

[Digitoxin poisoning: reversing ventricular fibrillation with Fab fragments of anti-digoxin antibody]. / Intoxication par la digitoxine: réversibilité d'une fibrillation ventriculaire par fragments Fab d'anticorps antidigoxine.

Purified Fab fragments of ovine anti-digoxin antibodies (Wellcome Foundation) were used to treat a patient who attempted suicide by absorbing 10 mg of digitoxin (serum concentration 265 micrograms/l). The poor prognosis, as assessed clinically and from serum potassium levels (7.5 mEq/l), seemed to warrant such a treatment. The weak (6.85%) cross-reactivity elicited in vitro between the anti-digoxin antibodies and digitoxin was compensated by increasing the doses, but improvement was observed with 3.6 g, i.e. about half the effective dosage initially considered. The criteria of effectiveness were clinical, electrocardiographic (reversal of the ventricular fibrillation), biochemical (simultaneous and opposite changes in extra- and intracellular potassium levels, suggesting that ATPase inhibition by digitalis is a reversible process) and toxicological: there was an increase in digitoxin serum levels suggesting displacement of the drug from tissue sites to plasma and other extracellular compartments where the Fab fragments are distributed, and Fab-bound digitoxin appeared fairly rapidly in the urine, which suggested shunting of the normal hepatic metabolic pathway.

[Paraquat poisoning. Prognostic and therapeutic evaluation in 28 cases]. / Intoxication par le paraquat. Evaluation du pronostic et du traitement à partir de 28 cas.

Since a mouthfull of the herbicidal compound Paraquat usually results in death from caustic burns, renal tubular necrosis, circulatory failure of pulmonary fibrosis, the fact that 11 out of 28 people poisoned in the period 1972-1980 survived deserves consideration. The most significant prognostic factors appear to be: (1) the mode of penetration: all 4 patients poisoned through the skin and/or the respiratory tract survived; (2) the volume of Paraquat absorbed: death from circulatory failure occurs within less than 72 hours with more than 50 mg/kg, while 35 to 50 mg/kg produce progressive pulmonary fibrosis; (3) the content of the stomach at the time of ingestion: food can neutralize the compound; (4) the finding of gastric lesions on early endoscopy; (5) evidence of acute renal failure; finally and mostly (6) Paraquat blood levels during the first 24 hours, as measured by radioimmune assays; lethal levels are 2.0, 0.6, 0.3, 0.16 and 0.10 mg/l at 4, 6, 10, 16, and 24 hours respectively. There is no overlapping between values obtained in patients who died and survivors. In this series, the course of the intoxication, as predicted from the initial prognostic factors, was unmodified by the treatments applied (Fuller's earth, dialysis, charcoal haemoperfusion, furosemide, immediate hypooxygenation). The survival of two patients with restrictive respiratory pathology seems to be ascribable to the circumstances of poisoning rather than to the treatment.

Plasma pharmacokinetics of morphine after i.m., extradural and intrathecal administration.

Eighteen patients received morphine 0.2 mg kg-1 in 0.9% saline i.m. (n = 6), extradurally (n = 6), or in a 10% dextrose solution intrathecally (n = 6) for pain relief operation. Plasma unmetabolized morphine was isolated by extraction using liquid-solid chromatography and measured by radioimmunoassay. Conjugated morphine was calculated from the difference between total immunoreactive morphine and unmetabolized morphine. Initial vascular absorption was significantly less in the intrathecal group than in the i.m. and extradural groups. This accounts for persistence of plasma unmetabolized morphine at 24 h and for more prolonged analgesia in the intrathecal group. Prolonged analgesia observed following extradural and intrathecal administration was caused by a small quantity of unmetabolized morphine. Extradural and i.m. groups showed the same pharmacokinetic patterns although extradural analgesia is much more prolonged. Morphine glucuronide appeared later in blood in the intrathecal group than in the two other groups.

[Pharmacology of narcotics administered by the epidural or intrathecal route (author's transl)]. / Pharmacologie des morphiniques administrés par voies péridurale et intrathécale.

Owing to the presence of specific opiate receptors in the spinal cord, analgesia can be obtained with epidural or intrathecal injections of morphine derivatives. The duration of analgesia depends upon the degree of water solubility of the compound. Compounds with low coefficient of distribution in lipids (e.g. morphine) do not readily cross the blood-brain barrier and have a prolonged action, whereas the duration of analgesia induced by highly lipid-soluble compounds, such as dextromoramide and phenoperidine, is not very different from that obtained with more conventional routes of administration. The fact that large amounts of narcotics are taken up by the spinal cord explains that central effects are relatively rare. However, side-effects may be observed, and their frequency mainly depends upon the quantity of narcotic injected. These side-effects reduce the number of indications, which cannot yet be precisely determined. Epidural and intrathecal analgesia appears to be particularly useful during the post-operative period in patients liable to respiratory complications.