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A Perret

Publications and source records attributed to A Perret.

13 recordsLinked to original sources
PubMed2002

Does Switzerland train tomorrow's surgeons today? Today's reflections on tomorrow's surgeons.

Various factors are influencing the Swiss health care system, and therefore, surgeons' actual and future profession. Initiated by the current president of the Swiss Society of Surgery, a group of eight young Swiss surgeons constituted the ad hoc committee "Chirurgie 2020". The goal was to develop several scenarios of the surgeon's professional situation in 20 years. The future direction of surgery will be markedly influenced by medical innovation, political and economic relationships between Switzerland and Europe. However, the development of health care costs represents the most powerful factor predicting all further changes. The current situation of today's surgeons is best characterised as "hamsters in the treadmill" who try to fulfill a multitude of diverging tasks causing major demotivation. In order to retain a leading role in the health care system, surgeons must take part in social and political activities. To provide an excellent curriculum, university and county hospitals must join together to form clinical and educational networks. A clearly defined and structured curriculum must be introduced by the Swiss Society of Surgery. From our current point of view, only everyone's strong personal commitment will help to find solutions and to improve the current and future situation. In particular, today's surgical residents must actively take part in the development of tomorrow's surgery.

Curriculum↗
PubMed1998

Differential redox and electron-transfer properties of purified yeast, plant and human NADPH-cytochrome P-450 reductases highly modulate cytochrome P-450 activities.

Saccharomyces, human and two Arabidopsis (ATR1 and ATR2) NADPH-P-450 reductases were expressed in yeast, purified to homogeneity and used to raise antibodies. Among the P-450-reductases, ATR2 contrasted by its very low FMN affinity and required a thiol-reducing agent for efficient cofactor binding to the FMN-depleted enzyme. Analysis of reductase kinetic properties using artificial acceptors and different salt conditions suggested marked differences between reductases in their FAD and FMN environments and confirmed the unusual properties of the ATR2 FMN-binding domain. Courses of flavin reductions by NADPH were analysed by rapid kinetic studies. The human enzyme was characterized by a FAD reduction rate sixfold to tenfold slower than values for the three other reductases. Following the fast phase of reduction, expected accumulation of flavin semiquinone was observed for the human and ATR1 but not for ATR2 and the yeast reductases. Consistently, redox potential for the FMN semiquinone/reduced couple in the yeast enzyme was found to be more positive than the value for the FMN oxidized/semiquinone couple. This situation was reminiscent of similar inversion observed in bacterial P-450 BM3 reductase. Affinities of reductases for rabbit P-450 2B4 and supported monooxygenase activities in reconstituted systems highly depended on the reductase source. The human enzyme exhibited the highest affinity but supported the lowest kcat whereas the yeast reductase gave the best kcat but with the lowest affinity. ATR1 exhibited both high affinity and efficiency. No simple relation was found between reductase activities with artificial and natural (P-450) acceptors. Thus marked differences in kinetic and redox parameters between reductases dramatically affect their respective abilities to to support P-450 functions.

Animals↗
PubMed1998

Electron shuttle between membrane-bound cytochrome P450 3A4 and b5 rules uncoupling mechanisms.

Contradictory mechanisms involving conformational or redox effects have been proposed for the enhancement of cytochrome P450 activities by cytochrome b5 in reconstituted systems. These mechanisms were reinvestigated for human liver P450 3A4 bound to recombinant yeast membranes including human P450 reductase and various levels of human b5. Species conversions were calculated on the basis of substrate, oxygen, and electronic balances in six different substrate conditions. Electron flow from P450 reductase to ferric 3A4 was highly dependent on the nature of substrate but not on the presence of b5. P450 uncoupling by hydrogen peroxide formation was decreased by b5, leading to a corresponding increase in the rate of ferryl-oxo complex formation. Nevertheless, the major b5 effects mainly relied on an increased partition of ferryl-oxo complex to substrate oxidation compared to reduction to water, which could support a conformation change based mechanism. However, further steady-state investigations evidenced that electron carrier properties of b5 were strictly required for this modulation and that redox state of b5 was ruled by the nature and concentration of 3A4 substrates. Moreover, rapid kinetic analysis of b5 reduction following NADPH addition suggested that b5 was reduced by the 3A4 ferrous-dioxygen complex and reoxidized by subsequent P450 oxygenated intermediates. A kinetic model involving a 3A4-b5 electron shuttle within a single productive P450 cycle was designed and adjusted. This model semiquantitatively simulated all presented experimental data and can be made compatible with the effect of the redox-inactive b5 analogue previously reported in reconstituted systems. In this model, synchronization of the b5 and 3A4 redox cycles, binding site overlap between b5 and reductase, and dynamics of the b5-3A4 complex were critical features. This model opened the way for designing complementary experiments for unification of b5 action mechanisms on P450s.

Catalysis↗
PubMed1997

[Poisoning with "poppers", a rare cause of methemoglobinemia observed in emergency cases].

BACKGROUND: Methemoglobulinemia should be entertained as a differential diagnosis in patients with cyanosis. Recently in France there has been an increase in the number of cases of acquired methemoglobulinemia due to inhalation of poppers. CASE REPORTS: Four patients were admitted to the emergency room of a Paris hospital in a state of unconsciousness with cyanosis. All four patients had inhaled poppers shortly before admission. The clinical course was rapidly favorable after intravenous infusion of methylene blue in 3 cases. DISCUSSION: Poppers are inorganic aliphatic nitrites used for their relaxing effect on smooth muscle and for their aphrodisiac effect. One poorly recognized effect is the development of methemoglobulinemia. Tissue hypoxia results because methemoglobulin cannot bind oxygen, leading to a brown or blue coloration of the blood. Methemoglobulin usually results from exposure to a wide variety of oxidizing compounds including certain drugs. Methylene blue is the specific treatment for symptomatic methemoglobulinemia. These four cases emphasize the toxic effect of products sold in sex shops and calls attention to the life-threatening risks involved.

Adult↗
PubMed1997

Simulation of human xenobiotic metabolism in microorganisms. Yeast a good compromise between E. coli and human cells.

An overview of current heterologous expression systems for xenobiotic metabolising enzymes is given with a special emphasis on the yeast expression system. In a first part, basic properties and relative advantages and drawbacks of each expression system are considered. The second part is dedicated to humanized yeast strains allowing human P450 expression in a tailored redox environment and to the possibility to use such strains to simulate complex metabolisms involving a combination of phase I and phase II reactions. The last part presents how the association of numeric simulation to yeast expression can help in understanding rules controlling metabolic profiles in xenobiotic-acting multienzymatic systems.

Humans↗
PubMed1996

Contribution of human cytochrome P450 to benzo[a]pyrene and benzo[a]pyrene-7,8-dihydrodiol metabolism, as predicted from heterologous expression in yeast.

The metabolism of benzo[a]pyrene (B[a]P) and its proximate mutagen B[a]P-7,8-dihydrodiol (7,8-diol) was investigated in the presence of human microsomal epoxide hydrolase and P450 1A1, 1A2, 2C8, 2C9, 2C18, 2C19, 2D6 and 3A4 expressed in the yeast Saccharomyces cerevisiae. P450 1A1 had the highest turnover numbers for the formation of all B[a]P metabolites, including phenols and dihydrodiols. P450 1A2, 2C8, 2C9, 2C18, 2C19 and 3A4, which are well represented in the liver, gave rise to the formation of appreciable amounts of 3-hydroxy-B[a]P and of some dihydrodiols from B[a]P. When 7,8-diol was used as substrate, P450 1A1 also exhibited the highest turnover numbers for the formation of tetrols, the hydrolysis products of the diolepoxides, whereas P450 1A2, 2C8, 2C19 and 3A4 showed moderate activities. In order to test the validity of the yeast system, the contribution of each P450 isoform to B[a]P and 7,8-diol metabolism was evaluated as the product of the turnover numbers of recombinant P450s by specific contents of each P450 in human liver microsomes. Calculated formation rates for each B[a]P and 7,8-diol metabolite globally matched experimental values. There is evidence that P450 3A4 and 2C9 play a major role in the formation of 3-hydroxy-B[a]P from B[a]P. Accumulation of the proximate mutagen 7,8-diol was predicted to be mainly driven by P450 1A2, 2C9 and 2C19, while formation of the genotoxic diolepoxides from 7,8-diol appeared to be dependent on P450 1A2 and 3A4 in the liver.

Benzo(a)pyrene↗
PubMed1995

Genetically engineered yeast cells and their applications.

The first generation of yeast expression systems relies on inducible expression cassettes borne by multicopy plasmids for production of unmodified human P450s and on the endogenous NADPH-P450 reductase to support activities. A second generation of engineered yeast involved targeted genomic modifications allowing overexpression of the yeast reductase and coexpression of human cytochrome b5 and of a phase II enzyme such as epoxide hydrolase. These features allow improved P450 turnover numbers and simulation of some phase I-phase II couplings. In the third generation, the human reductase was substituted for the yeast reductase by genome engineering. Simultaneously, induction procedures were optimized to reach high P450 specific contents. Dramatic improvements (1000-fold) of yeast-expressed P450 activities have thus been obtained. To get more insight into complex metabolic events, such as that of a typical pollutant: benzo[a]pyrene, an approach was designed which involves a complementary use of yeast expression and computer simulations.

Benzo(a)pyrene↗
PubMed1993

Cardiac arrest: prognostic factors and outcome at one year.

This study was designed to determine by multivariate statistical methods the influence of 38 variables on outcome after cardiopulmonary resuscitation (CPR) and to assess neuropsychological status in long-term survivors. The charts of 181 consecutive patients resuscitated in a 1,100-bed University Hospital over a 2-year period were analyzed retrospectively. Of the 181 resuscitated patients, 23 (13%) could be discharged. Outcome was significantly affected by the following variables: presence of shock or renal failure before cardiac arrest (CA) (odds ratio = 10.6; 95% confidence interval = 1.3-85.8 and odds ratio = 13.8; 95% confidence interval = 1.7-109.2, respectively), administration of epinephrine (odds ratio = 11.2; 95% confidence interval = 3.2-39.2) or prolonged CPR (> 15 min) (odds ratio = 4.9; 95% confidence interval = 1.7-13.7). By contrast, when CA occurred in uncomplicated acute myocardial infarction a significantly better prognosis could be demonstrated (odds ratio = 0.2; 95% confidence interval = 0.0-0.6). The 10 long-term survivors investigated lead an independent life and all returned to former occupation. The most common complaint was moderate memory disturbance (five patients). The conclusion is that this study confirms the critical influence of cellular anoxia on prognosis and allows the improved delineation of the situations in which cardiopulmonary resuscitation appears to be hopeless or likely to be successful. The follow up in a small number of survivors has shown a good quality of life and minor neuropsychological sequellae.

Cardiopulmonary Resuscitation↗
PubMed1986

Sodium valproate monotherapy in childhood epilepsy.

154 patients with a mean age of 6 years 1 month were followed on valproate monotherapy for a period ranging from 5 to 27 months (mean 22 months). Absence epilepsies, benign myoclonic epilepsies and epilepsies with tonic-clonic seizures on awakening were the best controlled, followed by benign partial epilepsies and infantile spasms. Reduction to monotherapy resulted in improvement in 13 of 14 patients with primary generalized epilepsy. Sixteen per cent of the 154 patients suffered mild to moderate adverse effects. After cessation of treatment in 28 seizure-free patients, no recurrence was observed in absence epilepsy, benign myoclonic epilepsy, infantile spasms or benign partial epilepsy, whereas two thirds of the patients with generalized tonic-clonic seizures on awakening relapsed in the year following the cessation of the treatment.

Adolescent↗
PubMed1979

[Isoelectric electroencephalography approximately 6 hours after ventricular fibrillation due to myocardial infarct. Apropos of a case with favorable development].

A 59-year-old patient was resuscitated after ventricular fibrillation due to anterior myocardial infarction. Ventilatory and cardiac arrest lasted for more than 20 minutes. 5 h 50 min later the EEG was isoelectric. The evolution was nevertheless favourable and the patient was able to leave hospital one month later and to resume work half-time 5 months later. The problems of anoxic ischemic encephalopathies, isoelectric EEG and their treatment are discussed.

Aged↗