Construction of enantioenriched polysubstituted hexahydropyridazines via a sequential multicatalytic process merging palladium catalysis and aminocatalysis.

An efficient multicatalytic strategy for the construction of nitrogen-containing heterocycles has been reported. The powerful combination of organic and metal catalysis in a single vessel allowed the formation of enantioenriched polysubstituted cyclic 6-membered hydrazines bearing a quaternary stereocenter in good yields and selectivities.

Increasing mean arterial pressure during cardiac surgery does not reduce the rate of postoperative acute kidney injury.

INTRODUCTION: We hypothesized that the optimization of renal haemodynamics by maintaining a high level of mean arterial blood pressure (MAP) during cardiopulmonary bypass (CPB) could reduce the rate of acute kidney injury (AKI) in high-risk patients. METHODS: In this randomized, controlled study, we enrolled 300 patients scheduled for elective cardiac surgery under cardiopulmonary bypass. All had known risk factors of AKI: serum creatinine clearance between 30 and 60 ml/min for 1.73 m(2) or two factors among the following: age >60 years, diabetes mellitus, diffuse atherosclerosis. After a standardized fluid loading, the MAP was maintained between 75-85 mmHg during CPB with norepinephrine (High Pressure, n=147) versus 50-60 mmHg in the Control (n=145). AKI was defined by a 30% increased of serum creatinine (sCr). We further tested others definitions for AKI: RIFLE classification, 50% rise of sCr and the need for haemodialysis. RESULTS: The pressure endpoints were achieved in both the High Pressure (79 ± 6 mmHg) and the Control groups (60 ± 6 mmHg; p<0.001). The rate of AKI did not differ by group (17% vs. 17%; p=1), whatever the criteria used for AKI. The length of stay in hospital (9.5 days [7.9-11.2] vs. 8.2 [7.1-9.4]) and the rate of death at day 28 (2.1% vs. 3.4%) and at six months (3.4% vs. 4.8%) did not differ between the groups. CONCLUSION: Maintaining a high level of MAP (on average) during normothermic CPB does not reduce the risk of postoperative AKI. It does not alter the length of hospital stay or the mortality rate.

Evaluation of pollutant exposure by chemical and biological markers in a Mediterranean French urban stream: a step for in situ calibration of multixenobiotic resistance transporter expression as biomarker in Chironomidae larvae.

This study was aimed at semi-quantifying the membrane density of multixenobiotic resistance (MXR) transporters in Chironomidae Orthocladiinae larvae from an urban stream by ELISA assay. The relationships between the MXR transporter membrane density and limnological parameters and pollutant concentrations, 16 priority polycyclic aromatic hydrocarbons (PAHs), as per the US Environmental Protection Agency (EPA) and seven polychlorobiphenyl congeners (PCBs), were assessed. Midge larvae were collected, and limnological parameters and pollutant concentrations were measured in three sites of a French Mediterranean urban stream, two located after sewage treatment plants, and one closed to the river mouth, and in two additional sites, one on the stream tributary, and one in a non-urbanized stream located in the same region. Results show that the PAH and PCB contamination levels are different between sites and that some congener concentrations are above their threshold toxic effect level (TEL). The MXR transporter membrane density was significantly higher in larvae from the tributary, the most polluted site, as compared with larvae from the non-urbanized stream. The MXR transporter density was positively correlated with 10 of the 16 US-EPA PAH concentrations and the increase in the MXR transporter density seems to be due to the US-EPA PAH concentrations that were above their TEL. No relations with PCB concentrations or limnological parameters were found. The results suggest that the MXR transporter membrane density in Chironomidae larvae could be an interesting biological marker of PAH exposure in freshwater ecosystems.

ELISA detection of multixenobiotic resistance transporter induction in indigenous freshwater Chironomidae larvae (Diptera): A biomarker calibration step for in situ monitoring of xenobiotic exposure.

A new simple and sensitive method to distinguish chemically polluted from unpolluted situations in freshwater ecosystems is reported. For this purpose, Chironomus gr thumni larvae were collected from a polluted urban river downstream a sewage treatment plant. For the first time, ELISA assay was used to semi-quantify the multixenobiotic resistance transporters (MXR) in these small pertinent bioindicators. The use of samples immediately fixed in the field gives a delay to isolate larvae and allows multi-sampling along a longitudinal transect in a river at a given time. Results exhibit an induction of MXR proteins in larvae from the polluted river and a deinduction in larvae maintained 11days in unpolluted water. They show new evidences to use midge larvae in biomonitoring environmental programs. They answer to first biomarker calibration steps for the ongoing development of MXR transporters as a detection tool of xenobiotic impacts on bioindicator invertebrates in their freshwater habitats.

Chronic effects of triiodothyronine in combination with imipramine on 5-HT transporter, 5-HT(1A) and 5-HT(2A) receptors in adult rat brain.

Triiodothyronine (T3) has been shown to accelerate and potentiate the clinical response to tricyclic antidepressant (TCA) treatment in depressive disorders. The neurobiological mechanisms underlying these therapeutic effects of T3 are still unknown. Since brain serotonin (5-HT) changes have been implicated in the mode of action of TCA drugs, the effects of a chronic (7 or 21 days) administration of imipramine (10 mg/kg/day) and of a low dose of T3 (4 microg/kg/day), given alone or in combination, were investigated on the density of midbrain 5-HT transporters and of hippocampal 5-HT(1A) and cortical 5-HT(2A) receptors in adult Wistar rats. Neither single nor combined administration of imipramine and T3 for 7 days modified the density of 5-HT transporters and of 5-HT(1A) receptors. On day 21, the combination did not change imipramine- or T3-induced decrease in 5-HT transporter density whereas it prevented imipramine-induced increase in 5-HT(1A) receptor density. Whatever the treatment duration, imipramine-T3 combination potentiated imipramine-induced decrease in 5-HT(2A) receptor density. On both day 7 and day 21, T3 given alone had no effects on the density of 5-HT(1A) and 5-HT(2A) receptors. These data indicate that T3 is able to modulate the long-term adaptive changes which occur at the postsynaptic level of 5-HT neurotransmission after antidepressant treatment.

Heparin-associated thrombocytopenia syndrome: an underestimated etiology of adrenal hemorrhage.

A 74-year-old man developed bilateral arterial thrombosis of the lower limbs related to heparin-associated thrombocytopenia syndrome (HATS). On day 4 after thrombectomy of both limbs, abdominal pain, fever, hypotension, abdominal tenderness appeared. Acute acalculous cholecystitis was suspected and cholecystectomy was carried out although the gallbladder was not imflamed. Later on, hyponatremia in addition to the aforesaid signs suggested the diagnosis of adrenal insufficiency. Diagnosis was confirmed by low cortisol and aldosterone plasma concentration and by CT scan, which showen two enlarged adrenal glands. HATS might explain two unexpected facts: occurrence of adrenal hemorrhage during heparin therapy with coagulation tests within the therapeutic range and paradoxical thrombosis in the central vein of adrenal gland. HATS must be regarded as one cause of adrenal hemorrhage necrosis.

Red blood cell triiodothyronine uptake in unipolar major depression: effect of a chronic antidepressant treatment.

The evolution of kinetic parameters (Vmax, maximal velocity, and Km, Michaelis constant) of red blood cell (RBC) triiodothyronine (L-T3) initial uptake was followed in 19 inpatients suffering from unipolar depression after 1 week (D7) and 4 weeks (D28) of a chronic administration of fluvoxamine, in relation with the clinical efficacy of the drug. In a drug-free state (DO), Vmax (in pmol/min/10(8) cells) and Km (in nM) were significantly increased in depressed patients (Vmax +/- S.D.= 1.02 +/- 0.29, p< 0.01 and Km +/- S.D.= 68.8 +/-15.4, p< 0.05; n=19) compared to healthy volunteers matched for age and sex (Vmax +/- S.D.= 0.82 +/- 0.15 and Km S.D.= 58.8 +/- 9.0; n= 19). When patients were dichotomized on the basis of their treatment response, responders had kinetic parameters significantly increased (Vmax +/-S.D.= 1.03 +/- 0.26, p< 0.01 and Km +/- S.D.= 71.7 +/- 18.7, p< 0.05, n= 10) compared to controls, whereas non-responders had not (Vmax +/- S.D.= 1.00 +/- 0.33, NS and Km +/- S.D.= 65.7 +/- 10.9, NS, n= 9). At D7, Vmax differed from the one of controls only in the responders (Vmax +/- S.D.= 1.03 +/-0.26, p< 0.01). In addition, the percentage of variation of the individual Vmax values during the first week of treatment was significantly lower in responders than in non-responders (deltaVmax(D7-D0) +/- S.D. in % = 10.7 +/- 6.0 and 22.0 +/- 11. 1, p< 0.05, respectively). At D28, kinetics of L-T3 uptake normalized only in the responders (Vmax +/- S.D.= 0.91 +/- 0.13, NS; Km+/-S.D.= 65.7 +/- 7.4, NS). The results indicate that both RBC L-T3 uptake at the pretreatment level and its change during the first week of fluvoxamine treatment were related to the further clinical response to the antidepressant. RBC L-T3 uptake seems to be a biological correlate of the depressive symptomatology since the disturbances disappear only with the clinical remission.

Increase in red blood cell triiodothyronine uptake in untreated unipolar major depressed patients compared to healthy volunteers.

1. Kinetic parameters of red blood cell (RBC) L-triiodothyronine (T3) initial uptake (Vmax, maximal velocity and Km, Michaelis constant) were determined in 34 untreated inpatients suffering from unipolar depression and in 40 healthy volunteers. 2. Both Vmax and Km were significantly increased in depressed patients as compared to controls. The alterations in kinetic parameters were not associated with the severity of depression. 3. Out of the 19 depressed patients who were submitted to TRH test, 7 of them (36%) showed a blunted TRH-induced TSH response associated with a Vmax situated outside the control mean value +/- 1 S.D. 4. The authors found a significant positive correlation between Vmax of RBC L-T3 and L-tryptophan (TRP) uptakes which is in agreement with the assumption that L-T3 and L-TRP share a common carrier system at the erythrocyte level. 5. The results indicate that the uptake of L-T3 by RBC is increased in major depression. These transport perturbations might reflect alterations in the plasmatic metabolism of L-T3. Evaluation of RBC L-T3 uptake could be useful in a best biological characterization of the depressed patients with regard to their thyroid function.

[Cardiac surgery in aged patients; immediate and medium-term results in 100 patients over 75 years of age]. / Chirurgie cardiaque chez les patients âgés; résultats immédiats et à moyen terme chez 100 patients âgés de 75 ans et plus.

With improved operative technique and postoperative care, progressively older patients are being referred for cardiac surgery. One hundred out of 633 patients operated between September 1990 and December 1992, were over 75 years of age (Group I). These patients were compared with the last 100 patients under 75 years of age (Group II). Both groups were operated by the same surgical team with the same anaesthetic, cardiopulmonary bypass and myocardial protection techniques. The average age of the groups was 79.5 +/- 3.1 and 62.1 +/- 9.2 years, respectively. The procedures performed were: myocardial revascularisation (Group I, 28 cases; Group II, 59 cases), aortic valve surgery alone or associated with coronary bypass (56 and 22 cases respectively), and mitral valve surgery alone or associated with another procedure (11 and 12 cases). There were no significant differences between the two groups with respect to true low output state, the duration of mechanical ventilation and of intensive care and hospital stay. On the other hand, there were significant differences in: the number of blood transfusions (44 cases versus 20, p < 0.001), the occurrence of atrial fibrillation (52 cases versus 29, p < 0.001) and neuropsychiatric disturbances (27 cases versus 5, p < 0.0001). There were no cases of mediastinitis in either group. The hospital mortality was 6% in Group I and 5% in Group II (NS). The medium-term mortality after an interval of 5 to 32 months in the over 75 age group was 7 cases, including 4 cases of cerebrovascular accident. An enquiry was performed in the 87 survivors of Group I.(ABSTRACT TRUNCATED AT 250 WORDS)

[Retrograde cerebral perfusion for replacement of the aortic arch. Apropos of a case]. / Perfusion cérébrale rétrograde pour remplacement de la crosse aortique. A propos d'un cas.

The authors report a case of cerebral protection with retrograde cerebral perfusion during aortic arch surgery. The duration of retrograde cerebral perfusion and the favorable neurological outcome seem to confirm the promising results of this technique developed in Japan.

[Pharmacokinetics of paracetamol in the cerebrospinal fluid in the elderly]. / Pharmacocinétique du paracétamol dans le liquide céphalorachidien de sujets âgés.

We investigated acetaminophen pharmacokinetics in CSF in twelve operated arteritics patients with continuous spinal anesthesia. Nine men and three women aged 77 +/- 7 years and weighing 66 +/- 15 kg entered in the study after expressing verbal informed consent. They received intravenously a single dose of acetominophen (equivalent to 1 g). Fifteen minutes to six hours after the intravenous injection, blood and CSF samples were withdrawn every thirty minutes, except during the second to the third hour were it was every fifteen minutes. Acetaminophen concentrations in blood and in CSF were assayed by HPLC. Acetaminophen was detected in the earliest samples (1.32 +/- 1.32 micrograms.ml-1) and then increased up to 8.16 +/- 3.04 micrograms.ml-1 at 186 +/- 56 minutes. From 135th to 345th minute, acetaminophen concentration in CSF stay at about 6 micrograms.ml-1, which is the duration of its maximal analgesic central effect.

[Subcardial ulcer and the Nissen technic. Apropos of a case of recovery by partial release of the fundoplication]. / Ulcère sous-cardial et technique de Nissen. A propos d'une observation de Guérison par décomplètement de la fundo-plicature.

Gastric ulcer, an uncommon complication of Nissen technique, is nevertheless reported in all series (between 1 and 5% of cases). The authors report a case occurring after a complete fundoplication associated with a longitudinal stapling of the cardia (Rignault's procedure) which resolved after reoperation and transformation into a posterior hemi-valve. The pathogenesis of post-Nissen gastric ulcer is discussed; the mechanical factor appears to be decisive in the subcardial site. Surgical revision according to various modalities is generally unavoidable.

[Long-term retrograde cerebral perfusion in surgery of the aortic arch. Apropos of 2 cases]. / Perfusion cérébrale rétrograde de longue durée dans la chirurgie de la crosse aortique. A propos de deux cas.

The authors present two cases of aortic arch replacement for aortic dissection: one in a male patient 58 years old and the other in a female patient 78 years old. Cerebral protection during repair of the aortic arch was performed with retrograde cerebral perfusion (RCP). Durations of RCP were 75 and 120 minutes respectively. Good neurological recovery in both patients appeared to confirm the efficacy of RCP with respect to cerebral protection during surgery of the aortic arch.

[Final arrest of a pacemaker after use of electrocautery]. / Arrêt définitif d'un stimulateur cardiaque après utilisation du bistouri électrique.

A case is reported of irreversible damage being caused to a permanent programmable pacemaker by electrocautery used in the epigastric region. The pacemaker was rapidly replaced, and the patient had no adverse effects of this accident. The use of monopolar electrocautery in patients who have one of the new generation of programmable pacemakers is very dangerous. Bipolar forceps can reduce the level of interference between electrocautery units and pacemaker electrodes. With programmable pacemakers, the generator instruction manual should be consulted before surgery, as placing a magnet on the generator may not necessarily convert it to the asynchronous mode. When the use of electrocautery is unavoidable, external cardiac pacing electrodes should be placed on the patient, with an external cardiac pacemaker ready.

[Iloprost (Ilomedine) and extracorporeal circulation with conventional heparinization in a patient with heparin-induced thrombocytopenia]. / Iloprost (Ilomédine) et circulation extracorporelle avec héparinisation conventionnelle chez un patient ayant une thrombopénie à l'héparine.

A 73-year-old female patient was admitted for myocardial infarction. Conventional treatment with heparin was started, intraaortic balloon assistance was required for several days, together with heparin. The platelet counts decreased progressively, from 288 G.l-1 on admission to 41 G.l-1 on the 16th day, despite the use of low molecular weight heparin. The in vitro heparin platelet aggregation test remained positive. This aggregation ended on adding iloprost, an analogue of prostacyclin, to the platelet culture bath. A coronary aortic bypass graft was required. An infusion of iloprost was started just after induction of anaesthesia. The initial dose of 0.5 ng.kg-1 x min-1 was gradually increased to 20 ng.kg-1 x min-1. Heparin (400 IU.kg-1) was thereafter added. To maintain a mean blood pressure of a least 50 mmHg, an infusion of up to 10 micrograms.kg-1 x min-1 of phenylephrine was given. As it was insufficient, an infusion of up to 1 microgram.kg-1 x min-1 noradrenaline was required. The iloprost infusion was gradually stopped 15 min before the end of CPB, together with that of noradrenaline. Platelet aggregation tests were positive after protamine had been given, whereas they had been negative during the infusion of iloprost. There was no abnormal postoperative bleeding. An infusion of 2 ng.kg-1 x min-1 was started at the sixth postoperative hour for 48 h, until the coumarin-like agent had started taking its effects. It is concluded that iloprost might be useful for carrying out cardiac surgery in patients with heparin-induced thrombocytopaenia.

[Determination of thresholds of external cardiac pacing during anesthesia]. / Détermination des seuils de stimulation cardiaque externe pendant l'anesthésie.

The efficacy of transcutaneous pacing was studied in 33 patients during general anaesthesia. The temporary pacing was effective in all cases. Stimulation thresholds ranged from 85 to 150 mA (mean : 110 +/- 17). In all 33 patients, external pacing was effective in producing a pulse without significantly reducing arterial pressure. Stimulation thresholds were only influenced by electrode position; age, weight, thoracic diameter and cardiothoracic ratio did not have any effect on them. No adverse effects of transcutaneous pacing were recorded. Transcutaneous pacing can be an alternative to transvenous right ventricular endocardiac pacing in the operating room in some circumstances.

[Propofol in urological endoscopy in elderly patients. Comparison with methohexital]. / Le propofol en endoscopie urologique chez le sujet âgé. Comparaison avec le méthohexital.

Twenty patients undergoing cystoscopy (group A) and forty patients undergoing transurethral resection (group B), aged more than 65 years, were anaesthetized. Duration of anaesthesia was less than 15 min for cystoscopy, and more than 30 min for transurethral resection. No premedication was given. The patients were ASA I or ASA II. Group A patients were allocated randomly to receive either 1.5 mg . kg-1 propofol (n = 10) or 2 mg . kg-1 methohexitone (n = 10) for induction of anaesthesia. Anaesthesia was maintained using incremental doses of propofol or methohexitone and 60% N2O with a face-mask. Forty group B patients undergoing transurethral resection were randomly assigned to four equal groups (PB: propofol 1.5 mg . kg-1; MB: methohexitone 2 mg . kg-1; PF: propofol and 1.5 micrograms . kg-1 fentanyl; PFV: propofol, 2 micrograms . kg-1 fentanyl and 0.1 mg . kg-1 vecuronium). Suxamethonium (1 mg . kg-1; groups PB, MB and PF) and vecuronium (0.1 mg . kg-1; group PFV) were given to facilitate endotracheal intubation. Anaesthesia was maintained by infusion of propofol or methohexitone, using a calibrated pump started immediately after intubation. Ventilation was controlled only in group PFV. Induction with 1.5 mg . kg-1 propofol resulted in stopping counting after 62 s and loss of the eye-lash reflex after 84 s versus 47 and 67 s respectively with methohexitone. The anaesthesist's assessment was favourable for cystoscopy with propofol and methohexitone; recovery times were similar for the two drugs in cystoscopy lasting less than 30 min.(ABSTRACT TRUNCATED AT 250 WORDS)

[Anaphylactic shock during the use of high doses of aprotinin in cardiac surgery]. / Choc anaphylactique lors de l'utilisation de l'aprotinine à fortes doses en chirurgie cardiaque.

A 77-year-old man was admitted for mitral valve replacement, 46 days after a failed conservative mitral surgery where he received high-dose aprotinin. Twenty minutes after induction of anaesthesia, 250 UPh E of aprotinin were infused intravenously; before the end of this infusion, bronchospasm, systemic hypotension and generalized rash were noted. Immediate treatment included intravenous adrenaline and methylprednisolone; cardiovascular stability was restored after 10 minutes. Immediate histamine liberation was confirmed by the analysis of the time course of the clinical events, a previous contact and positive skin tests. Aprotinin has the antigenic molecular structure of natural proteins. Since 1987, it is used in cardiac surgery to reduce postoperative blood loss: to prevent serious allergic reactions to aprotinin, it is necessary, in patients known to have had previous aprotinin therapy, to perform skin testing with diluted aprotinin before infusion.

[Comparison of vascular effects of magnesium sulfate and nicardipine during extracorporeal circulation]. / Comparaison des effets vasculaires du sulfate de magnésium et de la nicardipine pendant la circulation extracorporelle.

OBJECTIVE: To evaluate the hypothesis that magnesium sulphate (SO4Mg), usually administered for protecting the myocardium and decreasing the rate of arrhythmias in cardiac surgery, was able to control the hypertensive peaks occurring during cardiopulmonary bypass (CPB), as efficiently as nicardipine (N). STUDY DESIGN: Randomized controlled trial. PATIENTS: Forty patients were allocated into two groups when hypertensive peaks occurred during CPB. The patients of the N group were then given nicardipine 0.016 mg.kg-1 and those of the SO4Mg group received magnesium sulphate 50 mg.kg-1. METHODS: Anaesthesia technique was identical and during normothermic CPB the flow remained constant at 2.4 L.min-1, during the 10 min following N or SO4Mg administration. The usual haemodynamic variables were monitored. RESULTS: Both N and SO4Mg decreased significantly the MAP and the SVR over the 9 min following their administration. The decrease was more marked after SO4Mg. As the flow of the pump was unchanged after their injection the decrease can be attributed to the relaxing effect of these agents on the smooth vascular muscles. CONCLUSIONS: SO4Mg permits to treat hypertensive peaks occurring during CPB as efficiently as N. Three grammes of SO4Mg have an hypotensive effect equivalent to that of 1 mg of nicardipine. However repetitive injections of SO4Mg cannot be recommended because of the risk for hypermagnesemia.