[Colchicine intoxication in four elderly patients: how to prevent it?]. / Risque d'intoxication à la colchicine chez les personnes âgées et moyens de prévention: à propos de quatre observations.

INTRODUCTION: In France, unlike other countries, the use of colchicine is preferred to other anti-inflammatory drugs for the treatment of gout. CASE REPORTS: We report a case series of four elderly patients (range from 72 to 83 years of age) who presented with colchicine intoxication, all notified to the Basse-Normandie pharmacovigilance centre in 2007. For each patient, one or more risk factors were identified: renal failure, high initial dosage, absence of laboratory monitoring. CONCLUSION: It would be useful to establish specific guidelines for colchicine use in the elderly population.

Mitomycin C and Vinorelbine for second-line chemotherapy in NSCLC--a phase II trial.

Single-agent therapy with Docetaxel or Pemetrexed is the current therapy of choice for second-line treatment in advanced non-small-cell lung cancer (NSCLC). The role of older agents was underattended over the last years. This study presents the combination of Mitomycin C and Vinorelbine in pretreated patients. Forty-two patients (stage IIIB and IV, pretreated with platinum-based chemotherapy) received 8 mg m(-2) Mitomycin C on day 1 and 25 mg m(-2) Vinorelbine on days 1 and 8 of a 28-day cycle. End points were objective tumour response, survival, and toxicity. Additionally, quality of life (QoL) was assessed. Five patients (11.9 %) achieved partial responses and 13 patients (31.9%) stable disease. Progression-free survival was 16 weeks. The median overall survival was 8.5 month. Eleven patients (26.2 %) suffered from grade 3 or 4 neutropenia and four patients (9.52%) from grade 3 or 4 anaemia. Evaluation of QoL showed that some items ameliorated during therapy. The therapeutic concept including Mitomycin C and Vinorelbine offers an efficacious and well-tolerated regimen, with relatively low toxicity. Objective response and survival data correlate with other second-line studies using different medication. As costs of Mitomycin C and Vinorelbine are lower compared with current drugs of choice, this regimen is likely to be cost-saving.

Identification and characterization of a divalent metal ion-dependent cleavage site in the hammerhead ribozyme.

We describe a new RNA cleavage motif, found in the hammerhead ribozyme. Cleavage occurs between nucleotides G8 and A9, yielding a free 5'-hydroxyl group and a 2',3'-cyclic phosphate. This cleavage is dependent upon divalent metal ions and is the first evidence for a metalloribozyme known to show preference for Zn(2+). Cleavage is also observed in the presence of Ni(2+), Co(2+), Mn(2+), Cd(2+), and Pb(2+), while negligible cleavage was detected in the presence of the alkaline-earth metal ions Mg(2+), Ca(2+), Sr(2+), and Ba(2+). A linear relationship between the logarithm of the rate and pH was observed for the Zn(2+)-dependent cleavage, which is indicative of proton loss in the cleavage mechanism, either prior to or in the rate-determining step. We postulate that a zinc hydroxide complex, bound to the known A9/G10.1 metal ion binding site, abstracts the proton from the 2'-hydroxyl group of G8, which attacks the A9 phosphate and initiates cleavage. This hypothesis is supported by a previously reported crystal structure [Murray, J. B., Terwey, D. P., Maloney, L., Karpeisky, A., Usman, N., Beigelman, L., and Scott, W. G. (1998) Cell 92, 665-673], which shows the conformation required for RNA cleavage and proximity of the 2'-hydroxyl group to the metal ion complex.

4-amino-1H-benzo[g]quinazoline-2-one: a fluorescent analog of cytosine to probe protonation sites in triplex forming oligonucleotides.

We developed a new fluorescent analog of cytosine, the 4-amino-1H-benzo[g]quinazoline-2-one, which constitute a probe sensitive to pH. The 2'-O-Me ribonucleoside derivative of this heterocycle was synthesized and exhibited a fluorescence emission centered at 456 nm, characterized by four major excitation maxima (250, 300, 320 and 370 nm) and a fluorescence quantum yield of Phi = 0.62 at pH 7.1. The fluorescence emission maximum shifted from 456 to 492 nm when pH was decreased from 7.1 to 2.1. The pK(a) (4) was close to that of cytosine (4.17). When introduced in triplex forming oligonucleotides this new nucleoside can be used to reveal the protonation state of triplets in triple-stranded structures. Complex formation was detected by a significant quenching of fluorescence emission (approximately 88%) and the N-3 protonation of the quinazoline ring by a shift of the emission maximum from 485 to 465 nm. Using this probe we unambiguously showed that triplex formation of the pyrimidine motif does not require the protonation of all 4-amino-2-one pyrimidine rings.

Benzoquinazoline derivatives as substitutes for thymine in nucleic acid complexes. Use of fluorescence emission of benzo[g]quinazoline-2,4-(1H,3H)-dione in probing duplex and triplex formation.

Triple helix formation obeys structural features that do not allow accommodation of every double-stranded sequence; it requires the occurrence of homopurine stretches. A further constraint comes from the weak energy of interaction between the third strand and the double-stranded target. In an attempt to design bases leading to increased stability of triplexes, we explored the ability of modified bases with an extended aromatic domain to increase third strand binding through stacking interactions. We report here the use of benzo[g]- and benzo[f]quinazoline-2,4-dione-(1H,3H)-dione as substitutes for thymine in the canonical TAT triplet. The synthesis and characterization of the beta nucleoside derivatives of benzoquinazolines are described. Triplex-forming oligonucleotides containing these modified bases have been prepared, and their ability to form triplexes has been evaluated by UV absorption-monitored thermal denaturation measurements. Benzo[g]quinazoline and benzo[f]quinazoline formed triple-stranded structures with slightly decreased stabilities. In addition, benzo[g]quinazoline revealed strong fluorescence emission properties which can be used to monitor selectively the formation of triple-helical structures. Annealing of benzo[g]quinazoline to complementary strands did not produce any fluorescence modification. But when it was introduced into the Hoogsteen strand of PyPuPy complexes, the fluorescence intensity was reduced and the emission maximum was shifted to short wavelengths.

A fluorescent base analog for probing triple helix formation.

Benzo[g]quinazoline-2,4-(1H,3H)-dione (BgQ), a fluorescent thymine analog, was incorporated into an oligopyrimidine (III) able to give rise to a triple-stranded structure by clamping a purine 11-mer (I). The formation of the I-III complex resulted in both a shift of the fluorescence emission maximum and a decreased fluorescence intensity. No such variations were observed on the formation of a Watson-Crick duplex between I and the complementary strand in which a T residue was substituted for BgQ. Therefore, the fluorescence emission of BgQ can be used to selectively monitor the formation of triple helices.

[Neonatal hypoxemia due to misaligned pulmonary vessels with alveolar capillary dysplasia]. / Hypoxémie néonatale par mésalignement des vaisseaux pulmonaires avec dysplasie alvéolocapillaire.

BACKGROUND: Refractory hypoxemia in the newborn requires a precise diagnostic investigation for optimal and fast management. CASE REPORT: A full term newborn presented with refractory hypoxemia associated with radiologically clear lung fields and extrapulmonary shunt. Echocardiography ruled out a cardiac malformation. The persistence of hypoxemia despite treatment of the extrapulmonary shunt and the absence of parenchymatous pulmonary disease led to suspect misaligned lung vessels with alveolar capillary dysplasia. This diagnosis was confirmed by post mortem microscopic examination of the lung. CONCLUSION: The diagnosis of misaligned lung vessels with alveolar capillary dysplasia can be suspected on clinical features. The disposition of pulmonary veins must be checked to recognize this disease in case of neonatal death with pulmonary hypertension.

[Effects of PGE1 in neonatal aortic coarctation]. / Effets de la PGE1 dans les coarctations aortiques néonatales.

In order to estimate the efficacity of prostaglandine E1 (PGE1) to dilate the obstruction in coarctation of the aorta (CoAo), we studied 16 full term neonates with heart failure. Over the 16 neonates, there was 5 with isolated CoAo and 11 with an intracardiac shunt. Over the 11 neonates, 7 had pulmonary hypertension. PGE1, at a dose of 0.05 microgram/kg/min associated to the classical treatment of heart failure were given on the 6 day of life. Effects of PGE1 were evaluated on clinical basis (presence of femoral pulse, blood pressure), echocardiographical basis (ductus arteriosus and aortic isthmus diameter) and morphological basis. In 15 neonates, the ductus arteriosus was open, in all cases CoAo diameter was the same. In 7 neonates with pulmonary hypertension, femoral pulse appeared. In conclusion, PGE1 increases post ductal perfusion by a right to left shunt through the ductus arteriosus, only in cases where pulmonary hypertension is present. No direct action on the aortic isthmus was observed.

[Conventional mechanical ventilation in the premature infant and the full-term newborn]. / Ventilation mécanique conventionnelle du prématuré et du nouveau-né à terme.

Convention mechanical ventilation (MV) is installed after nasotracheal intubation by means of a volume generator or pressure reducer. Careful monitoring of the child's respiratory status is indispensable; sedatives and/or muscle relaxants may facilitate MV. The method is indicated in case of oxygen-resistant hypoxaemia or of global alveolar hypoventilation, or to cope with a severe general or neurological stress. While MV is being applied, there main and dangerous complications may occur: respiratory obstruction, pneumothorax and lower respiratory tract superinfection. Weaning must be progressive. As regards the practical handing of MV, the best way to adjust the respirator constants is to evaluate the time constant according to the nature of the lung disease and to the stage it has reached in its course. In the most severe situations, and particularly in case of hyaline membrane disease, one must try to obtain the best possible adequation between severity of the disease and ventilatory stress, without preestablished arbitrary limits.