[Fanconi anemia: cellular and molecular features]. / L'anémie de Fanconi : aspects cellulaires et moléculaires.

Fanconi anemia (FA) is a recessive human cancer prone syndrome featuring bone marrow failure, developmental abnormalities and hypersensitivity to DNA crosslinking agents exposure. 11 among 12 FA gene have been isolated. The biochemical functions of the FANC proteins remain poorly understood. Anyhow, to cope with DNA crosslinks a cell needs a functional FANC pathway. Moreover, the FANC proteins appear to be involved in cell protection against oxidative damage and in the control of TNF-alpha activity. In this review, we describe the current understanding of the FANC pathway and we present how it may be integrated in the complex networks of proteins involved in maintaining the cellular homeostasis.

Genetic manipulations of adenovirus type 5 fiber resulting in liver tropism attenuation.

The development of genetically modified adenoviral vectors capable of specifically transducing a given cell population requires the addition and functional presentation of particular tropism determinants within the virus capsid, together with the abrogation of the molecular determinants that dictate their natural tropism in vivo. The human adenovirus serotype 5 (Ad5) first attaches to the cell surface following high-affinity binding of the C-terminal knob of the fiber capsid protein to the coxsackie and adenovirus receptor (CAR). Here we have assessed whether genetic shortening of the fiber shaft (virus BS1), or replacing the Ad5 fiber shaft and knob with their Ad3 counterparts (virus DB6), could cripple this interaction in vitro and in vivo. A 10-fold decrease in the binding of the modified capsids to soluble CAR was evidenced, which correlated with a similar reduction of their ability to transduce CAR-positive cells in vitro. The ability of BS1 to interact with cellular integrins was also impaired, suggesting that the penton base and the short-shafted fiber when embedded in the capsid preclude each other from efficiently interacting with their cognate cell surface receptors (CAR and integrins respectively). BS1 and DB6 intravenous injections in mice further supported a profound impairment of the ability of the capsid-modified viruses to transduce the liver as demonstrated by a 10-fold reduction of intracellular viral DNA and transgene expression. Interestingly enough, the host humoral response was also specifically weakened in BS1- and DB6-inoculated animals. Taken together, these observations indicate that (i) fiber shortening and (ii) pseudo-typing of Ad5-based vectors with the shaft and knob from non-CAR-binding serotypes constitute two promising strategies to successfully attenuate their native tropism in vitro and most importantly in vivo.

Stress in birds due to routine handling and a technique to avoid it.

The stress that might result in animals from the routine handling that most experimental studies involve, e.g., weighing, injecting, and blood sampling, is usually assumed to be minimal when the animals look quiet. However, the intensity of this stress remains largely ignored. We have developed a system that allows blood samples to be taken from freely behaving geese without entering the animal room. In these entirely undisturbed geese, the humoral indexes of stress, i.e., blood levels of catecholamines, corticosterone, and lactate, were as low or even lower than the lowest values previously reported for birds. Remarkably, the mean basal values for epinephrine and norepinephrine were 90-fold and 5-fold, respectively, below the lowest values in the literature. Stress-induced variations in pH that would have concealed detection of nutrition-induced changes in pH were eliminated. In contrast, even though the birds looked quiet during a short 5-min routine handling procedure, to which they had been accustomed for weeks, there was a dramatic increase in the level of humoral indexes of stress. These increased severalfold within only 2 min, and the return to initial values could take up to 1 h. Acid-base balance was also disrupted. Thus, in studies on animals, the absence of stress cannot be deduced from only behavioral observations. Only a system for taking blood without human interference may enable stress-free investigations.

Alfentanil, recuperaçäo mais rápida da anestesia: estudo comparativo duplo-cego com fentanil / Alfentanyl: faster recovery from anesthesia: a double blind comparison with fentanyl

O alfentanil, novo analgésico de açäo central, sintetizado a partir do fentanil e do sufentanil, apresenta como características fundamentais um início e um tempo de açäo mais rápidos que o fentanil. A necessidade de opiáceos de curta duraçäo de açäo resulta de sua crescente utilizaçäo em anestesia geral, especialmente ambulatorial. O objetivo deste estudo é testar a eficiência do alfentanil en procedimentos cirúrgicos que provocam forte estimulaçäo do sistema nervoso simpático, mas que, ao mesmo tempo, exigem uma recuperaçäo rápida da anestesia: no nosso caso, laringoscopia rígida, seguida de esofagoscopia sob intubaçäo traqueal. O alfentanil é um analgésico adequado para utilizaçäo em perfusäo contínua, o que possibilita uma reduçäo da resposta hemodinâmica à estimulaçäo cirúrgica. Esta técnica é utilizada no nosso estudo duplo-cego com o fentanil. Os seguintes parâmetros säo estudados: a) resposta cardiovascular ao estímulo cirúrgico, para a determinaçäo de doses equipotentes de alfentanil com relaçäo ao fentanil; b) tempo de recuperaçäo imediata da anestesia: a farmacocinética do alfentanil, que possui uma meia-vida de eliminaçäo mais curta que o fentanil, permitia-nos esperar uma recuperaçäo mais rápida de anestesia. Nossos resultados indicam que a relaçäo de dose entre fentanil e alfentanil (F;AF) de 1: 5, utilizada por diversos autores em cirugia de curta duraçäo, é insuficiente para a obtençäo de uma estabilidade cardiovascular satisfatória neste tipo de cirugia. Na realidade, uma relaçäo de dose F: AF entre 1:8 e 1:10 deve ser empregada. Quanto à recuperaçäo anestésica, quando doses equipotentes dos dois analgésicos säo utilizadas nas mesmas condiçöes de administraçäo, näo existe nenhuma diferença significativa em relaçäo ao tempo de recuperaçäo imediata da anestesia...

[Captopril potentiation of the hypotension induced by halothane]. / Potentialisation par le captopril de l'hypotension induite par l'halothane.

In a double-blind study, twenty-four ASA 1 and II patients scheduled for otosclerosis surgery were randomized in two groups according to the premedication given orally 1 h before anaesthesia: placebo (group P; n = 12) or 25 mg captopril (group C; n = 12). Anaesthesia was induced with thiopentone, fentanyl and vecuronium and was maintained, after oral tracheal intubation, with N2O/O2 (50/50); 5 min after intubation, the inspired halothane concentration (FIH) was set at 1.8-2% in order to obtain a mean arterial pressure (Pa) of 45-55 mmHg; thereafter, FIH was increased or decreased (+/- 0.5% every 3 min) in order to maintain this Pa value. Ventilation was controlled in order to assure normocapnia (35-40 mmHg). Inspired and expired (FEH) halothane concentrations were monitored by an halothane analyser. The plasma renin (ARP) and conversion enzyme activities (AEC) were measured before anaesthesia (ARP1, AEC1), 5 min (ARP2) and 55 min (ARP3, AEC2) after the start of anaesthesia. In group C, AEC1 and AEC2 were reduced by half, confirming the efficiency of captopril in inhibiting the conversion enzyme. ARP1 and ARP2 were increased in group C (5.42 +/- 4.2 and 9.92 +/- 7.35 micrograms.l-1.h-1. ARP3 increased in both groups (20.75 +/- 8.42 micrograms.l-1.h-1 in group C, and 24.60 +/- 15.40 in group P). Pa decreased to 55 mmHg more rapidly in group C (9 min in group C; 18 min in group P; p less than 0.05) and FEH could be reduced by a third (1.38 +/- 0.29% in group P; 0.90 +/- 0.17% in group C; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Estudo comparativo entre atracúrio e vecurônio em dose única / Comparative study between atracurium and vecuronium using single dose

O estabelecimento do bloqueio neuromuscular do músculo adutor do polegar foi comparado após injeçäo única de atracúrio na dose de 0,6 mg kg e vecurônio na dose de 0,1 mg.kg em 23 pacientes ASA I e II sob anestesia geral. Foram avaliados os parâmetros de tempo desde o momento da injeçäo até a recuperaçäo da seqüência de quatro estímulos a 75% (Figura 1). Houve um aumento estatisticamente significativo de cerca de 10 min na duraçäo de açäo do atracúrio (p <0,05) em relaçäo ao vecurônio, assim como de outros parâmetros de tempo (Quadro 2). Näo ocorreram alteraçöes cardiocirculatórias (FC e PAM) nos 5 min subseqüentes às injeçöes de atracúrio e vecurônio. Foi observado um caso de eritema sobre o trajeto venoso no grupo que recebeu atracúrio. O atracúrio e o vecurônio säo bloqueadores neuromusculares indicados para cirurgias com duraçäo igual ou menor que 1 h

[Clinical use in adults of 2 new muscle relaxants: atracurium and vecuronium]. / Utilisation clinique chez l'adulte de deux nouveaux myorelaxants: l'atracurium et le vécuronium.

115 general and urologic surgery adult patients, ASA class I-II, were divided in four groups according to initial bolus and relaxant used: group A atracurium 0.6 mg X kg-1, group B 0.5 mg X kg-1, group C vecuronium 0.1 mg X kg-1 and group D pancuronium 0.1 mg X kg-1. When the single twitch recovered to 25% of control height (T25), subgroups were individualized depending on whether repeat doses of 1/3 of initial bolus were given or not, and whether reversal was spontaneous or obtained by a standard dose of neostigmine 2.5 mg and atropine 1.25 mg. By ulnar nerve stimulation at the wrist, the force of thumb adduction was recorded on a polygraph; single twitch (tw), train of four (tof) and ratio tof 4/1 (Rtof) were measured. Anaesthesia was induced with thiopentone and fentanyl without premedication and maintained with fentanyl and N2O in oxygen; the trachea was intubated once the block was at its maximum. The onset time of maximal block was 5 min for groups A, B and C, and 7.9 min for group D. T25 was 39.9 +/- 8.5 min for group A, 34.4 +/- 9.7 min for group B, 28.9 +/- 9.9 min for group C and 70.7 +/- 25.9 min for group D. A Rtof equal to 75% was achieved in less than 65 min with atracurium and vecuronium, but much later with pancuronium. Reversal at T25 was efficient, but not really required, for atracurium and vecuronium, but necessary and useful for pancuronium.(ABSTRACT TRUNCATED AT 250 WORDS)