ATM mediates constitutive NF-kappaB activation in high-risk myelodysplastic syndrome and acute myeloid leukemia.

The anti-apoptotic transcription factor nuclear factor-kappaB (NF-kappaB) is constitutively activated in CD34(+) myeloblasts from high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) patients. Inhibition of NF-kappaB by suppressing the canonical NF-kappaB activation pathway, for instance by knockdown of the three subunits of the inhibitor of NF-kappaB (I kappaB) kinase (IKK) complex (IKK1, IKK2 and NEMO) triggers apoptosis in such cells. Here, we show that an MDS/AML model cell line exhibits a constitutive interaction, within the nucleus, of activated, S1981-phosphorylated ataxia telangiectasia mutated (ATM) with NEMO. Inhibition of ATM with two distinct pharmacological inhibitors suppressed the activating autophosphorylation of ATM, blocked the interaction of ATM and NEMO, delocalized NEMO as well as another putative NF-kappaB activator, PIDD, from the nucleus, abolished the activating phosphorylation of the catalytic proteins of the IKK complex (IKK1/2 on serines 176/180), enhanced the expression of I kappaB alpha and caused the relocalization of NF-kappaB from the nucleus to the cytoplasm, followed by apoptosis. Knockdown of ATM with small-interfering RNAs had a similar effect that could not be enhanced by knockdown of NEMO, PIDD and the p65 NF-kappaB subunit, suggesting that an ATM inhibition/depletion truly induced apoptosis through inhibition of the NF-kappaB system. Pharmacological inhibition of ATM also induced the nucleocytoplasmic relocalization of p65 in malignant myeloblasts purified from patients with high-risk MDS or AML, correlating with the induction of apoptosis. Altogether, these results support the contention that constitutively active ATM accounts for the activation of NF-kappaB in high-risk MDS and AML.

[Truncal anesthesia of the foot at the level of the ankle: an additional reference mark for the approach to the posterior tibial nerve]. / Anesthésie tronculaire du pied au niveau de la cheville: un repère supplémentaire pour l'abord du nerf tibial postérieur.

Nerve trunk blocks at the ankle could be a most interesting technique of regional anaesthesia. Unfortunately the posterior tibial nerve is difficult to locate with the usual recommended anatomical landmarks (the tibialis posterior artery). The use of the flexor hallucis longus tendon as an additional landmark has been tested in 71 patients scheduled for surgery on the foot (emergency trauma surgery, amputations, ingrowing toe-nails, removal of bedsores, verrucas). Seventy per cent were males. Their age ranged from 3 to 92 years (average 62 years), with 26% being less than 50 years old, and 43% more than 70. A block of the subcutaneous nerves, at the level of the ankle, (medial and lateral sural cutaneous, superficial peroneal, saphenous, medial calcaneal nerves) was followed by a block of the posterior tibial and deep peroneal nerves (sub-aponeurotic nerves). The total number of nerves blocked depended on the use of an ankle tourniquet, and the area involved by surgery. For each nerve blocked, 3 to 6 ml of a mixture containing equal parts of 2% lignocaine and 0.5% bupivacaine were used. The maximum doses injected were 4 mg.kg-1 lidocaine and 1 mg.kg-1 bupivacaine. Anaesthesia was obtained in 10 +/- 3 min, lasting from 180 to 240 min. There were 88.7% excellent results (n = 63), with 7% fair (n = 5) and 4.2% bad (n = 3) results. Failure concerned 5 cases of tibial nerve block, often due to landmark difficulties (great toe previously amputated, significant ankle oedema, lack of operator experience) and, in 3 cases, forgetting to block a nerve involved.(ABSTRACT TRUNCATED AT 250 WORDS)

East Pacific Rise Near 13{degrees}N: Geology of New Hydrothermal Fields.

Abundant massive sulfide deposits are present at the crest of the East Pacific Rise near 13 degrees North, where the opening rate is about 12 centimeters per year. Large manganese and helium-3 anomalies in seawater samples, evidence of intense present-day activity of hydrothermal springs, indicate that sulfides are still being produced along this segment of the rise. Massive sulfides also occur on adjacent off-axis seamounts.