Cerebral cavernous malformations (CCMs) are hamartomatous vascular malformations characterized by abnormally enlarged capillary cavities without intervening brain parenchyma. They cause seizures and cerebral hemorrhages, which can result in focal neurological deficits. Three CCM loci have been mapped, and loss-of-function mutations were identified in the KRIT1 (CCM1) and MGC4607 (CCM2) genes. We report herein the identification of PDCD10 (programmed cell death 10) as the CCM3 gene. The CCM3 locus has been previously mapped to 3q26-27 within a 22-cM interval that is bracketed by D3S1763 and D3S1262. We hypothesized that genomic deletions might occur at the CCM3 locus, as reported previously to occur at the CCM2 locus. Through high-density microsatellite genotyping of 20 families, we identified, in one family, null alleles that resulted from a deletion within a 4-Mb interval flanked by markers D3S3668 and D3S1614. This de novo deletion encompassed D3S1763, which strongly suggests that the CCM3 gene lies within a 970-kb region bracketed by D3S1763 and D3S1614. Six additional distinct deleterious mutations within PDCD10, one of the five known genes mapped within this interval, were identified in seven families. Three of these mutations were nonsense mutations, and two led to an aberrant splicing of exon 9, with a frameshift and a longer open reading frame within exon 10. The last of the six mutations led to an aberrant splicing of exon 5, without frameshift. Three of these mutations occurred de novo. All of them cosegregated with the disease in the families and were not observed in 200 control chromosomes. PDCD10, also called "TFAR15," had been initially identified through a screening for genes differentially expressed during the induction of apoptosis in the TF-1 premyeloid cell line. It is highly conserved in both vertebrates and invertebrates. Its implication in cerebral cavernous malformations strongly suggests that it is a new player in vascular morphogenesis and/or remodeling.

Maurotoxin is a toxin isolated from the venom of the Tunisian chactoid scorpion Scorpio maurus. It is a 34-amino-acid peptide cross-linked by four disulfide bridges. Maurotoxin competes with radiolabeled apamin and kaliotoxin for binding to rat-brain synaptosomes. Due to its very low concentration in venom (0.6% of the proteins), maurotoxin was chemically synthesized by means of an optimized solid-phase technique. The synthetic maurotoxin was characterized. It was lethal to mice following intracerebroventricular injection (LD,,, 80 ng/mouse). The synthetic maurotoxin competed with '*'I-apamin and 'Z51-kaliotoxin for binding to rat-brain synaptosomes with half-maximal effects at concentrations of 5 nM and 0.2 nM, respectively. Synthetic maurotoxin was tested on K' channels and was found to block the Kvl.1, Kv1.2, and Kv1.3 currents with half-maximal blockage (I&) at 37, 0.8 and 150 nM, respectively. Thus, maurotoxin is a scorpion toxin with four disulfide bridges that acts on K' channels. The half-cystine pairings of synthetic maurotoxin were identified by enzymatic cleavage. The pairings were Cys3 -Cys24, Cys9-Cys29, Cysl3-Cysl9 and Cys31 -Cys34. This disulfide organization is unique among known scorpion toxins. The physicochemical and pharmacological properties of synthetic maurotoxin were indistinguishable from those of natural maurotoxin, which suggests that natural maurotoxin adopts the same half-cystine pairing pattern. The conformation of synthetic maurotoxin was investigated by means of circular dichroism spectroscopy and molecular modeling. In spite of its unusual half-cystine pairings, the synthetic-maurotoxin conformation appears to be similar to that of other short scorpion toxins.Keywords: maurotoxin; scorpion toxin; half-cystine pairing ; apamin-sensitive K' channels ; voltage-gated K' channels.Because polypeptide animal toxins interact with ion channels and modulate their activities [ 1 -31, these toxins are useful pharmacological probes to investigate ion-specific channel proteins and their function. In recent years, toxins acting on various K+ channels have been isolated from diverse scorpion venoms [4]. Maurotoxin has recently been purified from the venom of the chactoid scorpion Scorpio maurus, and characterized (Kharrat, R., Mansuelle, P., Sampieri, F., Crest, M., Martin-Eauclaire, M. F., Rochat, H. and El Ayeb, M., unpublished results). Maurotoxin is a basic toxin of 34 amino acid residues cross-linked by four disulfide bridges. Maurotoxin was found to compete with radiolabeled apamin and kaliotoxin for binding to rat-brain synaptosomes (Kharrat, R., Mansuelle, P., Sampieri, F., Crest, M., Martin-Eauclaire, M. F., Rochat, H. and El Ayeb, M., unpublished results). Thus, it is a scorpion toxin with four disulfide bridges that acts on K' channels. Due to its sequence, maurotoxin does not belong to any of the four groups of K+-channel Maurotoxin is only 0.6% of the total proteins in a crude venom, which is not readily available. Thus, we performed chemical solid-phase synthesis of this toxin to e...

BgK is a peptide from the sea anemone Bunodosoma granulifera, which blocks Kv1.1, Kv1.2, and Kv1.3 potassium channels. Using 25 analogs substituted at a single position by an alanine residue, we performed the complete mapping of the BgK binding sites for the three Kv1 channels. These binding sites included three common residues (Ser-23, Lys-25, and Tyr-26) and a variable set of additional residues depending on the particular channel. Shortening the side chain of Lys-25 by taking out the four methylene groups dramatically decreased the BgK affinity to all Kv1 channels tested. However, the analog K25Orn displayed increased potency on Kv1.2, which makes this peptide a selective blocker for Kv1.2 (K D 50-and 300-fold lower than for Kv1.1 and Kv1.3, respectively). BgK analogs with enhanced selectivity could also be made by substituting residues that are differentially involved in the binding to some of the three Kv1 channels. For example, the analog F6A was found to be >500-fold more potent for Kv1.1 than for Kv1.2 and Kv1.3. These results provide new information about the mechanisms by which a channel blocker distinguishes individual channels among closely related isoforms and give clues for designing analogs with enhanced selectivity.

Devaux, Jerome, Maurice Gola, Guy Jacquet, and Marcel Crest. Effects of K ϩ channel blockers on developing rat myelinated CNS axons: identification of four types of K ϩ channels. J Neurophysiol 87: 1376 -1385, 2002; 10.1152/jn.00646.2001. Four blockers of voltagegated potassium channels (Kv channels) were tested on the compound action potentials (CAPs) of rat optic nerves in an attempt to determine the regulation of Kv channel expression during the process of myelination. Before myelination occurred, 4-aminopyridine (4-AP) increased the amplitude, duration, and refractory period of the CAPs. On the basis of their pharmacological sensitivity, 4-AP-sensitive channels were divided in two groups, the one sensitive to kaliotoxin (KTX), dendrotoxin-I (DTX-I), and 4-AP, and the other sensitive only to 4-AP. In addition, tetraethylammonium chloride (TEA) applied alone broadened the CAPs. At the onset of myelination, DTX-I induced a more pronounced effect than KTX; this indicates that a fourth group of channels sensitive to 4-AP and DTX-I but insensitive to KTX had developed. The effects of KTX and DTX-I gradually disappeared during the period of myelination. Electron microscope findings showed that the disappearance of these effects was correlated with the ongoing process of myelination. This was confirmed by the fact that DTX-I and KTX enlarged the CAPs of demyelinated adult optic nerves. These results show that KTX-and DTX-sensitive channels are sequestrated in paranodal regions. During the process of myelination, KTX had less pronounced effects than DTX-I on demyelinated nerves, which suggests that the density of the KTX-sensitive channels decreased during this process. By contrast, 4-AP increased the amplitude, duration, and refractory period of the CAPs at all the ages tested and to a greater extent than KTX and DTX-I. The effects of TEA alone also gradually disappeared during this period. However, effects of TEA on CAPs were observed when this substance was applied after 4-AP to the adult optic nerve; this shows that TEAsensitive channels are not masked by the myelin sheath. In conclusion, the process of myelination seems to play an important part in the regulation and setting of Kv channels in optic nerve axons. I N T R O D U C T I O NPeripheral myelinated fibers have been found to contain three main voltage-gated potassium channels (Kv channels): a Kv channel sensitive to tetraethyl-ammonium chloride (TEA) that is present throughout the axons, and two channels sensitive to 4-aminopyridine (4-AP), that are distinguishable by their differential sensitivity to dendrotoxin and are located in internodal and paranodal regions (for review, see Vogel and Schwarz 1995). Although the molecular composition of channels sensitive to TEA or to 4-AP has not yet been determined, the channels sensitive to DTX are assumed to result from the association of the Kv1.1 and Kv1.2 ␣ subunits (Reid et al. 1999; Stuhmer et al. 1989). These subunits have been detected in juxtaparanodal regions of peripheral myelinated fibers (Arroyo et ...

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Survival rates for newly diagnosed patients were better than those reported in previous phase III trials. The combination of Gliadel and radiochemotherapy with TMZ was well tolerated and appeared to increase survival without increasing AEs.

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Two cases of sciatica secondary to nerve root compression by a "synovial cyst" of a zygapophyseal joint are described. In light of these 2 cases and on reviewing the literature, it appears that zygapophyseal joint osteoarthritis with degenerative (or articular) spondylolisthesis can be a predisposing factor to the formation of such synovial expansions and, consequently, the cause of nerve root compression. The coexistence of a lumbar degenerative spondylolisthesis with a radicular syndrome should therefore encourage early investigation by computed tomography scan, so that conservative treatment would not be unnecessarily prolonged.The most common cause of sciatic pain is nerve root compression secondary to disc herniation, but nerve root compression can be caused by other structures, and computed tomography (CT) scanning may reveal, and can often differentiate, them. It appears that capsulosynovial expansions of the zygapophyseal joints occur with relative frequency. Most often, the expansions are related to zygapophyseal joint osteoarthritis (OA), which in some cases, is also responsible for an anterior displacement of the upper vertebrae (degenerative spondylolisthesis). We describe here 2 typical cases, with documentation by CT scan, neurosurgery, and histologic examination.CASE REPORTS Patient 1. The patient, a 77-year-old female homemaker, was hospitalized because of a 1-month history of left-sided lumbosciatic pain that had no precise radicular radiation. The pain was not aggravated by coughing or defecating and was not accompanied by paresthesias. There was no history of preceding tpauma. Since 1974, this patient had been treated with levodopa because of Parkinson's disease. In 1982, she experienced a transitory cerebrovascular accident.Physical examination findings indicated that the patient's general state of health was good. She presented with an acute vertebral syndrome, mostly on the left side. Pain limited dorsolumbar mobility in all 4 directions, particularly in extension, which was almost impossible. Results of the neurologic examination were entirely normal, including the absence of Las8gue's sign. The laboratory test results were normal.Standard films of the lumbar spine showed a first-degree degenerative spondylolisthesis of L4 on L5, in connection with a severe L4-L5 zygapophyseal joint OA. In addition, there was advanced disc degeneration of L5-S 1 , showing a "vacuum phenomenon" (Figure 1).