Delayed hydrocephalus after excision of a colloid cyst: a case report.

BACKGROUND: In this case report we describe an unusual case of a patient who underwent resection of a colloid cyst and then presented 6 weeks postoperatively with obstructive hydrocephalus. There appear to be no prior reports of such a delayed complication after colloid cyst resection. CASE PRESENTATION: A 50-year-old Caucasian woman underwent resection of a colloid cyst with an uncomplicated perioperative course. Postoperative imaging demonstrated complete resection of the cyst. She was discharged home on postoperative day 4 but presented 6 weeks later with symptoms of obstructive hydrocephalus resulting in poor neurologic outcome and ultimately death. CONCLUSION: Patients presenting with symptoms of hydrocephalus after resection of a colloid cyst should be followed closely, and timely placement of an external ventricular drain may be critical.

Specific inhibition of the plasmodial surface anion channel by dantrolene.

The plasmodial surface anion channel (PSAC), induced on human erythrocytes by the malaria parasite Plasmodium falciparum, is an important target for antimalarial drug development because it may contribute to parasite nutrient acquisition. However, known antagonists of this channel are quite nonspecific, inhibiting many other channels and carriers. This lack of specificity not only complicates drug development but also raises doubts about the exact role of PSAC in the well-known parasite-induced permeability changes. We recently identified a family of new PSAC antagonists structurally related to dantrolene, an antagonist of muscle Ca++ release channels. Here, we explored the mechanism of dantrolene's actions on parasite-induced permeability changes. We found that dantrolene inhibits the increased permeabilities of sorbitol, two amino acids, an organic cation, and hypoxanthine, suggesting a common pathway shared by these diverse solutes. It also produced parallel reductions in PSAC single-channel and whole-cell Cl- currents. In contrast to its effect on parasite-induced permeabilities, dantrolene had no measurable effect on five other classes of anion channels, allaying concerns of poor specificity inherent to other known antagonists. Our studies indicate that dantrolene binds PSAC at an extracellular site distinct from the pore, where it inhibits the conformational changes required for channel gating. Its affinity for this site depends on ionic strength, implicating electrostatic interactions in dantrolene binding. In addition to the potential therapeutic applications of its derivatives, dantrolene's specificity and its defined mechanism of action on PSAC make it a useful tool for transport studies of infected erythrocytes.

Plasmodial surface anion channel-independent phloridzin resistance in Plasmodium falciparum.

The plasmodial surface anion channel (PSAC) is an unusual ion channel induced on the human red blood cell membrane after infection with the malaria parasite, Plasmodium falciparum. Because PSAC is permeant to small metabolic precursors essential for parasite growth and is present on red blood cells infected with geographically divergent parasite isolates, it may be an ideal target for future antimalarial development. Here, we used chemically induced mutagenesis and known PSAC antagonists that inhibit in vitro parasite growth to examine whether resistance mutations in PSAC can be readily induced. Stable mutants resistant to phloridzin were generated and selected within 3 weeks after treatment with 1-methyl-3-nitro-1-nitrosoguanidine. These mutants were evaluated with osmotic lysis and electrophysiological transport assays, which indicate that PSAC inhibition by phloridzin is complex with at least two different modes of inhibition. Mutants resistant to the growth inhibitory effects of phloridzin expressed PSAC activity indistinguishable from that on sensitive parasites, indicating selection of resistance via mutations in one or more other parasite targets. Failure to induce mutations in PSAC activity is consistent with a highly constrained channel protein less susceptible to resistance mutations; whether this protein is parasite- or host-encoded remains to be determined.

Malaria parasites are rapidly killed by dantrolene derivatives specific for the plasmodial surface anion channel.

Dantrolene was recently identified as a novel inhibitor of the plasmodial surface anion channel (PSAC), an unusual ion channel on Plasmodium falciparum-infected human red blood cells. Because dantrolene is used clinically, has a high therapeutic index, and has desirable chemical synthetic properties, it may be a lead compound for antimalarial development. However, dantrolene derivatives would need to preferentially interact with PSAC over the sarcoplasmic reticulum (SR) Ca2+ release channel to avoid unwanted side effects from antimalarial therapy. Furthermore, dantrolene's modest affinity for PSAC (K(m) of 1.2 microM) requires improvement. In this study, we tested 164 derivatives of dantrolene to examine whether these hurdles can be surmounted. A simple screen for PSAC block defined the minimal scaffold needed and identified compounds with > or =5-fold higher affinity. Single-channel patch-clamp recordings on infected human red blood cells with two derivatives also revealed increased blocking affinity that resulted from slower unbinding from a site on the extracellular face of PSAC. We tested these derivatives in a frog skeletal muscle contractility assay and found that, in contrast to dantrolene, they had little or no effect on SR Ca2+ release. Finally, these blockers kill in vitro parasite cultures at lower concentrations than dantrolene, consistent with an essential role for PSAC. Because, as a class, these derivatives fulfil the requirements for drug leads and can be studied with simple screening technology, more extensive medicinal chemistry is warranted to explore antimalarial development.