Selective inhibition of choline kinase simultaneously attenuates MAPK and PI3K/AKT signaling.

Choline is an essential anabolic substrate for the synthesis of phospholipids. Choline kinase phosphorylates choline to phosphocholine that serves as a precursor for the production of phosphatidylcholine, the major phospholipid constituent of membranes and substrate for the synthesis of lipid signaling molecules. Nuclear magnetic resonance (NMR)-based metabolomic studies of human tumors have identified a marked increase in the intracellular concentration of phosphocholine relative to normal tissues. We postulated that the observed intracellular pooling of phosphocholine may be required to sustain the production of the pleiotropic lipid second messenger, phosphatidic acid. Phosphatidic acid is generated from the cleavage of phosphatidylcholine by phospholipase D2 and is a key activator of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/AKT survival signaling pathways. In this study we show that the steady-state concentration of phosphocholine is increased by the ectopic expression of oncogenic H-Ras(V12) in immortalized human bronchial epithelial cells. We then find that small interfering RNA (siRNA) silencing of choline kinase expression in transformed HeLa cells completely abrogates the high concentration of phosphocholine, which in turn decreases phosphatidylcholine, phosphatidic acid and signaling through the MAPK and PI3K/AKT pathways. This simultaneous reduction in survival signaling markedly decreases the anchorage-independent survival of HeLa cells in soft agar and in athymic mice. Last, we confirm the relative importance of phosphatidic acid for this pro-survival effect as phosphatidic acid supplementation fully restores MAPK signaling and partially rescues HeLa cells from choline kinase inhibition. Taken together, these data indicate that the pooling of phosphocholine in cancer cells may be required to provide a ready supply of phosphatidic acid necessary for the feed-forward amplification of cancer survival signaling pathways.

Leukemoid reaction response to chemotherapy and radiotherapy in a patient with cervical carcinoma.

A white blood cell count more than 50 x 10(9)/l associated with a cause outside the bone marrow is termed a leukemoid reaction. Although it simulates leukemia, most of its causes are benign. Malignancy as a cause of a leukemoid reaction is still a medical dilemma. It is thought to be attributed to granulocyte colony-stimulating factor (G-CSF) secreted by the tumor cells. To our knowledge this is the first time a leukemoid reaction has been reported in association with cervical cancer. We even managed to monitor the leukemoid reaction response to chemotherapy and radiotherapy.

Acute profound thrombocytopenia following angioplasty: the dilemma in the management and a review of the literature.

Abciximab, heparin, and clopidogrel are often used together in the setting of coronary syndromes. These drugs are associated with thrombocytopenia and it is important to quickly discriminate the cause of this complication as it has implications for the management of thrombocytopenia and the coronary syndrome. This case highlights some of the dilemmas that may arise as no test can definitively identify the offending drug, and stopping these drugs can affect the outcome of the coronary event including stent thrombosis.

Some pyrrolidine and pyrrolizine derivatives as inhibitors of blood platelet aggregation.

N-Substituted 4-(substituted benzylidene)pyrrolidine-2,3-diones and 2-substituted benzylidene pyrrolizine-1-ones-inhibit blood platelet aggregation when tested against collagen induced aggregation in citrated human blood. The pyrrolidine derivatives showed potency closely related to the Hammett functions of the substitutents on the benzene rings. Maximal potency was observed in N-isopropyl-4-(2',6'-dichlorobenzylidene pyrrolidine-2,3-dione. The pyrrolizine derivatives were much less active.

Community based schistosomiasis control in Zimbabwe

The project was established to investigate the feasibility of a national schistosomiasis control programme in Zimbabwe based upon an intergrated approach. The project involved community self help sanitation and water programmes; health education; chemotherapy of school children with praziquantel; and focal mollusciciding. The project was carried out in two rural areas of Zimbabwe with a combined population of over 40;000 people. Madziwa (32;00 people) had all of the above interventions; and Bushu (8.000 people) had only the chemotherapy intervention. Infection with schistosomiasis was determined by the use of reagent strip examination for haematuria. This low cost method of diagnosis was found to be very appropriate and feasible for the examination of large numbers of children and the method was recommended for use in a national control programme. Pretreatment infection levels with schistosomiasis generally exceeded 60in both areas although there was considerable heterogenity in distribution