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Glibenclamide is well known to interact with the sulphonylurea receptor (SUR) and has been shown more recently to inhibit the cystic fibrosis transmembrane conductance regulator protein (CFTR), both proteins that are members of the ABC [adenosine 5'-triphosphate (ATP)-binding cassette] transporters. The effect of glibenclamide and two synthetic sulphonylcyanoguanidine derivatives (dubbed BM-208 and BM-223) was examined on P-glycoprotein, the major ABC transporter responsible for multidrug resistance (MDR) in cancer cells. To this end, we employed different cell lines that do or do not express P-glycoprotein, as confirmed by Western blotting: first, a tumour cell line (VBL600) selected from a human T-cell line (CEM) derived from an acute leukaemia; second, an epithelial cell line derived from a rat colonic adenocarcinoma (CC531(mdr+)) and finally, a non tumour epithelial cell line derived from the proximal tubule of the opossum kidney (OK). Glibenclamide and the two related derivatives inhibited P-glycoprotein because firstly, they acutely increased [3H]colchicine accumulation in P-glycoprotein-expressing cell lines only; secondly BM-223 reversed the MDR phenomenon, quite similarly to verapamil, by enhancing the cytotoxicity of colchicine, taxol and vinblastine and thirdly, BM-208 and BM-223 blocked the photoaffinity-labelling of P-glycoprotein by [3H]azidopine. Furthermore, glibenclamide is itself a substrate for P-glycoprotein, since the cellular accumulation of [3H]glibenclamide was low and substantially increased by addition of P-glycoprotein substrates (e. g., vinblastine and cyclosporine) only in the P-glycoprotein-expressing cell lines. We conclude that glibenclamide and two sulphonylcyanoguanidine derivatives inhibit P-glycoprotein and that sulphonylurea drugs would appear to be general inhibitors of ABC transporters, suggesting an interaction with some conserved motif.

The clinical features and preoperative and postoperative electrodiagnostic studies were reviewed in two professional pitchers with a suprascapular neuropathy. These studies demonstrate that denervation of the infraspinatus and/or supraspinatus muscle is not always due to entrapment of the nerve at the suprascapular or spinoglenoid notches, as is often proposed. Similar studies in healthy pitchers during spring training and again at midseason demonstrate that slowing of suprascapular nerve conduction is detectable in some cases as the season progresses. Sagittal sections of a cadaver with the arm fixed in the acceleration phase of the pitching motion demonstrate five possible sites of trauma to the suprascapular nerve. Mechanisms proposed to explain these progressive, but potentially reversible, changes include consideration of biomechanical factors as well as anatomical features. An alternative hypothesis to nerve trauma that explains this symptom complex is intimal damage to the axillary or suprascapular artery and subsequent production of microemboli which become trapped in the suprascapular nerve vasa nervorum.

We investigated the kinetics of tissue-specific mRNA expression and systemic production of tumor necrosis factor alpha (TNF-␣) and the kinetics of splenic expression of mRNAs of gamma interferon (IFN-␥) and interleukin-4 (IL-4), cytokines that may regulate TNF-␣ production, during the early phase of blood-stage infection with Plasmodium chabaudi AS. Northern blot analysis revealed that resistant C57BL/6 mice, which clear the infection by 4 weeks, had higher levels of TNF-␣ mRNA in the spleen and liver early during infection than did susceptible A/J mice, which succumb to the disease 10 days after initiation of infection. Treatment of resistant mice with a polyclonal anti-TNF-␣ antibody confirmed the protective role of TNF-␣ early during the course of infection. Furthermore, resistant C57BL/6 mice also expressed high levels of mRNA of IFN-␥ (a Th1 marker) and low levels of mRNA of IL-4 (a Th2 marker) in the spleen, whereas susceptible A/J mice had low levels of IFN-␥ mRNA but high levels of IL-4 mRNA in the spleen early during infection. On the other hand, susceptible A/J mice expressed high levels of TNF-␣ mRNA in the liver and had high levels of TNF-␣ protein in serum, as measured by enzyme-linked immunosorbent assay, later during infection just before death occurred. These results demonstrate that a Th1-associated increase in TNF-␣ mRNA expression in the spleen early during infection correlates with resistance to P. chabaudi AS, whereas increased TNF-␣ mRNA levels in the liver and excessive levels of the TNF-␣ protein in serum later during infection correlate with susceptibility. Thus, the role of TNF-␣ during malaria appears to depend on the timing and site of its expression and the presence of cytokines regulating its production.

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