The role of stomach pathology as a risk factor in ulcer formation at different times of chronic dialysis treatment

Two groups of patients with chronic renal failure (CRF) underwent chronic hemodialysis within 1976-1990. Acute ulcerogenic situation in them arose during month 1-3 of the treatment. Formation of ulcers was closely related to the acid-peptic factor. Hemodialysis procedure was found to contribute to ulcerogenesis, chronic hemodialysis being somewhat an iatrogenic risk factor in such patients. Modern policy of managing duodenal ulcers in hemodialysis patients is discussed.     

Identification of a novel inhibitor (NSC 665564) of dihydroorotate dehydrogenase with a potency equivalent to brequinar

A novel inhibitor of dihydroorotate dehydrogenase (DHO-DH) has been discovered using data from the National Cancer Institute's in vitro drug screen. Upon analysis of cytotoxicity results from the sixty tumor cell lines used in this screen, the COMPARE program predicted that NSC 665564 was likely to have the same mechanism of inhibition as brequinar, a known potent inhibitor of DHO-DH. We validated this prediction experimentally using MOLT-4 lymphoblast and found the IC50 of brequinar (0.5 microM) and NSC 665564 (0.3 microM) were comparable and that this induced cytotoxicity was reversed by either uridine or cytidine. The enzyme target of NSC 665564 was shown to be identical to that of brequinar when incubation with each drug followed by a 1 h pulse with [14C] sodium bicarbonate resulted in cellular accumulation of [14C]N-carbamyl-L-aspartic acid and [14C]L-dihydroorotic acid, with concurrent marked depletion of CTP and UTP. The Ki's for NSC 665564 and brequinar were 0.14 and 0.24 microM, respectively, when partially purified MOLT-4 mitochondria (the site of DHO-DH) were used. These results show that mechanistic predictions obtained using correlations from the COMPARE algorithm are independent of structure since the structure of NSC 665564 is dissimilar to that of other established DHO-DH inhibitors.     

Contractile patterns in patients with severe chronic dyspepsia

The Shaker superfamily encodes voltage-gated potassium (Kv) channels. The amino (N) terminus is important for channel assembly and mediates fast inactivation. We recently isolated a Kv channel from rabbit kidney, denoted rabKv1.3 (Yao et al., J. Clin. Invest. 97, 2525-2533, 1996) and found that deleting a region (T0 domain, amino acids 3-39) proximal to the T1 recognition domain (a.a 42-185) leads to a 13-fold amplification of Kv current as compared to wild type channels (Yao et al., BBRC 249, 492-498). Here we show that deleting the T0 domain affects neither single channel conductance nor channel open probability. Instead, it increases the absolute number of channel proteins present in the membrane. We conclude that the T0 domain is a previously unrecognized Shaker Kv1.3, N-terminal regulatory region that modulates steady state channel protein density in the plasma membrane.     

Geranoyl-CoA carboxylase: a novel biotin-containing enzyme in plants

Geranoyl-CoA carboxylase (EC 6.4.1.4) is a biotin-containing enzyme previously described in two genera of bacteria. Here we report the presence of geranoyl-CoA carboxylase in kingdom Plantae. Geranoyl-CoA carboxylase was purified 180-fold from maize leaves. The enzyme has a biotin-containing subunit of 122 kDa. The pH optimum for activity is 8.3. The apparent Km values for the substrates geranoyl-CoA, bicarbonate, and ATP are 64 +/- 5 microM, 0. 58 +/- 0.04 mM, and 8.4 +/- 0.4 microM, respectively. Subcellular fractionations indicate that geranoyl-CoA carboxylase is located in plastids. Geranoyl-CoA carboxylase activity is ubiquitous in organs of monocots and dicots and varies with development. We postulate that geranoyl-CoA carboxylase plays an important role in isoprenoid catabolism in plants, in a pathway analogous to that shown in Psuedomonas sp. In plants, this catabolic pathway would require the interaction of at least three subcellular compartments (plastids, microbodies, and mitochondria) and two biotin-containing enzymes, geranoyl-CoA carboxylase and 3-methylcrotonyl-CoA carboxylase.     

Modulation of p27(Kip1) levels by the cyclin encoded by Kaposi's sarcoma-associated herpesvirus

DNA tumour viruses have evolved a number of mechanisms by which they deregulate normal cellular growth control. We have recently described the properties of a cyclin encoded by human herpesvirus 8 (also known as Kaposi's sarcoma-associated herpesvirus) which is able to resist the actions of p16(Ink4a), p21(Cip1) and p27(Kip1) cdk inhibitors. Here we investigate the mechanism involved in the subversion of a G1 blockade imposed by overexpression of p27(Kip1). We demonstrate that binding of K cyclin to cdk6 expands the substrate repertoire of this cdk to include a number of substrates phosphorylated by cyclin-cdk2 complexes but not cyclin D1-cdk6. Included amongst these substrates is p27(Kip1) which is phosphorylated on Thr187. Expression of K cyclin in mammalian cells leads to p27(Kip1) downregulation, this being consistent with previous studies indicating that phosphorylation of p27(Kip1) on Thr187 triggers its downregulation. K cyclin expression is not able to prevent a G1 arrest imposed by p27(Kip1) in which Thr187 is mutated to non-phosphorylatable Ala. These results imply that K cyclin is able to bypass a p27(Kip1)-imposed G1 arrest by facilitating phosphorylation and downregulation of p27(Kip1) to enable activation of endogenous cyclin-cdk2 complexes. The extension of the substrate repertoire of cdk6 by K cyclin is likely to contribute to the deregulation of cellular growth by this herpesvirus-encoded cyclin.     

Diltiazem and pentoxifylline determination in postmortem specimens

A 78-year-old woman was found dead in her basement. Qualitative screening of available postmortem specimens detected the presence of diltiazem and pentoxifylline. Quantitations were carried out by gas chromatography using nitrogen-phosphorus detection and confirmed by gas chromatography-mass spectrometry with the following results: blood, 0.59 mg/dL diltiazem and 0.63 mg/dL pentoxifylline; urine, 1.17 mg/dL diltiazem and 0.08 mg/dL pentoxifylline; bile, 0.40 mg/dL diltiazem and 0.22 mg/dL pentoxifylline; gastric contents, 0.28 mg/dL diltiazem and 0.02 mg/dL pentoxifylline. Both drugs were found qualitatively in formaline-fixed tissues.