Very low birth weight children at school age: comparison of neonatal management methods

The outcome of 293 infants born to a geographically defined community and weighing 501-1500 g was investigated. Medical intervention in the newborn period had been avoided. Morbidity was assessed at school age. Of the infants, 236 had been live born in the labour ward of this hospital; of these, 117 (49.6%) died in the neonatal period, one (0.4%) died in the first year, four (1.7%) were untraced, 13 (5.5%) had major handicap, 29 (12.3%) had minor handicap, and 72 (30.5%) were considered to be normal. In terms of survival, handicap, and intellectual with that of infants born over the same period (1963-71) in areas where intensive methods of perinatal care were used. These results imply that postnatal survival and potential of infants of very low birth weight are by no means prejudiced when only experienced nursing care is available.     

Absence of tonic electromyographic activity during sleep in normal and spastic nonmimetic skeletal muscles in man

An electromyographic study of nonmimetic skeletal muscles was carried out in 8 normal adults and 4 patients with spastic hemiparesis during all stages of sleep for a total of 21 nights. All normal subjects showed absence of tonic electromyographic activity in all nonmimetic skeletal muscles in all stages of sleep. Also, during quiet, relaxed wakefulness, tonic muscle discharges disappeared in the normal subjects. Three patients with upper motor neuron spasticity demonstrated results during sleep similar to those obtained in the normal subjects. In the fourth patient, tonic muscle discharges persisted into stage 2 non-REM sleep, disappeared within 30 to 240 seconds following the onset of stage 2 sleep, and were absent during stages 3 and 4 sleep and REM sleep.     

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.     

Inhibition of vascular endothelial growth factor prevents retinal ischemia-associated iris neovascularization in a nonhuman primate

The antiestrogenic drug tamoxifen induces liver tumors in rats by a genotoxic mechanism. The key step has been proposed to be the formation of a reactive carbocation from the metabolite alpha-hydroxytamoxifen. This compound reacts with DNA in vitro to a small extent (1 in 10(5) DNA bases), giving products identical to those found in rat liver cells treated with tamoxifen. Now we have prepared the more reactive alpha-acetoxytamoxifen, which reacts with DNA in vitro to a much greater extent (1 in 50 bases). The products of this reaction were subjected to 32P postlabeling and shown by both TLC and reverse-phase liquid chromatography to be identical to those isolated from DNA treated with alpha-hydroxytamoxifen and to those found in the liver DNA of rat hepatocytes treated with tamoxifen or of the livers of rats treated with tamoxifen. The major product was also isolated as the nucleoside and characterized by UV, mass, and proton magnetic resonance spectroscopy. It is an adduct of tamoxifen and deoxyguanosine in which the alpha position of tamoxifen is linked covalently to the exocyclic amino group of deoxyguanosine.     

Inhibition of 2-nitropropane-induced rat liver DNA and RNA damage by benzyl selenocyanate

We observed that pretreatment of male F344 rats with benzyl selenocyanate, a versatile organoselenium chemopreventive agent in several animal model systems, decreases the levels of DNA and RNA modifications produced in the liver by the hepatocarcinogen 2-nitropropane. To clarify the mechanisms involved, we pretreated male F344 rats with either benzyl selenocyanate, its sulfur analog benzyl thiocyanate, phenobarbital or cobalt protoporphyrin IX; the latter is a depletor of P450. We then determined (1) the ability of liver microsomes to denitrify 2-nitropropane, (2) effects on 2-nitropropane-induced liver DNA and RNA modifications and (3) amount of nitrate excreted in rat urine following administration of the carcinogen. Pretreatment with benzyl selenocyanate or phenobarbital increased the denitrification activity of liver microsomes by 217 and 765%, respectively, increased liver P4502B1 by 31- and 435-fold, respectively, decreased the levels of 2-nitropropane-induced modifications in liver DNA (29-70% and 17-30%, respectively) and RNA (67-85% and 30-50%, respectively), and increased the 24-h urinary excretion of nitrate by 157 and 209%, respectively. Pretreatment with benzyl thiocyanate had no significant effect on any of these parameters. Pretreatment with cobalt protoporphyrin IX decreased liver P4502B 1 by 87%, decreased the denitrification activity of liver microsomes by 76%, decreased the 24 h urinary excretion of nitrate by 88.5%, but increased the extent of 2-nitropropane-induced liver nucleic acid modifications by 17-67%. These results indicate that the metabolic sequence from 2-nitropropane to the reactive species causing DNA and RNA modifications does not involve the removal of the nitro group. Moreover, they suggest that benzyl selenocyanate inhibits 2-NP-induced liver nucleic acid modifications in part by increasing its detoxication through induction of denitrification, although it is evident that other mechanisms must also be involved.