Mouse lung epithelial cell lines--tools for the study of differentiation and the neoplastic phenotype

Several dozen lung epithelial cell lines have been established in culture over the past 20 years from normal lung explants and their spontaneous transformants, and from lung tumors that arose spontaneously or were induced with chemicals, viruses, or oncogenic transgenes. To provide information from which to choose appropriate lines for investigating problems in lung cell biology and pulmonary neoplasia, this review describes the origins of these lines and some of their characteristics. These include growth, morphology, tumorigenicity, ability to metastasize, xenobiotic metabolism, mutational status, signal transducing activities, cytogenetics, ability to form domes, and electric conductance. In addition to collecting this information in a single place for the first time, we describe previously unpublished apoptosis features of some of these lines. An increasing number of investigations are beginning to use these lines and this review contains references into 1997.     

Short and long latency cortical potentials evoked by electrical stimulation of the oesophageal mucosa in normal alert humans

BACKGROUND: The type of remodeling of the human femoral artery (enlargement or shrinkage) is related to the percentage luminal stenosis. OBJECTIVE: To assess how local changes in vessel size, together with plaque load, determine luminal narrowing in atherosclerotic human coronary arteries. METHODS: We obtained 576 segments of 28 coronary arteries from 10 patients who had died from noncardiac causes. The lumen area and area circumscribed by the internal elastic lamina (IEL) area, a measure of local vessel size in each histologic cross-section were measured, and the mean lumen diameter and mean IEL diameter were calculated. To correct for arterial tapering, expected reference diameter values were calculated at the same location using linear regression of all data points along the artery. The IEL diameter and lumen diameter were expressed as percentages of the calculated IEL diameter and lumen diameter at the same location (percentage lumen diameter stenosis and relative IEL diameter, respectively). RESULTS: We found a negative relation between the relative IEL diameter and the percentage lumen diameter stenosis. On average, a narrower than expected lumen diameter was accompanied by a smaller than expected IEL diameter. A larger than expected lumen diameter was accompanied by a larger than expected IEL diameter. This relation was found for the left anterior descending, circumflex, and right coronary arteries (y = -0.60x + 105.33, r = 0.48; y = -0.45x + 100.69, r = 0.84; and y = -0.39x + 101.84, r = 0.61, respectively, all P < 0.05). CONCLUSIONS: Local luminal narrowing was correlated with a decrease in vessel size. Local remodeling of the artery is one of the determinants of luminal narrowing in the atherosclerotic human coronary artery.     

Novel phosphoserine phosphatase inhibitors

Phosphoserine phosphatase (EC 3.1.1.3) catalyzes the final step in the major pathway of L-serine biosynthesis in brain. This enzyme may also regulate the levels of glycine and D-serine, the known and putative co-agonists for the glycine site of the N-methyl-D-aspartate receptor in caudal and rostral brain regions, respectively. Using L-phosphoserine as substrate, the rank order potency for inhibition of phosphoserine phosphatase was p-chloromercuriphenylsulfonic acid (CMPSA) > glycerophosphorylcholine > hexadecylphosphocholine > or = phosphorylcholine > N-ethylmaleimide > or = L-serine > fluoride > D-2-amino-3-phosphonopropionic acid (D-AP3). Glycerylphosphorylcholine (IC50 18 microM) was found to be an uncompetitive inhibitor of phosphoserine phosphatase. Glycerylphosphorylcholine probably binds a novel site on the enzyme since the known allosteric inhibitor L-serine is highly selective for its feedback regulatory site, indicated by the inactivity of 25 L-serine analogs. Fluoride ion (IC50 770 microM) may bind the active site as has been shown for other Mg2+-dependent enzymes. The sulfhydryl reagent CMPSA is a potent, noncompetitive inhibitor of the enzyme using L-phosphoserine as substrate (IC50 9 microM) but is > 300-fold less potent using D-phosphoserine as substrate. Substrate-dependent differences are also observed with the sulfhydryl alkylator N-ethylmaleimide, which inhibits L-phosphoserine, but stimulates D-phosphoserine hydrolysis. These sulfhydryl reagents may dissociate multimeric forms of the enzyme to form monomers; the multimeric forms and monomers may preferentially cleave L- and D-phosphoserine, respectively. Phosphorylcholine esters and sulfhydryl reagents may prove useful in determining the contribution of phosphoserine phosphatase to the biosynthesis of glycine and D-serine in neuronal tissue in vitro.     

A phase I study of high-dose tamoxifen for the treatment of refractory malignant gliomas of childhood

Recent studies have indicated that the proliferation of malignant gliomas is in part dependent on excessive activation of protein kinase C (PKC)-mediated pathways. Conversely, inhibiting PKC may provide a novel approach for blocking glioma growth. The antiestrogen tamoxifen, a moderately potent PKC inhibitor, has been shown in vitro to block the proliferation of malignant glioma cell lines at concentrations several-fold higher than those typically attained during the treatment of breast cancer; such serum concentrations may be achieved with doses > 40 mg/m2 b.i.d. The safety and efficacy of these high doses for producing disease control in patients with malignant gliomas has recently been noted anecdotally, although a rigorous study of this agent has been lacking. To address this issue, we examined the safety and efficacy of high-dose tamoxifen in a series of children with malignant gliomas that had progressed after conventional therapy. An initial group was treated with 60 mg/m2 p.o. b.i.d. and a second group with 100 mg/m2 b.i.d. Steady-state serum tamoxifen and metabolite levels were measured in most patients. Toxicity with the regimen was minimal; two patients treated at the higher dose required reduction to the lower dose because of asymptomatic prolongation of the QT interval on an electrocardiogram. Although none of the patients exhibited clear-cut tumor regression, 4 of 14 patients had stabilization of previously progressive disease for at least 3 months; the longest survivor lived for 17 months after beginning tamoxifen. The moderate efficacy of this agent in otherwise end-stage disease coupled with its low toxicity and the relative ease of oral administration provides a rationale for proceeding with larger studies of this agent in patients with malignant gliomas, possibly as a means for potentiating the effects of conventional chemotherapeutic agents, which to date have shown limited efficacy in the treatment of these tumors.     

The recent health reforms in the United Kingdom: some tentative observations on their impact on nurses and nursing in hospitals

The British National Health Service has recently undergone the most profound reforms since it was conceived some 50 years ago. In an attempt to contain the rising cost of spending the principles of market competition have been introduced. Similar developments are occurring internationally. This paper describes briefly the history of the reforms in the United Kingdom. It outlines the rationale for a market in health services which is largely publicly funded. The paper then provides an analysis of the serious impact of the new business culture on the control of nurses and nursing work in hospitals. In doing so, it identifies the threats which confront the future well-being of the nursing profession. It concludes with a brief resumé of opportunities which the profession must seize if it is to retain its identity.     

Targeted deletion of the PEX2 peroxisome assembly gene in mice provides a model for Zellweger syndrome, a human neuronal migration disorder

Zellweger syndrome is a peroxisomal biogenesis disorder that results in abnormal neuronal migration in the central nervous system and severe neurologic dysfunction. The pathogenesis of the multiple severe anomalies associated with the disorders of peroxisome biogenesis remains unknown. To study the relationship between lack of peroxisomal function and organ dysfunction, the PEX2 peroxisome assembly gene (formerly peroxisome assembly factor-1) was disrupted by gene targeting. Homozygous PEX2-deficient mice survive in utero but die several hours after birth. The mutant animals do not feed and are hypoactive and markedly hypotonic. The PEX2-deficient mice lack normal peroxisomes but do assemble empty peroxisome membrane ghosts. They display abnormal peroxisomal biochemical parameters, including accumulations of very long chain fatty acids in plasma and deficient erythrocyte plasmalogens. Abnormal lipid storage is evident in the adrenal cortex, with characteristic lamellar-lipid inclusions. In the central nervous system of newborn mutant mice there is disordered lamination in the cerebral cortex and an increased cell density in the underlying white matter, indicating an abnormality of neuronal migration. These findings demonstrate that mice with a PEX2 gene deletion have a peroxisomal disorder and provide an important model to study the role of peroxisomal function in the pathogenesis of this human disease.