Chimeric cytotoxin IL2-PE40 inhibits relapsing experimental allergic encephalomyelitis.

IL2-PE40 is a chimeric protein composed of human interleukin-2 (IL2) genetically fused to a modified form of Pseudomonas exotoxin lacking the cell recognition domain. IL2-PE40 is cytotoxic for IL2 receptor-bearing lymphocytes in culture and can inhibit activation of T cells in vivo. IL2-PE40 can significantly diminish antigen-stimulated proliferation of lymphocytes sensitized to myelin basic protein. Intraperitoneal administration of IL2-PE40 not only markedly inhibits the clinical manifestations of adoptively transferred relapsing experimental allergic encephalomyelitis but also dramatically reduces both inflammation and demyelination characteristic of the disease.     

Additive interactions of calcitonin gene-related peptide and calcitonin on pancreatic exocrine function in conscious dogs

By convention, establishing a physiologic role for a gut peptide requires demonstration of biologic activity that can be reproduced by exogenous administration of the peptide in amounts that yield plasma concentrations that are not higher than those found after a meal. We have tested the hypothesis that the combined action of two inhibitory peptides may lower the effective doses of each. We further hypothesize that combined peptide responses may be responsible for the action of peptide hormones that have been difficult to demonstrate as physiologically relevant mediators, when examined as independently acting substances. In conscious dogs prepared with chronic pancreatic cannulas, stimulated pancreatic exocrine secretions were depressed in a dose-related manner by intravenous infusions of calcitonin (CT) and calcitonin gene-related peptide (CGRP). Doses of 2.0 nmol/kg/hr of both CT and CGRP yielded maximal inhibition of stimulated secretions of both bicarbonate (greater than 85% inhibition) and protein (greater than 55% inhibition). The lowest effective dose for either CT or CGRP, given alone, was 0.75 nmol/kg/hr, but when infused simultaneously, each at the subthreshold dose of 0.50 nmol/kg/hr, significant inhibition of protein and bicarbonate secretion was achieved. Combined infusions of the submaximal dose of 0.75 nmol/kg/hr resulted in an enhanced inhibitory response. To prove that this effect is not simply combined activation of a common receptor, we tested peptide YY (0.1 to 0.5 nmol/kg/hr) combined with CGRP and obtained similar results. Because a meal simultaneously releases a large number of active peptides, we speculate that such potentiated responses do occur physiologically. Cooperative interaction with other agents may be the primary mode of action for certain gut peptides.     

Expression of human mu or alpha class glutathione S-transferases in stably transfected human MCF-7 breast cancer cells: effect on cellular sensitivity to cytotoxic agents.

Increased expression of certain glutathione S-transferase (GST) isoenzymes has frequently been associated with the development of resistance to alkylating agents and other classes of antineoplastic drugs in drug-selected cell lines. The question arises whether this phenomenon is causal or is a stress-induced response associated with drug resistance in these cell lines. We have constructed mammalian expression vectors containing the human GST mu and GST alpha 2 (Ha2) cDNAs and stably transfected them into the human breast cancer cell line MCF-7. Whereas the parental and pSV2neo-transfected cell lines display low GST activity, three individual transfected clones were identified in each group that expressed either GST mu or GST alpha 2. The range of GST activities was similar to those observed in cells selected for anticancer drug resistance. The GST mu specific activities were 56, 150, and 340 mlU/mg, compared with 10 mlU/mg of endogenous GST mu in control lines. Specific activities in GST alpha 2-transfected clones were 17, 28, and 52 mlU/mg, compared with no detectable alpha class GST in control lines. These clonal lines and the parental and pSV2neo-transfected control lines were tested for sensitivity to antineoplastic agents and other cytotoxic compounds. The clones with the highest activity in each group were 1.7-fold (GST alpha 2) to 2.1-fold (GST mu) resistant to the toxic effects of ethacrynic acid, a known substrate for GSTs. However, the GST-transfected cell lines were not resistant to doxorubicin, L-phenylalanine mustard, bis(2-chloroethyl)-1-nitrosourea, cisplatin, chlorambucil, or the GST substrates 1-chloro-2,4-dinitrobenzene or tert-butyl hydroperoxide. Thus, although L-phenylalanine mustard, bis(2-chloroethyl)-1-nitrosourea, chlorambucil, tert-butyl hydroperoxide, and 1-chloro-2,4-dinitrobenzene are known to be metabolized by glutathione-dependent GST-catalyzed reactions, there was no protection against any of these agents in MCF-7 cell lines overexpressing GST mu or GST alpha 2. We conclude that, at the levels of GST obtained in this transfection model system, overexpression of GST mu or GST alpha 2 is not by itself sufficient to confer resistance to these anticancer agents. These studies do not exclude the possibility that GST may be a marker of drug resistance or that other gene products not expressed in MCF-7 cells might cooperate with GST to confer drug resistance.     

Neuropsychological function in restrained versus unrestrained motor vehicle occupants who suffer Closed Head Injury

It is known that using seatbelts reduces the incidence and severity of closed head injury CHI from motor vehicle crashes. One would expect unrestrained occupants in motor vehicle crashes to suffer more severe CHIs than restrained occupants, as reflected by Glasgow Coma Scale GCS scores. One might also expect an increased risk of focal injury due to contact forces in unrestrained occupants. The purpose of this study was to test the hypothesis that failure to use seatbelts results in increased severity of neuropsychological sequelae, even with GCS controlled. We also examined the impact of demo graphic variables on seatbelt use. Subjects included patients admitted to a hospital trauma service who were suspected of having suffered CHI. All patients completed neuropsychological testing, which was entered into a data base along with demographic and clinical information. People who had docu mented use of seatbelt restraints were compared with those who were unrestrained. Results confirmed that certain demographic variables are associated with the use of seatbelts. Results also suggested that failure to use seatbelt restraints is associated with more severe impairment on tests that are sensitive to frontal lobe dysfunction.     

Videothoracoscopy in the treatment of early empyema: an initial experience.

Seventeen consecutive patients were referred for management of empyema between April 1991 and March 1992. Fourteen patients defined as having an 'early' empyema were initially treated by videothoracoscopy. The other three patients, defined as having a 'late' empyema proceeded directly to thoracotomy. Videothoracoscopy was successful in 10 out of the 14 patients. The mean postoperative stay was 7.8 days. At a mean follow-up at 16.7 months, these patients were rendered apyrexial with full lung expansion and no residual pleural collection. The postoperative results were at least equivalent to other conventional forms of treatment without an undue level of complications. In this series, thoracoscopy was found to be successful when symptoms had been present up to 31 days before presentation at the first hospital, and the mean length of treatment before referral to Harefield was 47 days. It is now our policy to videothoracoscope all patients with empyema thoracis, regardless of the length of referral. It may circumvent the need for a thoracotomy, it does not add any increased risk of complications, and does not appreciably increase the length of hospital stay should thoracotomy ultimately be required.     

The Alcohol Beverage Warning Label: When Did Knowledge Increase?

This article presents data on the awareness of the alcohol beverage warning label among a sample of 5,169 inner city African-American gravidas seeking prenatal care. While the label law was implemented in November 1989, a significant increase in knowledge of the label did not occur until March 1990. Women who predominantly consumed wine coolers and beer, and those under age 30 were more likely to know about the label than their counterparts.     

A comparison of the insulinotropic and the insulin-inhibitory actions of gut peptides on newborn and adult rat islet cells

The objective of this study was to examine the release of insulin from cultured islet cells, taken from the pancreas of newborn and adult rats, in response to gastric inhibitory polypeptide (GIP), cholecystokinin-8 (CCK-8), calcitonin gene-related peptide (CGRP), and pancreastatin. GIP (10(-9)-10(-7) M) potentiated glucose-stimulated release of insulin in a dose-dependent fashion from both newborn and adult islet cells. CCK-8 (greater than 10(-8) M) also increased glucose-stimulated release of insulin from newborn islet cells, however its effect was not significant and not as strong as that observed with adult islet cells. Culture of newborn islet cells for 3 weeks with media containing high concentrations of glucose (16.7 mM) enhanced insulin release in response to CCK-8. CGRP did not affect the release of insulin from newborn islet cells, whereas at 10(-10) M, it reduced the release of insulin from adult islet cells by 66 +/- 4%. Pancreastatin (10(-9)-10(-8) M) did not affect the release of insulin from newborn islet cells when cells were incubated with 4.2 mM glucose, whereas it stimulated the release of insulin from adult islet cells in a dose-dependent fashion. When incubated with 16.7 mM glucose, pancreastatin inhibited the release of insulin from both newborn and adult islet cells. These results indicate that newborn islet cells experience developmental changes which render them responsive to enteric peptides.     

Building bridges between neural models and complex decision making behaviour.

Diffusion processes, and their discrete time counterparts, random walk models, have demonstrated an ability to account for a wide range of findings from behavioural decision making for which the purely algebraic and deterministic models often used in economics and psychology cannot account. Recent studies that record neural activations in non-human primates during perceptual decision making tasks have revealed that neural firing rates closely mimic the accumulation of preference theorized by behaviourally-derived diffusion models of decision making. This article bridges the expanse between the neurophysiological and behavioural decision making literatures specifically, decision field theory [Busemeyer, J. R. & Townsend, J. T. (1993). Decision field theory: A dynamic-cognitive approach to decision making in an uncertain environment. Psychological Review, 100, 432-459], a dynamic and stochastic random walk theory of decision making, is presented as a model positioned between lower-level neural activation patterns and more complex notions of decision making found in psychology and economics. Potential neural correlates of this model are proposed, and relevant competing models are also addressed.