Different response to epidermal growth factor of hepatocytes in cultures isolated from male or female rat liver. Inhibitor effect of estrogen on binding and mitogenic effect of epidermal growth factor

Deoxyribonucleic acid (DNA) synthesis in hepatocytes isolated from the livers of male and female rats has been compared in monolayer culture. Plating efficiency, DNA and protein content, viability, and morphologic appearance were the same in cultures prepared with hepatocytes isolated from male or female rats. Epidermal growth factor (EGF)-induced DNA synthesis was significantly higher in hepatocytes from male rats than in hepatocytes from female rats. This was the case whether hepatocytes were isolated from normal or partially hepatectomized male or female rats. Hepatocytes isolated from regenerating liver synthesize more DNA than those isolated from normal liver in response to EGF. This increased response to EGF in hepatocytes derived from regenerating liver was relatively the same for male- and female-derived hepatocytes, but the magnitude of the response was considerably higher in male-derived hepatocytes. In contrast, in vivo DNA synthesis in the liver remnant after partial hepatectomy was similar in male and female rats if measured 24 h after the operation. A comparison of EGF binding to male- and female-derived hepatocytes maintained in primary culture indicated a lower number of high-affinity receptors for EGF in the female hepatocytes. The addition of estrogen to primary cultures of hepatocytes isolated from male rats inhibited EGF binding as well as EGF-induced DNA synthesis. Our studies show significant differences in DNA synthesis in response to EGF when male and female hepatocytes are compared in primary culture. The regenerative response after partial hepatectomy, on the other hand, was the same in male and female rats. Thus, our studies indicate that the sex of the donor rat is important when hepatocytes in culture are used for a variety of studies, such as hepatocyte metabolism, induction and control of DNA synthesis, and hepatocarcinogenesis. In addition, our results indicate that caution is advised when inferences are made from in vitro findings for in vivo conditions. © 1987

Setting a research agenda for progressive multiple sclerosis: The International Collaborative on Progressive MS

Despite significant progress in the development of therapies for relapsing MS, progressive MS remains comparatively disappointing. Our objective, in this paper, is to review the current challenges in developing therapies for progressive MS and identify key priority areas for research. A collaborative was convened by volunteer and staff leaders from several MS societies with the mission to expedite the development of effective disease-modifying and symptom management therapies for progressive forms of multiple sclerosis. Through a series of scientific and strategic planning meetings, the collaborative identified and developed new perspectives on five key priority areas for research: experimental models, identification and validation of targets and repurposing opportunities, proof-of-concept clinical trial strategies, clinical outcome measures, and symptom management and rehabilitation. Our conclusions, tackling the impediments in developing therapies for progressive MS will require an integrated, multi-disciplinary approach to enable effective translation of research into therapies for progressive MS. Engagement of the MS research community through an international effort is needed to address and fund these research priorities with the ultimate goal of expediting the development of disease-modifying and symptom-relief treatments for progressive MS

Towards a Robuster Interpretive Parsing

The input data to grammar learning algorithms often consist of overt forms that do not contain full structural descriptions. This lack of information may contribute to the failure of learning. Past work on Optimality Theory introduced Robust Interpretive Parsing (RIP) as a partial solution to this problem. We generalize RIP and suggest replacing the winner candidate with a weighted mean violation of the potential winner candidates. A Boltzmann distribution is introduced on the winner set, and the distribution’s parameter $T$ is gradually decreased. Finally, we show that GRIP, the Generalized Robust Interpretive Parsing Algorithm significantly improves the learning success rate in a model with standard constraints for metrical stress assignment

The effect of estrogen and tamoxifen on hepatocyte proliferation in Vivo and in Vitro

We have previously shown that changes in estrogen‐hepatocyte interaction occur during liver regeneration. Following 70% hepatectomy, estrogen levels in the blood were elevated, the number of estrogen receptors in the liver was increased and there was an active translocation of estrogen receptors from the cytosol to the nucleus. The injection of tamoxifen, an estrogen antagonist, inhibits hepatocyte proliferation following partial hepatectomy. The administration of 1 μg tamoxifen per gm body weight at zero time or 6 hr after the operation resulted in a significant inhibition both of DNA synthesis and of the number of cells in mitosis. Injections of tamoxifen 12 hr or later after the operation had no effect. Concomitant injections of equimolar amounts of estrogen abolished the inhibition by tamoxifen. The effects of estrogen and tamoxifen were also tested on hepatocytes in primary culture. Estrogens in the presence of 5% normal rat serum stimulated hepatocyte DNA synthesis as determined by [3H]thymidine incorporation and the labeling index, whereas epidermal growth factor‐induced DNA synthesis in the absence of normal rat serum was strongly inhibited. Tamoxifen, in contrast, inhibited DNA synthesis of hepatocytes in the presence of 5% normal rat serum and reversed the stimulatory effect of estrogen in the same system. Attempts to elucidate the mechanism of tamoxifen inhibition in vitro indicated that one effect of tamoxifen is to prevent the amiloride‐sensitive Na+ influx necessary to initiate hepatocyte proliferation. Copyright © 1989 American Association for the Study of Liver Disease

Immunolocalization of KATP channel subunits in mouse and rat cardiac myocytes and the coronary vasculature.

BACKGROUND: Electrophysiological data suggest that cardiac KATP channels consist of Kir6.2 and SUR2A subunits, but the distribution of these (and other KATP channel subunits) is poorly defined. We examined the localization of each of the KATP channel subunits in the mouse and rat heart. RESULTS: Immunohistochemistry of cardiac cryosections demonstrate Kir6.1 protein to be expressed in ventricular myocytes, as well as in the smooth muscle and endothelial cells of coronary resistance vessels. Endothelial capillaries also stained positive for Kir6.1 protein. Kir6.2 protein expression was found predominantly in ventricular myocytes and also in endothelial cells, but not in smooth muscle cells. SUR1 subunits are strongly expressed at the sarcolemmal surface of ventricular myocytes (but not in the coronary vasculature), whereas SUR2 protein was found to be localized predominantly in cardiac myocytes and coronary vessels (mostly in smaller vessels). Immunocytochemistry of isolated ventricular myocytes shows co-localization of Kir6.2 and SUR2 proteins in a striated sarcomeric pattern, suggesting t-tubular expression of these proteins. Both Kir6.1 and SUR1 subunits were found to express strongly at the sarcolemma. The role(s) of these subunits in cardiomyocytes remain to be defined and may require a reassessment of the molecular nature of ventricular KATP channels. CONCLUSIONS: Collectively, our data demonstrate unique cellular and subcellular KATP channel subunit expression patterns in the heart. These results suggest distinct roles for KATP channel subunits in diverse cardiac structures

Application of bifurcation methods for the prediction of low-speed aircraft ground performance

The design of aircraft for ground maneuvers is an essential part in satisfying the demanding requirements of the aircraft operators. Extensive analysis is done to ensure that a new civil aircraft type will adhere to these requirements, for which the nonlinear nature of the problem generally adds to the complexity of such calculations. Small perturbations in velocity, steering angle, or brake application may lead to significant differences in the final turn widths that can be achieved. Here, the U-turn maneuver is analyzed in detail, with a comparison between the two ways in which this maneuver is conducted. A comparison is also made between existing turn-width prediction methods that consist mainly of geometric methods and simulations and a proposed new method that uses dynamical systems theory. Some assumptions are made with regard to the transient behavior, for which it is shown that these assumptions are conservative when an upper bound is chosen for the transient distance. Furthermore, we demonstrate that the results from the dynamical systems analysis are sufficiently close to the results from simulations to be used as a valuable design tool. Overall, dynamical systems methods provide an order-of-magnitude increase in analysis speed and capability for the prediction of turn widths on the ground when compared with simulations. Nomenclature co = oleo damping coefficient, N s2 =m2 cz = tire vertical damping coefficient Fco = damping force in oleo due to the orifice,

Serogrouping and sulphonamide sensitivity of Neisseria meningitidis isolates from the south-western Cape

CITATION: Donald, P.R. et al. 1989. Serogrouping and sulphonamide sensitivity of Neisseria meningitidis isolates from the south-western Cape. S Afr Med J, 76:453.The original publication is available at http://www.samj.org.zaNeisseria meningitidis infections were first reported from the south-western Cape Province in 1883. Since then, against a backdrop of a relatively low incidence with winter exacerbation, epidemic periods have occurred at 10 - IS-year intervals. During the 1978 - 1979 epidemic more than 95% of isolates at Tygerberg Hospital were of serogroup B and only 5% were resistant to sulphonamides. Seventy-seven per cent of patients notified as suffering from meningococcal infections were under 4 years of age.3 In this report we briefly describe the pattern of serogrouping and sulphonamide resistance of N. meningitidis for the period 1980 - 1987.Publisher’s versio