Genetic knockouts in mice: An update

Gene disruption technology in mammals, by homologous recombination in embryonic stem cells, is a powerful method to manipulate the mouse germ line. In the past decade it has produced a wealth of knowledge concerning neuronal development, neurodegenerative disorders and the roles of oncogenes, Hox genes and growth factors during development. A surprising variety of genes, however, have given unexpected and disappointing results. A gene/function redundancy theory proposed by many investigators to explain the unexpected results has been supported in certain cases by the generation of double knockout mice. Modification of the basic technology now allows the investigators to carry out a variety of manipulations including conditional or tissue-specific knockout. This may provide a better opportunity in the future for the gene therapy approach to correct the genetic disorder.     

Inflamed-tissue factor(s): An autoregulatory mechanism of some acute inflammatory responses

Zusammenfassung Bei Ratten wurde aus entzündetem Gewebe ein Hemmer für das Komplementsystem extrahiert, welcher die durch Carrageenin oder Kaolin erzeugten Entzündungen zu unterdrücken vermag.     

Tumor necrosis factor as an antineoplastic agent: pitfalls and promises

The discovery and cloning of the cytokine tumor necrosis factor α (TNF) gave rise to new hopes for a significant victory in the war against cancer. Preclinical in vitro studies in cell cultures and in vivo studies in animal models demonstrated the antitumor capacities of TNF. Although clinical studies were largely made possible by the availability of recombinant TNF, phase I and II clinical trials showed very quickly that the systemic administration of TNF induced severe side effects mainly due to its pleiotropic action on immunocompetent cells. The clinical manifestations of the side effects were similar to those observed during a severe infection and inflammation. Very recently, lessons from these clinical studies yielded refined approaches whereby the toxicity of TNF is limited through local administration, a combination with other therapeutic regimens and targeted gene therapy. These new approaches are slated for larger clinical trials and in the near future might demonstrate the limited but powerful usefulness of TNF as an antineoplastic agent for different types of cancer. Received 7 September 1998; received after revision 15 October 1998; accepted 15 October 1998     

Antibody to tumor necrosis factor (TNF) reduces endotoxin fever

Summary Antibody to tumor necrosis factor (TNF), injected intravenously, reduced endotoxin fever in the rabbit. The fever-reducing effect was apparent in the latter half of the febrile response.This work was supported by a Grants-in-Aid from the Ministry of Education, Science and Culture of Japan (Grant No. 62480112).     

Assessment of superoxide-mediated release of vascular-inhibitory factor(s) from endothelial cells by using a two-bath system

Summary Release of a vascular-inhibitory factor from endothelial cells (EC), different from endothelium-derived relaxant factor (EDRF), was identified through use of a two-bath system. This two-bath system precluded the effects of oxygen-free radicals that appear when electrical field stimulation (EFS) is directly imposed on detector muscle.     

Immunohistochemical detection of a substance resembling growth hormone-releasing factor in the brain of the rainbow trout (Salmo gairdneri)

Summary We studied the distribution of an immunoreactive substance resembling growth hormone-releasing factor (GRF) in the hypothalamus and pituitary gland of the rainbow trout by immunofluorescence methods. The GRF-like immunoreactive perikaryon was observed in colchicine-treated fish. The majority of GRF-containing neurons were located in the nucleus lateral tuberis; others were located in the caudal part of the preoptic nucleus of the hypothalamus. The GRF-like immunoreactive neuronal processes projected into the pars distalis via the pars nervosa of the pituitary gland. The distribution of the GRF-like immunoreactive substance in the hypothalamus and pituitary gland suggests that GRF plays a physiological role in the regulation of growth hormone release from the pituitary gland of rainbow trout, as it does in mammals.     

(R)-(Z,E)-9,11-octadecadien-13-olide: An intriguing lactone fromHeliconius pachinus (Lepidoptera)

Summary A fourteen-membered lactone,(R)-(Z,E)-9,11-octadecadien-13-olide, was isolated from extruded abdominal glands of a Neotropical, nymphalid butterfly,Heliconius pachinus (Lepidoptera). This compound was obtained from mature adults of both sexes, but was not detected in young adults or pupae.     

Retroviruses released from a human tumor xenograft in nude mice induce colony-stimulating factor (CSF) activity in human fibroblastic cells

Summary A human colony-stimulating factor (CSF)-producing tumor transplanted into athymic nude mice released retroviruses in vitro. The viruses induced CSF activity in human fibroblastic cell lines.     

Bootstrapping forecast intervals: An application to AR(p) models

Forecast intervals typically depend upon an assumption of normal forecast errors due to lack of information concerning the distribution of the forecast. This article applies the bootstrap to the problem of estimating forecast intervals for an AR(p) model. Box-Jenkins intervals are compared to intervals produced from a naive bootstrap and a bias-correction bootstrap. Substantial differences between the three methods are found. Bootstrapping an AR(p) model requires use of the backward residuals which typically are not i.i.d. and hence inappropriate for bootstrap resampling. A recently developed method of obtaining i.i.d. backward residuals is employed and was found to affect the bootstrap prediction intervals.     

Glucose does not influence the insulin-like growth factor (IGF) binding to carrier proteins (IGFBPs): Analysis of rat and human serum by western ligand blotting

The insulin-like growth factors (IGFs) circulate bound to specific proteins (termed IGFBP-1 through IGFBP-6) that modulate IGF bioactivity in tissues. The aim of this study was to analyse the effects of glucose on IGF binding to IGFBPs in rat and human serum by means of western ligand blotting. Serum samples were incubated with increasing concentrations of glucose (0 to 50 mmol/l), and EDTA (25 mmol/l) was added to inhibit protease activity. To analyse the effect of glucose on protection of IGFBPs from protease activity, serum from pregnant women (reported to be very rich in proteolytic activity against IGFBPs) was added to rat serum previously incubated with glucose. Glucose did not affect the¹²⁵I-IGF binding to rat and human serum IGFBPs. The intensity of IGFBP-3 bands decreased considerably during the incubation. This appeared to be due to endogenous protease activity, since the decrease was blocked by addition of EDTA. The incubationi of rat serum with pregnant human serum produced a marked attenuation of IGFBP-3 and disappearance of IGFBP-4 bands. In conclusion, our study shows that glucose does not influence the IGF binding to IGFBP-3 either in rat or in human serum, confirms the presence of endogenous proteolytic activity in normal non-pregnant serum, and demonstrates that glucose has no protective action against protease activity.     

Regulatory steps in sex pheromone biosynthesis inMamestra brassicae L. (Lepidoptera: Noctuidae)

Summary The de novo biosynthesis of (Z)-11-hexadecenyl acetate, the most abundant pheromone component inM. brassicae, starting from acetate via palmitic acid, requires the presence of a pheromone-biosynthesis-activating neurohormone. Moreover, the conversion of palmitic acid to (Z)-11-hexadecenyl acetate is strongly dependent on the presence of the neurohormone. However, no significant dependence was found for the conversion of (Z)-11-hexadecenoic acid to (Z)-11-hexadecenyl acetate. This indicates that the neurohormonal control of pheromone biosynthesis inM. brassicae occurs at the level of palmitic acid.