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Biomedical subjects

K Gordon

Publications and source records attributed to K Gordon.

At least 163 records · Page 9Linked to original sources

In vitro expression of cauliflower mosaic virus genes.

The eight major open reading frames (ORFs) of cauliflower mosaic virus (CaMV) have been cloned for in vitro transcription and translation. All the ORFs could be translated. Using antisera against either purified virus or specific gene products, the translation products were screened by immunoprecipitation. The products of ORFs III, IV and V were confirmed as components of the virions. Molecular weights of primary translation products were determined and compared with those found in vivo. A further series of constructs was designed to test whether translation of adjacent ORFs is coupled in a relay-race fashion as proposed on the basis of earlier in vivo mutagenesis studies. Downstream genes on dicistronic RNAs could be translated, although inefficiently. In view of the similarity between the arrangement of the CaMV coat protein and reverse transcriptase genes and the corresponding genes of retroviruses, we asked whether the CaMV reverse transcriptase could be expressed in vitro as a fusion protein, e.g. by ribosomal frame shifting. No such fusion was observed, suggesting that the polymerase gene is translated from its own ATG.

Journal Article↗

A milk protein gene promoter directs the expression of human tissue plasminogen activator cDNA to the mammary gland in transgenic mice.

Whey acidic protein (WAP) is a major whey protein in mouse milk. Its gene is expressed in the lactating mammary gland and is inducible by steroid and peptide hormones. A series of transgenic mice containing a hybrid gene in which human tissue plasminogen activator (tPA) cDNA is under the control of the murine WAP gene promoter had previously been generated. In this study, 21 tissues from lactating and virgin transgenic female mice containing the WAP-tPA hybrid gene were screened for the distribution of murine WAP and human tPA transcripts. Like the endogenous WAP RNA, WAP-tPA RNA was expressed predominantly in mammary gland tissue and appeared to be inducible by lactation. Whereas WAP transcripts were not detected in 22 tissues of virgin mice, low levels of WAP-tPA RNA, which were not modulated during lactation, were found in tongue, kidney, and sublingual gland. These studies demonstrate that the WAP gene promoter can target the expression of a transgene to the mammary gland and that this expression is inducible during lactation.

Animals↗

The determination of an immunologically active dose of interferon-gamma in patients with melanoma.

This study was undertaken to determine an immunologically active regimen for the administration of recombinant gamma-interferon (rIFN-gamma). The patient population included patients with completely resected melanoma, stage I (Clark's level IV or V) or stage II. All patients exhibited no evidence of disease (NED) at the time of the study. Patients received rIFN-gamma by intramuscular (IM) injection daily for 15 days at 0.0001 mg/m2, 0.001 mg/m2, 0.01 mg/m2, 0.1 mg/m2 (ten patients/group), or 0.25 mg/m2 (five patients). Interferon (IFN) was well tolerated, with non-dose-limiting constitutional symptoms occurring in the majority of patients at 0.1 mg/m2 and 0.25 mg/m2. All five patients receiving 0.25 mg/m2 developed elevated transaminase levels, which led to a discontinuation of therapy in one patient. Immunological activity was assessed by serial measurements of natural killer (NK) cell activity, hydrogen peroxide production by monocytes, and changes in expression of Fc receptors and human leukocyte class II antigen (HLA-DR) on monocytes. These changes were determined at baseline (X2), six to seven time points during rIFN-gamma therapy, and two times after the last dose of rIFN-gamma. No changes were observed at the two lowest doses. At the 0.01 mg/m2 dose, all parameters were elevated but not as consistently nor to the same levels as seen following administration of 0.1 mg/m2. At 0.25 mg/m2, H2O2 production was enhanced, but unlike at 0.1 mg/m2, it declined during the last few days of IFN therapy. Subcutaneous (SC) administration was compared with IM administration using the 0.1 mg/m2 dose. SC administration resulted in enhanced H2O2 production and Fc receptor expression by monocytes. More consistent elevations in peroxide generation and higher levels of Fc receptor expression were seen following SC administration. No significant difference was found between the two routes of administration. A comparison of two schedules, daily and three times weekly, suggested that monocyte activation may return to normal 72 hours after IFN administration. Of the doses tested, 0.1 mg/m2 administered daily appeared to be the most effective biological response modifier (BRM) regimen, and because of ease of administration, we favor the SC route.

Dose-Response Relationship, Drug↗

Prolonged duration of gonadotropin inhibition by a third generation GnRH antagonist.

The dose-response effects of a single administration of Nal-Lys-GnRHant (antagonist) on serum LH and FSH concentrations were compared to the effects of Nal-Glu-GnRHant in monkeys. Twenty ovariectomized monkeys were divided into four sc treatment groups: a) 1.0 mg/kg Nal-Glu-GnRHant; or Nal-Lys-GnRHant at b) 0.3; c) 1.0; d) 3.0 mg/kg. Each monkey received vehicle (propylene glycol/water, 1:1) on day 0, followed by an antagonist preparation on day 11. Serum LH and FSH were measured by RIA; serum LH was also measured by in vitro bioassay. The short-term effects were similar among the four treatment groups. Typically, serum LH declined (p less than 0.05) within 4 to 8 h, achieving maximal reduction by 24 h. Serum FSH levels declined more slowly, but were significantly reduced by 24 h (p less than 0.05). Recovery during the study interval to pretreatment control values occurred in only two groups: a) Nal-Glu-GnRHant (1.0 mg/kg) by day 4 post-treatment and b) Nal-Lys-GnRHant (0.3 mg/kg) by day 2 post-treatment. Monkeys receiving 1.0 or 3.0 mg/kg Nal-Lys-GnRHant had a prolonged inhibition of serum LH and FSH levels. In all animals, serum FSH and LH returned to control levels within 2 months. The duration of gonadotropin inhibition was also prolonged when the Nal-Lys-GnRHant was administered iv. In contrast, Nal-Glu-GnRHant reduced serum LH and FSH for 3 days or less in all monkeys. The serum bioassayable LH levels paralleled those of immunoassayable LH. The prolonged inhibition of gonadotropin secretion following Nal-Lys-GnRHant distinguishes its action from those of previous GnRH antagonists and make this compound of great interest for clinical investigations.

Animals↗

Reactivation of the quiescent corpus luteum and diapausing embryo after temporary removal of the sucking stimulus in the tammar wallaby (Macropus eugenii).

Pouch young of wallabies presumed to be carrying diapausing blastocysts were removed from the teat for times varying between 24 and 96 h and then returned to the same teat. The mothers were monitored for termination of diapause and checked for births or oestrus. In this way we were able to determine the critical time required to reactivate the quiescent corpus luteum and diapausing blastocyst after withdrawal of the sucking stimulus. When pouch young were removed from the teat for 76-96 h the corpus luteum and blastocyst were reactivated, with birth and/or oestrus occurring in 10/11 animals. When pouch young were removed for 72 h or less (n = 22) reactivation did not take place. We conclude that it takes longer than 72 h for the maternal endocrine system to become committed to reactivation. The precise sequence of endocrine events which precede blastocyst reactivation still remains to be determined.

Animals↗

Release of prolactin is independent of the secretion of thyrotrophin-releasing hormone into hypophysial portal blood of sheep.

In order to determine whether pituitary prolactin release was directly related to the secretion of TRH into hypophysial portal blood, serial portal and jugular venous blood samples were collected from seven lactating and three non-lactating ewes. In another experiment, samples were collected from five ovariectomized ewes while being exposed to an audio-visual stress and then later administered with chlorpromazine. Secretion of TRH was pulsatile in all ewes and independent of prolactin secretion; TRH pulses coincided with significant increases in prolactin secretion in only 15% of cases and only 29% of prolactin pulses were associated with TRH pulses. Sixty-seven per cent of suckling bouts were associated with increases in prolactin secretion, but only 22% of these were associated with significant increases in TRH secretion. Chlorpromazine increased prolactin levels fourfold but did not affect portal concentrations of TRH. Audio-visual stress was not a reliable method of causing prolactin release in this model. Mean portal concentrations of TRH and jugular concentrations of prolactin were not significantly correlated. These results show that hypothalamic TRH and pituitary prolactin are secreted independently in the sheep, implying that increases in prolactin release caused by suckling or chlorpromazine are not the direct result of increased TRH secretion.

Animals↗

Microinjection into the lateral ventricle: validation of the procedure in estrogen-treated ovariectomized cynomolgus monkey.

To demonstrate that microinjection into the lateral ventricle intracerebroventricular (i.c.v.) of the brain of monkeys does not perturb normal function of the hypothalamic-pituitary axis, ovariectomized cynomolgus monkeys were treated with a bolus of estradiol benzoate (E2beta) (To hours) and an i.c.v. injection of 100 microliters of saline solution at T-6 (group I: four monkeys) or at T+26 hours (group II: three monkeys). The lack of disturbance of the normal biphasic luteinizing hormone response to estrogen and low prolactin (PRL) concentrations allow us to conclude that this microinjection procedure did not disrupt normal endocrine events.

Animals↗

Chromatin decondensation and DNA synthesis in human sperm activated in vitro by using Xenopus laevis egg extracts.

An in vitro sperm activation system was used to study nuclear swelling-chromatin decondensation and DNA synthesis; processes that occur in vivo following fertilization. Lysolecithin-permeabilized human sperm were incubated in Xenopus laevis egg extract and examined by using phase-contrast light microscopy, electron microscopy, and autoradiography. During a 3-hour incubation, the activated sperm nuclear chromatin underwent a decondensation-recondensation cycle during which DNA was synthesized. This also occurred when egg extract was given a 3-hour preincubation before the addition of the sperm, suggesting that the factor(s) required for initiating the decondensation-recondensation cycle is associated with the sperm. Because both nuclear swelling and DNA synthesis were found to be reproducible and quantifiable, we studied the effect of various agents on the two processes, characterizing the critical component(s) in the egg extract that induces these events. EGTA was found to have no effect on the induced nuclear swelling or DNA synthesis that occurs in the activated sperm. Freezing and thawing the extract or treating the extract with aphidicolin also had no effect on subsequent nuclear swelling; however, the DNA synthesis activity was blocked. Sperm incubated in extract treated with alkaline phosphatase (AP) had both nuclear swelling and DNA synthesis blocked. However, if the sperm were pretreated with DTT, and then incubated with the AP-treated extract, only the DNA synthesis activity of the extract was blocked. When the extract was treated with serine protease inhibitors (PMSF, soybean trypsin inhibitor, or alpha-2-macroglobulin), nuclear swelling occurred; however, DNA synthesis was blocked. These data suggest that phosphoproteins are involved in one or more of the activation events and that a serine protease(s) is involved in the synthesis of DNA.

Alkaline Phosphatase↗

Hypothalamo-pituitary portal blood concentrations of beta-endorphin during suckling in the ewe.

Matched hypothalamo-pituitary portal and jugular blood samples were collected over about 6 h from 7 lactating Corriedale ewes penned with their lambs, and a careful record was kept of ewe/lamb behaviour. Hypothalamo-pituitary portal blood concentrations of beta-endorphin were measured by radioimmunoassay and the secretion rates were calculated; these were related to peripheral plasma prolactin and LH concentrations, and the sucking bouts of the lambs. Basal LH concentrations remained less than 1 ng/ml with 0-2 pulses of 1.5-3.5 ng/ml amplitude per 6-h collection period. Prolactin secretion was episodic with individual baselines varying from 24 to 286 ng/ml, and peak concentrations of 50-631 ng/ml. Portal beta-endorphin was secreted in an episodic pattern with individual baseline secretion rates varying from 0.125 to 0.495 ng/min, and peak secretion rates of 0.768 to 3.216 ng/min. A close correlation was seen between sucking bouts and the secretion of portal beta-endorphin and peripheral prolactin; 86% of sucking bouts resulted in a significant release of beta-endorphin, and 46% of sucking bouts resulted in a significant release of prolactin. These results show that hypothalamic beta-endorphin is released in response to the sucking stimulus. This provides support for the hypothesis that, during lactation, beta-endorphin acts within the hypothalamus to reduce GnRH release and hence depress pituitary gonadotrophin secretion.

Animals↗

Gene transfer into mouse embryos.

Gene transfer into the murine genome was accomplished nearly a decade ago by use of chimeras and teratocarcinomas; however, the low frequencies of transfer into the germ line and other difficulties stemming from mosaicism and karyotypic abnormalities in chimeric mice have limited the general usefulness of this procedure in achieving transformation in mammalian embryos. The introduction of cloned genes into teratocarcinoma cells, selection for a mutant phenotype, and transfer of those cells into mouse embryos holds some promise as a technique to employ mouse chimeras for gene transfer into mice. Infection with animal viruses and retroviral vectors provides another way to introduce exogenous DNA into mouse embryos. Infection with Mo-MuLV has been utilized to characterize the relationship between sites of integration and gene function in developing and adult mice. Gene transfer by microinjection of cloned recombinant DNA has been used by many laboratories for the transfer of DNAs into mouse embryos. The factors affecting transformation frequencies and sites of integration are unknown at present, although it seems that integration is not strictly mediated by homology-dependent events. Many genes have been introduced into mouse embryos by these procedures and many of these are expressed at high levels in appropriate tissues. No realistic possibility exists at the present time for the utilization of embryo gene transfer in the medical field for the correction of genetic defects for several reasons. First, in order to effectively provide "gene therapy" it would be necessary to determine the genotype of each recipient egg, a technical impossibility. The genetic diseases that would be amenable to germ line intervention are recessive diseases and there would be only a 25% chance of any one embryo derived from heterozygous parents being a homozygous recessive. Moreover, it would be impossible to distinguish the normal from abnormal embryos. Second, the frequencies of transformation are so low as to exclude work on human beings on ethical grounds. Third, the parameters effecting chromosomal integration sites and gene expression have not been fully characterized. Until it becomes experimentally possible to target the newly introduced DNA into expressable chromosomal sites and actively replace or supplement defective genes, the possibility of gene therapy through manipulation of embryos is remote. Yet, efforts to provide gene therapy in somatic tissues have been promising, leading to expression of a modified phenotype (Anderson, 1984). In contrast to embryo gene therapy, gene therapy in somatic tissues would not lead to germ line propagation of the manipulated genotype.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

The multi-state Kalman Filter in medical monitoring.

In order to gain the best advantage from a computer database the way in which the information is displayed is vitally important. On-line statistical techniques could prove to be a great bonus to medical monitoring but have been limited by the methodology available. The Kalman Filter is one of the most powerful methods for time series analysis, and we have now shown it to be useful in a variety of settings, including the detection of kidney transplant rejection, where detection in some patients precedes that of experienced clinicians.

Algorithms↗

Flow cytometric monitoring of cellular anthracycline accumulation in murine leukemic cells.

Cellular accumulation of daunorubicin (DNR), N-trifluoroacetyl-adriamycin-14-valerate, and THP-Adriamycin (THP-ADR) in doxorubicin sensitive and resistant murine leukemic P388 cells was studied with laser excited flow cytometry. Appearance of DNR fluorescence in P388/S cells was rapid in contrast to that of P388/R cells. A comparison of P388/S and P388/R cells incubated for 20-30 min showed that DNR fluorescence in P388/R cells was one-sixth that of P388/S cells. In contrast, the difference between fluorescence value of P388/S and P388/R cells similarly incubated with N-trifluoroacetyl-adriamycin-14-valerate or THP-ADR was less than 2-fold. Chlorpromazine, verapamil, and trifluoperazine increased the cellular accumulation and cytotoxicity of DNR and THP-ADR but had no major effect on N-trifluoroacetyl-adriamycin-14-valerate fluorescence or cytotoxicity in P388/R cells. Fluorometric and soft agar assays confirmed the data on the effect of these modulators on drug accumulation obtained by the more rapid method of laser flow cytometry.

Animals↗

In vitro activation of human sperm induced by amphibian egg extract.

In this paper we characterize a system for the activation of human sperm using cell-free extracts from Xenopus laevis eggs. We characterize the kinetics of sperm activation in terms of morphological and DNA synthetic parameters. We have optimized some of the components which are necessary for chromatin decondensation and present data to demonstrate that the in vitro process is efficient over a wide range of salt concentrations and amounts of supplementary reducing agents.

Animals↗

Effect of amphotericin B on Adriamycin transport in P388 cells.

In Adriamycin-sensitive and -resistant P388 cells, coincubation with amphotericin B causes a marked increase in Adriamycin retention, as determined by laser flow cytometry. P388/S cells were generally more affected than were P388/R cells. Preincubation with amphotericin B had a greater effect on Adriamycin retention than did co- or postincubation. In splenocytes, bone marrow, and ascites from mice, enhanced Adriamycin retention was seen in all the tissues. However, bone marrow cells showed heterogeneous response, with some populations being more sensitive than others.

Amphotericin B↗

Utilization of maternal and embryonic histone RNA in early sea urchin development.

Histone RNA in early sea urchin embryos is derived from maternal stores and from new transcription. We show that the sedimentation of maternal free RNPs, containing histone RNA, is somewhat more rapid than the sedimentation of the newly made histone RNPs. Yet, prior to the 2- to 4-cell stage, both the maternally derived and the newly synthesized histone RNA are localized to the same extent in the non-polysomal-free RNPs, and the timing of their recruitment into embryonic polysomes appears to be the same. The levels of hybridization of histone probe to RNAs in cleaving embryos increases severalfold in intensity, and the increase occurs primarily in the polysomes. These data suggest that new transcription may provide an important contribution to the total histone RNA mass by as early as the 32- to 64-cell stage of development.

Animals↗