Biomedical subjects
Publications and source records attributed to D Murphy.
As our knowledge of cell regulation pathways becomes increasingly sophisticated, the tools and techniques that have emerged from in vitro studies are being applied to the whole organism through transgenesis. With the development of new ways of modifying cellular signalling in intact animals comes the ability to analyse physiological systems and their pathologies with greater spatial and temporal precision.
13 patients with minimal residual disease following platinum-based systemic therapy for epithelial ovarian cancer were treated with intraperitoneal iproplatin. A total of three cycles were given at monthly intervals. All patients had minimal residual disease (defined as less than 2 cm in diameter) or positive cytology documented at second look laparotomy following systemic chemotherapy. Iproplatin was administered via a temporary dialysis catheter (n = 11) or a semi permanent Tenckhoff peritoneal dialysis catheter (n = 2). The dose of iproplatin ranged from 150 to 450 mg/m2. No responses to therapy were documented. In this trial the major toxic side effects of iproplatin were thrombocytopenia, diarrhoea, nausea and vomiting. The maximum tolerated dose was 300 mg/m2.
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Transgenic animal techniques offer today's neuroscientist the ability to experimentally manipulate neurosecretory systems with a precision undreamt of by our predecessors. The range of techniques now available, building as it does on our growing knowledge of physiological systems at the inter- and intercellular level, allows us to critically define molecular lesions and ask about their consequences to the whole organism. Neuroscientist should grasp the opportunities afforded by these recent developments.
A study involving the measurement of glutathione S-transferase activities and isoenzyme distributions in human ovarian tumours has been carried out. These tumours have been obtained either at initial debulking surgery, prior to cytotoxic chemotherapy, or at second look laparotomy following chemotherapy. The response rates of these two groups to chemotherapy differ markedly, with patients who have relapsed following initial chemotherapy showing a reduction in response rates to subsequent chemotherapy. Analysis of these data show no statistically significant differences between the glutathione S-transferase activity or isoenzyme distribution in these two groups of patients. Significant differences were observed in the glutathione-S-transferase activities (GST) between tumours and normal ovaries. GST activities in pre-chemotherapy tumours (n = 33, P = 0.01) and post-chemotherapy tumours (n = 20, P = 0.001) where significantly higher than the GST activity in normal ovaries (n = 15). One feature was the expression of the basic isoenzyme which is expressed more in normal ovaries than in tumours. No differences in these parameters were observed in normal peritoneal tissue taken from patients before or after chemotherapy. These data do not support the hypothesis that changes in glutathione S-transferase enzyme activity or isoenzyme expression are major determinants of response to chemotherapy in ovarian tumours.
In thyroid hormone-depleted rats, the rate of transcription of the growth hormone (GH) gene in the anterior pituitary gland is lower than the rate in euthyroid controls, and there is a corresponding reduction in the abundance of the GH mRNA. Concomitantly, the poly(A) tail of the GH mRNA increases in length. Examination of nuclear RNA from anterior pituitary glands of control and thyroid hormone-depleted rats revealed no difference in the length of pre-mRNAs containing the first and last introns of the GH gene. However, mature nuclear GH RNA is differentially polyadenylated in euthyroid and hypothyroid animals. We suggest that the extent of polyadenylation of the GH transcript is regulated in the cell nucleus concomitant with or subsequent to the splicing of the pre-mRNA. Experiments with anterior pituitary gland explant cultures demonstrated that the GH mRNA from thyroid hormone-depleted rats is more stable than its euthyroid counterpart and that the poly(A) tail may contribute to the differential stability of free GH ribonucleoproteins.
Transgenic mice for the promoter sequence of bovine arginine vasopressin (AVP) gene fused to large SV40 T-antigen coding sequence develop pituitary tumors and insulin-producing pancreatic tumors. In order to establish the cellular composition of the pituitary tumors, histological, immunocytochemical, in situ hybridization, and electron microscopic technics were applied. Pituitary anterior lobe tumors were identified in 10 out of 14 glands examined. In 2 of these cases, intermediate lobe tumors were also found. The anterior lobe tumors contained a variable number of GH immunoreactive cells. In situ hybridization performed in 7 cases revealed a diffuse distribution of GH messenger RNA over all tumor cells. Ultrastructurally, the tumors contained undifferentiated cells with very small secretory granules and rare cells showing some resemblance to somatotrophs. The results indicate that these pituitary tumors are composed of undifferentiated somatotrophs. The presence of a few PRL immunoreactive cells in four tumors and scattered TSH immunoreactive cells in two tumors supports the view that somatotrophs have the potential to produce PRL and TSH. The intermediate lobe tumors were immunoreactive for ACTH and intensely positive for POMC mRNA. In the nontumorous adenohypophyses, no hyperplasia of any cell type was noted. Several GH immunoreactive cells exhibited pleomorphic, giant nuclei and mitoses. In conclusion, the majority of transgenic mice for AVP/large T-antigen develop pituitary tumors originating in and composed of somatotrophs. Less frequently, intermediary lobe tumors were present as well. AVP/SV40 transgenic mice provide a unique experimental model for somatotroph tumors that are neither preceded by, nor associated with somatotroph hyperplasia.
Carboxypeptidase-H (CPH) is a metallocarboxypeptidase implicated in the processing of peptide hormones. Consistent with such a role, the gene for CPH is expressed in cells that secrete regulatory peptides, such as those of the brain and endocrine tissues. In the rat brain, CPH is transcribed from a single transcriptional start site associated with the initiator-type element first described in the gene encoding lymphocyte-specific terminal deoxynucleotidyltransferase. We have used a combination of Northern blot analysis and S1 nuclease protection mapping to describe the expression and transcription initiation pattern of the gene for CPH in the peripheral tissues and brain regions of the normal rat. The single transcriptional start site is used in all tissues examined, except the pituitary, where two additional specific initiation sites are found. The expression of the CPH gene is up-regulated in the anterior pituitary gland as a consequence of systemic thyroid hormone depletion, and this increase is associated with a preferential utilization of the novel upstream transcriptional initiation sites. Thus, the use of different major transcriptional initiation sites of the CPH gene in the pituitary gland is subject to differential direct or indirect thyroid hormone regulation.
Intraperitoneal chemotherapy (IPCT) is under evaluation in patients with ovarian cancer. Computed tomographic peritoneography (CTP) prior to IPCT establishes the distribution of the infusate, which if complete, demonstrates the patient's suitability for this method of treatment. We report our method of CTP and describe the intraperitoneal fluid distribution and complications encountered in 28 patients with advanced ovarian carcinoma being considered for IPCT.
Where do opiate addicts obtain drugs? Interviews with patients in an Iowa methadone clinic reveal some surprising responses with definite implications for physicians who prescribe.
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Verapamil was shown to be capable of increasing intracellular daunorubicin levels in normal lymphocytes isolated from patients undergoing chemotherapy for epithelial ovarian cancer. The extent of the increase in daunorubicin accumulation was variable, occurring in the range of 0-123% as compared with intracellular daunorubicin levels attained in the absence of verapamil. No similar effect was seen in lymphocytes isolated from healthy volunteers. A tentative explanation of these data may be the induction of multidrug resistance (mdr)-like characteristics in normal lymphocytes following cytotoxic chemotherapy.
Modification of the benzodiazepine (BZ) receptor binding template 2-aryl[1,2,4]triazolo[1,5-c]quinazolin-5(6H)-one by replacement of the annelated benzene ring with various alicyclic and heterocyclic moieties led to novel structures with potent BZ receptor binding affinity. High affinity was found in some cycloalkyl-annelated [1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-ones and in some 7,8,9,10-tetrahydropyrido[3,4-e][1,2,4]triazolo[1,5-c]pyrimidin- 5(6H)-ones, in which the degree of activity was strongly dependent on the N-substituent in the 9-position. Nine compounds with BZ receptor IC50 binding affinity values equal or superior to diazepam were evaluated in secondary screening. One of these, 9-benzyl-2-phenyl-7,8,9,10-tetrahydropyrido[3,4-e] [1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one, showed good activity in rats as a potential anxiolytic agent without sedative liability. However, it increased the rotorod deficit produced by ethanol at anxiolytic doses, an indication of alcohol interaction. Thus, none of the compounds showed an advantage over CGS 9896 (Yokoyama et al. J. Med. Chem. 1982, 25, 337-339), which is free of sedative and alcohol interaction potential as measured by the test procedures described.
The metallothionein content of ovarian tumours is considerably higher than that found in normal ovaries (greater than 100-fold differences in mean values, P less than 0.001). There was no difference between the metallothionein content of tumours from patients who had completed chemotherapy, usually with a regimen containing a platinum drug, and tumours from untreated patients. Similarly, the level of metallothionein was not influenced by response to therapy, age, stage, histology, or tumour cell differentiation state. These data do not support the hypothesis that metallothionein content is a major determinant of tumour sensitivity in ovarian cancer.
1. Changes in blood pressure during the normal menstrual cycle are not well documented, and previous studies have given conflicting results. 2. Thirty normotensive women and ten mildly hypertensive women measured their blood pressure at home each morning for 6 weeks, under standardized conditions, using a UA-751 semi-automatic sphygmomanometer. All had normal menstrual cycles and subjects entered the study at different phases of the cycle. 3. Blood pressure was higher at the onset of menstruation than at most other phases of the cycle (systolic blood pressure, P less than 0.05; diastolic blood pressure, P less than 0.001). Adjusted diastolic blood pressure was higher in the follicular than in the luteal phase (mean difference 1.23 mmHg, P less than 0.001). Similarly, blood pressure was lower during days 17-26 than during the remainder of the cycle (adjusted mean difference in systolic blood pressure -0.65 mmHg, P = 0.07; adjusted mean difference in diastolic blood pressure -1.19 mmHg, P less than 0.001). 4. Similar patterns were seen in normotensive and hypertensive subjects, and changes in plasma 17 beta-oestradiol and progesterone concentrations were also similar in the two groups.
Development of a vaccine for acquired immunodeficiency syndrome (AIDS) has proven difficult, and so alternative approaches such as idiotypic manipulation have been suggested. As applied to AIDS, this approach could involve immunizing with an anti-CD4 antibody resembling gp120, to induce anti-idiotypic antibodies which would bind to gp120. The CD4 binding site on gp120 is conserved, and so, such an immune response should protect against all variants. Induction of anti-human immunodeficiency virus (HIV) immunity has been reported using anti-Leu3a, and this result has led to testing in humans. Negative results obtained by others have been attributed to differences in immunization protocols. Because of the importance of this question, we reinvestigated the potential of anti-Leu3a to induce anti-HIV antibodies, compared with control immunizations with OKT4A (another anti-CD4 antibody) and the irrelevant Ig MOPC-21. Responses to anti-Leu3a showed induction of high-titer anti-idiotypic activity, and included combining-site-related activity. Yet sera showed no binding to gp160 above controls and no detectable neutralizing activity in a sensitive HIV plaque assay, so the anti-idiotypes induced were not internal images of CD4. We conclude that the pronounced anti-HIV responses reported with anti-Leu3a cannot be generalized, and thus that anti-Leu3a does not offer promise as an HIV vaccine. However, these results do not negate the promise of the idiotypic approach, and a vaccine for AIDS based on idiotype manipulation remains a possibility.
OBJECTIVE: To determine whether nulliparae whose second stage of labour is conducted in an obstetric birth chair have a lower incidence of instrumental delivery than those using a conventional delivery bed. DESIGN: Randomized controlled trial using sealed, opaque envelopes for allocation. SETTING: Delivery ward in a busy teaching hospital. PATIENTS: 1250 nulliparae with a singleton live fetus with cephalic presentation, without epidural anaesthesia, who had achieved full dilatation. INTERVENTION: Intention to conduct second and third stages of labour in either the Birth-EZ chair or the conventional delivery bed, as randomly allocated. MAIN OUTCOME MEASURES: Primary measure: vaginal operative delivery; principal secondary measures: duration of second stage, perineal trauma, blood loss, women's views, and neonatal status. RESULTS: Delivery in the birth chair did not result in a reduction in operative delivery, overall. However, there was a reduction in vaginal operative delivery for fetal heart rate abnormality. There was no beneficial effect on perineal trauma or puerperal perineal pain. Post-partum haemorrhage was more frequent in the birth chair group. CONCLUSIONS: Delivery in the birth chair does not offer any obvious advantage to women over delivery on a bed.
Recombinant native human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins gp160 and gp120 (residues 1 to 511) expressed in insect cells quantitatively adsorbed the group-specific neutralizing antibodies found in human sera. However, these antibodies were not adsorbed by envelope fragment 1 to 471 or 472 to 857 or by both fragments sequentially, even though together they add up to the full-length gp160 sequence. A hybrid envelope glycoprotein was constructed with residues 342 to 511 of the HIV-1 sequence and residues 1 to 399 of the simian immunodeficiency virus type 1 sequence to vary the HIV-1 sequence while preserving its conformation. This hybrid glycoprotein quantitatively adsorbed human neutralizing antibodies, while native simian immunodeficiency virus type 1 envelope glycoprotein did not. These results identify a new neutralizing epitope that depends on conformation and maps to residues 342 to 511 of gp120. It overlaps the extended CD4-binding site but is distinct from the V3 loop described previously (K. Javaherian et al., Proc. Natl. Acad. Sci. USA 86:6768-6772, 1989; J. R. Rusche et al., Proc. Natl. Acad. Sci. USA 85:3198-3202). Since it is conserved among diverse HIV-1 isolates, this new epitope may be a suitable target for future vaccine development.