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Biomedical subjects

D A Morgan

Publications and source records attributed to D A Morgan.

At least 19 recordsLinked to original sources
PubMed1992

Modulation of homeobox gene expression alters the phenotype of human hematopoietic cell lines.

We have previously reported that certain genes of the HOX2 cluster of homeobox genes on human chromosome 17 are specifically expressed in human leukemic cell lines with erythroid potential, suggesting that these genes are involved in hematopoietic differentiation. We now show that the expression of the HOX 2.2 gene decreases during erythropoietin-induced differentiation of the erythroid cell line MB02. In order to study the role of the HOX 2.2 homeobox gene in hematopoiesis, vectors producing sense or antisense transcripts were introduced into K562 and HEL cells, pluripotent lines with erythroid and myeloid features. Overexpression of HOX 2.2 is associated with loss of erythroid features in both lines and an increase in certain myelomonocytic markers in K562 cells. Expression of antisense HOX 2.2 is associated with an increase in erythroid features in HEL cells and a mild decrease in myeloid characteristics in K562 cells. Overexpression of the adjacent HOX 2.1 gene in K562 cells does not produce similar phenotype changes. These data demonstrate that modulation of a specific HOX 2 homeobox gene can change the phenotype of somatic cells and suggest that certain HOX 2 genes play a role in blood cell differentiation.

Blotting, Northern↗
PubMed1992

Effect of brief myocardial ischemia on sympathetic coronary vasoconstriction.

The purpose of the present study was to determine whether sympathetic coronary vasoconstrictor responses are altered after brief ischemia and reperfusion. Adult mongrel dogs were anesthetized and instrumented for measurements of heart rate, arterial pressure, left ventricular pressure, left ventricular dP/dt, anterior myocardial wall thickening, and left circumflex coronary artery (LCX) and left anterior descending coronary artery (LAD) blood flow velocities. Changes in coronary vascular resistance were recorded during intravenous bolus doses of norepinephrine and bilateral electrical stimulation of the stellate ganglia. After beta-adrenergic blockade and bilateral vagotomy, electrical stimulation of the stellate ganglia increased coronary vascular resistance in the LAD and LCX beds by 38 +/- 5% and 39 +/- 5%, respectively. After a 15-minute LAD occlusion, repeat electrical stimulation produced increases in coronary resistance of 16 +/- 3% and 45 +/- 8%, respectively (p less than 0.05 for the LAD before versus after the occlusion). The peak increase in coronary vascular resistance to two doses of norepinephrine was unchanged. After a shorter period of myocardial ischemia (7 minutes), similar increase in coronary resistance to stellate stimulation were observed before (27 +/- 4%) and after (26 +/- 6%) myocardial ischemia. The mechanism of this impaired sympathetic coronary vasoconstriction was further tested by examining the responses to bretylium and tyramine. Brief ischemia did not alter the coronary constrictor responses to either bretylium or tyramine, suggesting that mechanisms governing prejunctional release of norepinephrine are intact in the postischemic coronary arterial bed.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Granulocyte-macrophage colony-stimulating factor-dependent growth and erythropoietin-induced differentiation of a human cell line MB-02.

Peripheral blood blasts from a patient with acute megakaryoblastic leukemia were placed into liquid cultures with recombinant growth factors. Growth, but not differentiation, was supported by interleukin-3 (IL-3) or granulocyte-macrophage colony-stimulating factor (GM-CSF) for the first 30 days of culture. Sustained growth occurred only with GM-CSF and gave rise to the cell line MB-02, which has been in continuous culture for over 1 year. The cell line retained the surface phenotype of the leukemic megakaryoblasts except for the loss of glycoproteins Ib and IIb/IIIa, which were induced after exposure to phorbol esters. The induction of erythropoiesis occurred when GM-CSF-deprived cells were cultured with erythropoietin (Epo). Well-defined morphologic stages of differentiation ranging from primitive erythroblasts to nuclei-extruding normoblasts were seen. Transforming growth factor-beta inhibited GM-CSF- and Epo-dependent growth, but not erythroid maturation. Indirect immunofluorescence using globin chain-specific monoclonal antibodies detected fetal, but not adult hemoglobin in the uninduced cells. beta-globin was induced and gamma-globin was increased after Epo exposure. Both globin species accumulated in the developing erythrocytes until terminal differentiation. Quantitative S1 analysis of beta-like globin transcripts showed very low levels of epsilon- and beta-globin expression and high levels of gamma-globin expression in cells maintained in GM-CSF. Five days after induction with Epo, epsilon message decreased to barely detectable levels while gamma and beta transcripts increased threefold and 20-fold, respectively. This novel cell line not only retains many characteristics of the leukemic megakaryoblasts from which it was derived, but also can be induced to recapitulate apparent normal erythropoiesis.

Antigens, CD↗
PubMed1991

Squamous carcinoma of the temporal bone: a revised staging.

Carcinoma of the middle ear is a difficult tumour to treat. We present ten cases and discuss staging of these tumours. Our results would suggest that a revised staging system may allow better identification of patients that would benefit from surgery whilst sparing some multilating surgery that offers little to improve their quality or quantity of life.

Aged↗
PubMed1991

A Medical Research Council phase II trial of alternating chemotherapy and radiotherapy in small-cell lung cancer. The Medical Research Council Lung Cancer Working Party.

In a non-randomised study in six centres in the UK, 24 patients with previously untreated small-cell lung cancer of limited extent were treated with a regimen of alternating chemotherapy and radiotherapy to assess response, toxicity, and the feasibility of applying such a regimen on a multicentre basis in the UK. The intention was to give six courses of chemotherapy on five consecutive days at 4-week intervals: etoposide 75 mg m-2 on days 1, 2, and 3; doxorubicin 40 mg m-2 on day 1; cisplatin 100 mg m-2 on day 2; and cyclophosphamide 300 mg m-2 on days 2, 3, 4 and 5. A dose of 20 Gy thoracic radiotherapy was to be given following the 2nd and the 3rd courses, and one of 15 Gy following the 4th course. After 12 patients had been admitted, the cisplatin dosage was reduced to 80 mg m-2 because of unacceptable toxicity. Two patients were withdrawn during treatment on review of their histology because their diagnosis was found to be incorrect. Only one patient of the 12 treated with cisplatin 100 mg m-2 was able to complete treatment, compared with five of the eligible ten given the lower dosage. Among the 22 patients with confirmed small-cell disease, a complete response was reported in 14 (64%) and a partial response in a further three (total response rate 77%). Myelosuppression was the commonest serious adverse effect. It occurred in 19 of the 24 patients and gave rise to septicaemia in five, four of whom were receiving the higher cisplatin dose. Sixteen patients required blood transfusion and ten platelet transfusion. Vomiting, oesophagitis, and peripheral neuropathy occurred in 12, four and four patients, respectively, and radiation pneumonitis developed in two. Treatment was considered a contributory cause of death in four. The working party concluded that the alternating regimen was feasible in only a small proportion of centres in the UK, and decided not to embark on a multicentre randomised trial comparing alternating with conventional scheduling.

Activities of Daily Living↗
PubMed1991

Radiotherapy of advanced laryngeal cancer using three small fractions daily.

Since 1983, we have treated advanced (UICC stages III and IV) squamous carcinomas of the larynx by primary radiotherapy, using three small fractions a day, 3-4 h interfraction interval, 5 days per week. The early patients received doses per fraction of 1.5 Gy, and a total dose of approximately 70 Gy, given as a split-course over 6 to 7 weeks. While overall tumor control and laryngeal preservation was good, a number of severe late radiation reactions were seen. The schedule was then modified, with a reduction in the fraction size to 1.1 Gy, the total dose to 60 Gy, and the overall time to 4 weeks, with omission of the mid-treatment "split." Since 1986, we have treated 26 patients in this way. Acute reactions are brisk, but rapidly healing. Loco-regional control was achieved in 22 patients, only one of whom has relapsed to date, in a solitary node, salvaged by radical neck dissection. Four have died of uncontrolled loco-regional malignancy, and three of intercurrent disease while in clinical remission. No serious late morbidity has been observed in surviving patients, and vocal quality is good in the majority. These results suggest that this hyperfractionated and accelerated radiotherapy schedule may offer an acceptable nonsurgical, voice-preserving treatment for advanced laryngeal carcinoma; it can be used in a normally working radiotherapy department.

Adult↗
PubMed1991

Concomitant chemo/radiotherapy for advanced carcinoma of the head and neck.

Giving chemotherapy and radiotherapy simultaneously (concomitant therapy) is one approach to improving results in advanced head and neck cancer. To assess the feasibility of one such regimen, 25 patients with advanced squamous carcinoma of the head and neck were treated with a continuous intravenous infusion of 5-fluorouracil, 1 g/m2 per 24 h for Days 1-5 (105 h) and mitomycin-C 14 mg/m2 intravenously on Day 3 during the first week of radiotherapy. Twenty had Stage IV disease; four Stage III; and one Stage II. Ages ranged from 21 to 73 years (median 60 years). The tumours involved were as follows: oral cavity (6); nasopharynx (8); oropharynx (5); secondary node from unknown primary (3); hypopharynx (2); paranasal sinus (1). Radiotherapy was delivered as 10 Gy per week (total dose 60-70 Gy). Chemotherapy was well tolerated and all received the intended dose. Mild nausea occurred in five patients and three experienced transient vomiting. A generalized "early" mucositis affected 16 out of 25 (64%), caused interruption of radiotherapy in three patients, and is thought to be chemotherapy related. Twenty-two patients received the dose of radiotherapy intended, and two stopped prematurely at 53 and 56 Gy. Three episodes of neutropaenic infection occurred. Two recovered uneventfully, but one toxic death occurred in a patient with alcoholic cirrhosis. A complete response was seen in 21 (84%). For 17 patients with non-nasopharyngeal carcinoma the 2-year survival is 40%, 24% disease free. The concomitant use of 5-fluorouracil, mitomycin and radiotherapy is well tolerated in this group of patients.

Adult↗
PubMed1991

Sympathetic nerve responses to sustained stimulation of somatic afferents in Dahl rats.

We tested the hypothesis that the hypotensive and sympathoinhibitory responses which occur after somatic afferent stimulation would be augmented in prehypertensive rats genetically predisposed to hypertension (Dahl salt-sensitive, DS) compared with rats resistant to the development of hypertension (Dahl salt-resistant, DR). For this purpose, we recorded mean arterial pressure (MAP), heart rate and renal sympathetic nerve activity (RSNA) during and following 30-min sciatic nerve stimulation in DS and DR rats fed a 0.4% NaCl diet. Baseline MAP did not differ significantly in the DS and DR rats. Somatic afferent stimulation in DS rats increased (P less than 0.05) MAP and heart rate and tended to increase RSNA whereas, in DR rats, stimulation increased (P less than 0.05) heart rate and tended to increase RSNA and MAP. Following somatic afferent stimulation, there were significant reductions (P less than 0.05) in both MAP (-20 +/- 6 mmHg) and RSNA (-36 +/- 8%) in DS rats. In contrast, DR rats did not exhibit significant poststimulation changes in MAP, and RSNA remained elevated from control following somatic afferent stimulation. These results suggest that the poststimulation inhibition of RSNA in DS rats may be related to the genetic predisposition of these rats to develop hypertension.

Afferent Pathways↗
PubMed1991

A prospective study of patient choice in treatment for primary breast cancer.

One hundred and sixty-three patients with primary breast cancer were prospectively studied. Using recently developed selection criteria 91 patients were offered a choice of treatment. Forty-one chose to undergo conservation treatment and 47 chose to undergo simple mastectomy. In those women who were offered a choice of treatment there was a significant tendency for younger patients to choose breast conserving treatment.

Adult↗
PubMed1990

Mammography in the pre-operative assessment and post-operative surveillance of patients treated by excision and radiotherapy for primary breast cancer.

To evaluate the place of mammography in the selection of patients for excision and radiotherapy for primary breast cancer a detailed analysis of pre-operative mammograms was performed in (i) a study group of 37 patients who developed local recurrence; (ii) a matched control group with a median local recurrence free survival of 57 months. There were significantly more multifocal tumours in the study group. Tumours were significantly larger (P = 0.02) and closer to the nipple (P = 0.008) in the study group compared to the control group. Regular follow-up mammograms were available in 26 of the study group. Twenty-one patients had mammographic evidence of either residual or recurrent tumour. We conclude that pre-operative mammography is essential in the selection of patients for excision and radiotherapy. Following treatment, mammography is useful in detecting residual or recurrent disease.

Adult↗
PubMed1990

Endothelial prostaglandin secretion: effects of typhus rickettsiae.

Cultured human umbilical vein-derived endothelial cells were incubated with typhus rickettsiae, and supernatants were examined for the presence of prostaglandins I2 (PGI2) and E2 (PGE2). Cells incubated with metabolically active rickettsiae secreted significantly more PGI2 and PGE2 than did those incubated with buffer alone or with killed rickettsiae. The amount of PGI2 secreted was directly related to the number of hemolytically active rickettsiae present; abolishing rickettsial hemolytic activity abolished their effect on PGI2 secretion. Mice injected with a lethal dose of native typhus rickettsiae exhibited a rapid rise in circulating PGI2 levels; mice given hemolytically inactive rickettsiae survived and exhibited no rise in plasma PGI2 levels. Finally, endothelial cells were infected with rickettsiae, and secretion of prostaglandins was monitored during rickettsial multiplication; intracellular accumulation of rickettsiae resulted in endothelial destruction and a dramatic increase in endothelial secretion of PGI2 and PGE2. Therefore, typhus rickettsiae can increase endothelial secretion of arachidonate-derived autocoids.

Cells, Cultured↗
PubMed1990

Inhibition of renal sympathetic activity and heart rate by vasopressin in hemorrhaged diabetes insipidus rats.

Hypotensive hemorrhage paradoxically decreases renal sympathetic nerve activity (SNA) and heart rate (HR) in normal rats. Interruption of vagal reflexes by cervical vagotomy prevents these inhibitory responses but does not unmask expected increases in either renal SNA or HR. Arginine vasopressin (AVP), which increases markedly during hemorrhage, may also exert an inhibitory action on responses of renal SNA and HR to hemorrhage. We tested the hypothesis that inhibition of renal SNA and HR by hemorrhage is absent in AVP-deficient diabetes insipidus (DI) rats and is restored by intravenous AVP replacement (1 mU.kg-1.min-1 before hemorrhage and 10 mU.kg-1.min-1 during hemorrhage). We also determined whether vagotomy unmasks significant increases in renal SNA and HR during hemorrhage in DI rats and whether AVP replacement prevents these increases. Under chloralose anesthesia, hemorrhage to 50 mmHg mean arterial pressure for 8 min did not decrease renal SNA or HR in AVP-deficient DI rats but decreased (P less than 0.05) renal SNA and HR in normal Long-Evans rats and in DI rats receiving AVP replacement. After vagotomy, hemorrhage increased (P less than 0.05) renal SNA and HR in AVP-deficient DI rats but did not alter renal SNA or HR in Long-Evans rats and AVP-treated DI rats. Thus renal SNA and HR during hemorrhage were consistently higher (P less than 0.05) in AVP-deficient DI rats compared with Long-Evans or AVP-treated DI rats both before and after vagotomy. In addition, vagotomy attenuated the inhibitory action of AVP on the response of HR but not the response of renal SNA to hemorrhage in DI rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Prolonged renal sympathoinhibition following sustained elevation in arterial pressure.

We tested the hypothesis that sustained elevations in mean arterial pressure (MAP) would produce an abbreviated suppression of renal sympathetic nerve activity (RSNA) in spontaneously hypertensive (SH) compared with Wistar-Kyoto (WKY) normotensive rats. For this purpose, we recorded RSNA during and after a 30-min elevation in MAP. Elevations in MAP (35-40 mmHg) induced by phenylephrine resulted in a suppression of RSNA in SH and WKY rats that persisted after MAP had returned to control levels. The prolonged suppression of RSNA was eliminated following sinoaortic denervation, indicating that this response was dependent on afferent baroreceptor mechanisms. The simultaneous recording of RSNA and aortic depressor nerve (ADN) activity provided additional evidence that baroreceptor afferents contribute to this prolonged suppression of RSNA in SH rats. Despite the return of MAP to control levels following the sustained pressure elevation in SH rats, there was a paradoxical increase in ADN activity (39 +/- 14%) compared with control values. In contrast, both ADN activity and MAP returned to control levels in WKY rats following the sustained pressure elevation. The sustained increase of ADN activity in SH rats did not account for the entire magnitude of the prolonged recovery of RSNA. In summary, both SH and WKY rats exhibit prolonged suppression of RSNA, whereas ADN activity is paradoxically elevated in only SH rats following a sustained elevation in MAP.

Animals↗
PubMed1990

Effects of interstrain renal transplantation on NaCl-induced hypertension in Dahl rats.

Previous studies using renal transplantation suggested that the genotype of a homograft kidney plays the primary role in determining chronic arterial pressure levels in Dahl salt-sensitive (DS) and salt-resistant (DR) rats, but this conclusion derived largely from observations during low NaCl diet. Recent studies indicate that extrarenal factors, including the sympathetic nervous system, play a critical role in the development of NaCl-induced hypertension in DS rats. To assess the contribution of extrarenal and renal factors in the development of NaCl-induced hypertension in Dahl rats, we performed renal transplantation in DS and DR rats. Both kidneys of the recipient were removed at the time of transplantation. Four groups of rats (n = 18-23 in each group) were fed a high NaCl (8.0%) diet for 2 weeks after renal transplantation. These included DRR, DRS, DSR, and DSS, where DR or DS indicates the recipient strain and the subscript indicates the homograft strain. Mean arterial pressure was measured from the femoral artery in conscious rats. On a high NaCl diet, mean arterial pressure was significantly lower (p less than 0.05) in DRR (103 +/- 2 mm Hg; mean +/- SEM) compared with DRS (145 +/- 5 mm Hg), DSR (151 +/- 7 mm Hg), and DSS (160 +/- 5 mm Hg). The finding that DR rats with a DS kidney (DRS) developed hypertension during high NaCl diet confirms the concept that the kidney plays an important hypertensinogenic role in the Dahl strain. The fact that DS rats with a DR kidney (DSR) also developed hypertension indicates that extrarenal factors also contribute significantly to NaCl-induced hypertension in DS rats.

Animals↗