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Biomedical subjects

S Jamieson

Publications and source records attributed to S Jamieson.

At least 19 recordsLinked to original sources

Impact of the recommendations of the British Pacing and Electrophysiology Group on pacemaker prescription and on the immediate costs of pacing in the Northern Region.

BACKGROUND: The report from the Working Party of the British Pacing and Electrophysiology Group recommends the use of more sophisticated pacemakers in most patients. These proposals were initially circulated in September 1990 and are likely to have major cost implications. Their impact on pacing practice and the immediate costs of pacemaker hardware in the Northern Region were retrospectively audited. METHODS: The pacing records of 550 patients undergoing a first pacemaker insertion at the Freeman Hospital between March 1990 and August 1991 were reviewed. The patient's age, indication for pacing, pacing mode, and the cost of generator and lead(s) were recorded. The cost was compared with the costs of pacing with the optimal and alternative modes recommended by the Working Party. The costs were calculated from the actual mean cost of the recommended unit over the 18 month period of study multiplied by the number of patients who would have received that unit. RESULTS: 96% of patients were paced for sinus node dysfunction, atrioventricular block, or atrioventricular block and atrial fibrillation. The mean (SD) ages of patients in each diagnostic group were: sinus node dysfunction 69.4 (14), sinus node disease and atrioventricular block 67.2 (17.6), atrioventricular block 73.9 (12.5), atrial fibrillation and atrioventricular block 74.0 (13.9), and carotid sinus hypersensitivity 74.6 (11.6) years. Over the 18 month audit period there was an increase in physiological pacing. AAI pacing in patients with sinus node dysfunction increased by 100% and DDD pacing in atrioventricular block increased by atrioventricular block increased by 56%. Over the whole 18 month period the adoption of the British Pacing and Electrophysiology Groups optimal recommendations would have increased expenditure on pacemaker hardware in the Northern Region by 94% and the use of the alternative mode would have increased it by 61%. For the last six months alone the excess would be 78% and 48%. CONCLUSIONS: The adoption of the recommendations of the British Pacing and Electrophysiology group in the Northern Region would greatly increase the cost of pacing hardware. The greater part of this increase would be attributable to the routine use of dual chamber pacing in patients with atrioventricular block and the increased use of rate responsive units. The benefits of sophisticated pacing in a predominantly elderly population need to outweigh the disadvantages of the increased cost and complexity of follow up.

Aged

Nonuniform expression of a mouse mammary tumor virus-driven int-2/Fgf-3 transgene in pregnancy-responsive breast tumors.

We have developed transgenic mice in which expression of the mouse int-2/Fgf-3 gene is regulated by a single long terminal repeat from mouse mammary tumor virus. Such mice contain and transmit a replica of the activated int-2/Fgf-3 allele present in a spontaneous mammary tumor from a BR6 mouse. Although free of infectious mouse mammary tumor virus and with a different genetic background, the transgenic mice develop pregnancy-responsive mammary epithelial proliferations that are similar to the early stages of tumorigenesis in the BR6 strain. Histological examination revealed that most of these tumors showed pronounced tubular and acinar structures, features usually associated with morphological differentiation. In some cases, the tumors were locally invasive, causing disruption of the dermis which manifested itself as local hair loss. In situ hybridization showed that patterns of transgene expression in the abnormal glands were markedly nonuniform. In contrast, mouse mammary tumor virus-induced neoplasms showed more uniform expression of int-2/Fgf-3, as did the urogenital epithelial proliferations that occur among males of this transgenic line. These data suggest that mammary tumors in virally infected animals may depend primarily on autocrine stimulation by the int-2/Fgf-3 gene product, whereas both autocrine and paracrine mechanisms may contribute to tumors and hyperplasias found in transgenic animals.

Animals

Transfection of a non-metastatic diploid rat mammary epithelial cell line with the oncogenes for EJ-ras-1 and polyoma large T antigen.

Transfection of rat mammary (Rama) 37 epithelial cells which yield non-metastasizing adenomas in syngeneic Wistar-Furth rats with a drug resistance plasmid containing both the neo gene and EJ-ras-1 (pSV2neo.ras) or with pSV2neo and a plasmid encoding the large T Antigen (pLT214) of polyoma virus yields drug-resistant transformants with a frequency of 10(-5). Representative transformants have been propagated in neo-selecting medium to yield various cell lines. The 7 lines transfected with pSV2neo.ras (EJ1 set) and the 10 lines co-transfected with pSV2neo and pLT214 (LT1 set) all produce tumours at subcutaneous (s.c.) sites with a shorter median latent period than tumours produced by the parental Rama 37 cells. In addition, the LT1 set of transformants yields a higher incidence of tumours than the Rama 37 cells. No metastases are produced when any of the oncogene transformants are inoculated s.c. into rats. However, when an EJ1 representative is inoculated intravenously (i.v.), tumour deposits are found in the lungs of the host animals. In contrast, other Rama 37 variants that metastasize from s.c. sites fail to produce any metastases when inoculated i.v. The oncogene transfectants contain integrated DNA that hybridizes to neo and to the requisite oncogenic DNAs; the pattern of hybridizing bands to the transfected genes and their expression as mRNA is complex, and is presented in detail.

Animals

Production of metastatic phenotype with DNA from metastatic cells but not with oncogenic DNA.

Although the tumorigenic phenotype can be transferred by transfecting DNA from a variety of human tumours into 3T3 mouse fibroblasts, the ability to transfer the metastatic phenotype in a similar manner in syngeneic animals is largely unknown. We now report that transfection of a rat mammary epithelial cell line Rama 37, which produces nonmetastasizing adenomatous tumours in syngeneic rats, with DNA from a metastasizing rat mammary cell line, Rama 800, yields some transfectants with reproducible metastatic capabilities. Nonspecific DNA or the oncogenes EJ-ras-1 or Polyoma Large T Antigen fail in this respect, although their transfectants often possess increased tumorigenic potential.

Animals

Generation of metastatic variants by transfection of a nonmetastatic rat mammary epithelial cell line with DNA from a metastatic rat mammary cell line.

Transfection of rat mammary (Rama) 37 epithelial cells, which yield nonmetastasizing adenomas in syngeneic Wistar-Furth rats, with HindIII-fragmented cellular DNA and the drug-resistance plasmids pSV2gpt or pSV2neo yields drug-resistant transformants with a frequency of 10(-4)-10(-5). Transformant cell lines transfected with the following, pSV2gpt alone, pSV2gpt and Rama 37 DNA, pSV2gpt and DNA from a metastasizing cell line Rama 800 (CT set), pSV2neo and salmon sperm DNA, pSV2neo and Rama 800 DNA (C set), all yield tumors when injected subcutaneously into syngeneic rats. A few transformants obtained by cotransfection with DNA from Rama 800 cells produce metastases in lungs and/or lymph nodes. The incidence of such metastases for two transfectants, termed CT4-41 and C18P, is significant at 20 and 24%, respectively, but only half (48%) that achieved with Rama 800 cells. Reintroduction into rats of cells cultured from a metastatic tumor of CT4-41 and of C18P, and from their lung or lymph node metastases, produces either a similar incidence (20-24%) or a significantly higher (48-52%) incidence of metastasis than that of the original transfectants. Cells cultured from nonmetastatic tumors fail to produce any metastatic lesions. When [32P]-labeled gpt or neo DNAs are hybridized to EcoRI-digested cellular DNA of the CT4-41 or C18P series of cell lines, tumors or metastases, gpt binds to one major fragment of 3,800 basepairs, and neo to two major fragments of 5,700 and 4,200 basepairs. The same cell lines produce hybridizing mRNAs of 1,500 and 1,900 bases for the CT4-41 series and 2,000-2,400 bases for the C18P series. It is suggested that transfection of DNA from the metastatic cells causes the nonmetastatic cells to become metastatic, in a genetically dominant manner, but additional steps are required for this process to become established and expressed at a level equivalent to that of the original, metastasizing donor cells.

Animals

Identification of metaplastic variants generated by transfection of a nonmetastatic rat mammary epithelial cell line with DNA from a metastatic rat mammary cell line.

The rat mammary 37 epithelial cell line yields non-metastasizing adenomas in syngeneic rats. On cellular DNA transfection, a series of cell lines have been isolated that grow in drug-selective medium. Representative transfected cell lines all yield tumors in rats that consist predominantly of spindle cells, but two also contain epithelial-like cells and glandlike elements (C18P, C19P). Immunocytochemical staining for milk fat globule membrane antigens, human callus keratin, and laminin confirms the identity of the epithelial cells and suggests a (myo)epithelial origin for the spindle cells. Some of the transfected cell lines also generate well-differentiated metaplastic elements in their tumors. One cell line (CT4-41) produces rhabdomyoblastic and possibly smooth-muscle-related elements; two (C18P, C19P) produce squamous metaplasia and sebaceous elements; and two (CL1-31, C11P) produce cartilaginous elements. The identities of the heterologous elements are confirmed by immunocytochemical staining for myoglobin, actin (CT4-41), keratin (C18P, C19P), type II collagen, and type II keratan sulfate (CL1-31). Those cell lines that have acquired the ability to metastasize from subcutaneous sites (CT4-41, C18P) reproduce the same metaplastic elements in their metastases. Thus, a cloned mammary epithelial cell line can be made to generate many of the well-differentiated, heterologous elements observed in human breast carcinomas, and this change is often associated with the rat cells acquiring metastatic properties.

Animals

Primary cardiac neoplasms. Early and late results of surgical treatment in 42 patients.

Forty-two patients underwent resection of primary cardiac neoplasms at Stanford University Medical Center and the Palo Alto Veterans Administration Medical Center between 1961 and 1986. A total of 27 atrial myxomas, seven benign nonmyxomatous tumors, and eight malignant tumors were resected. The mean age was 47 years (range 8 to 79) in 27 female and 15 male patients. The clinical presentations included congestive heart failure in 24 patients, palpitations in nine, neurologic symptoms in six, recurrent cardiac tamponade in three, vasculitis in two, and chest pain in two. Thirty-one of 34 benign lesions were completely resected, although one patient required cardiac transplantation to resect completely an "inoperable" benign tumor. All gross tumor was resected in four of eight patients with malignant lesions. All patients survived operation, but three with malignant disease died within 30 days. Late outcome was known for 41 of 42 (98%) patients. Total follow-up for the series was 200.1 patient-years, for an average of 4.7 years (range 1 month to 18 years). Excellent early and late results were obtained in patients with benign lesions, as there was no known tumor recurrence even if resection was incomplete. Effective palliation and local control of disease is possible with extensive resection of malignant primary tumors, but more effective adjuvant therapy will be necessary to improve long-term prognosis.

Adolescent

Beta 1- and beta 2-adrenergic-receptor subpopulations in nonfailing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective beta 1-receptor down-regulation in heart failure.

We used radioligand binding techniques and measurement of beta-agonist-mediated positive inotropic responses in isolated cardiac tissue to examine beta-adrenergic-receptor subpopulations in nonfailing and failing human left and right ventricular myocardium. In tissue derived from 48 human hearts the receptor subtypes identified in nonfailing ventricle by radioligand binding were beta 1 (77%) and beta 2 (23%), with no evidence of an "atypical" beta-adrenergic receptor. In failing left ventricle the beta 1:beta 2 ratio was markedly different, i.e., 60:38. This decrease in the beta 1 proportion and increase in the beta 2 proportion in the failing ventricles were due to a 62%, "selective" down-regulation of the beta 1 subpopulation, with little or no change in beta 2 receptors. In muscle bath experiments in isolated trabeculae derived from nonfailing and failing right ventricles, both beta 1- and beta 2-adrenergic receptors were coupled to a positive inotropic response. In nonfailing myocardium, beta 1 responses predominated, as the selective beta 1 agonist denopamine produced a response that was 66% of the total contractile response of isoproterenol. In heart failure the beta 1 component was markedly decreased, while the beta 2 component was not significantly diminished. Moreover, in heart failure the beta 2 component increased in prominence, as the contractile response to the selective beta 2 agonist zinterol increased from a minority (39%) to a majority (60%) of the total response generated by isoproterenol. We conclude that failing human ventricular myocardium contains a relatively high proportion of beta 2 receptors, due to selective down-regulation of beta 1 receptors. As a result, in the failing human heart the beta 2-receptor subpopulation is a relatively important mediator of inotropic support in response to nonselective beta-agonist stimulation and is available for inotropic stimulation by selective beta 2 agonists.

Adrenergic beta-Agonists

Dedifferentiation of rat mammary myoepithelial-like cell lines after passage in vivo or cloning in vitro.

Myoepithelial-like cell lines from normal mammary glands of neonatal Ludwig Wistar rats, rat mammary (Rama) 401 and Rama 704E, were injected into fat pads of syngeneic animals or were single-cell cloned in vitro. Rama 401 produced tumors that were predominantly composed of elongated cells, while the subclones of both cell lines yielded multilayered structures of elongated cells when grown on floating 0.3% collagen gels in vitro. Immunocytochemical analysis of histologic sections for markers of myoepithelial cells revealed that anti-actin-myosin and human keratin sera failed to stain the Rama 401 tumor cells or subclones of both cell lines on collagen gels, but both were stained with antilaminin serum. Immunofluorescent analysis of cultures of Rama 401 tumors showed that the resulting elongated cells failed to stain with antikeratin serum, but abundant staining was observed with antilaminin and antivimentin sera, as in the tumors. Ultrastructural analysis of the Rama 401 tumor cells identified intermediate junctions and extracellular basement membrane-like material in the vicinity of plasma membrane-associated pinocytotic vesicles, but neither true desmosomes nor myofilamental bundles were observed. Thus growth of rat mammary myoepithelial-like cells as tumors in syngeneic animals or as subclones in vitro can lead to selective loss of myofilaments and prekeratin-containing intermediate filaments. Similar relatively undifferentiated elongated cells may be responsible for some of the cellular heterogeneity observed in certain carcinogen-induced rat mammary tumors.

9,10-Dimethyl-1,2-benzanthracene

Cardiac allograft survival in rhesus primates treated with combined total lymphoid irradiation and rabbit antithymocyte globulin.

Eighteen abdominal heterotopic cardiac allografts were performed in outbred rhesus primates. For immunosuppression seven animals received six 100-rad/day total lymphoid irradiation (TLI) doses the week preceding transplant and three 3-mg/kg i.m. rabbit antithymocyte globulin (RATG) doses on postoperative days -1, 0, and +1; five animals were given this RATG dose but no irradiation; three were given TLI alone; and three were given no immunosuppressive therapy. Circulating T lymphocyte counts were monitored in all animals (rosettes). Graft survival in the combined TLI-RATG therapy group (169 +/- 15 days) was significantly greater than in untreated (11 +/- 1 days), RATG alone (22 +/- 12 days), or TLI alone (38 +/- 6 days) treated animals (P less than 0.001, 0.0001, and 0.001, respectively). The animals receiving combined TLI-RATG therapy also achieved significantly greater and more prolonged T lymphopenia than that obtained in the other three groups. Six of seven cardiac allografts placed in animals receiving TLI-RATG therapy were removed electively before cessation of electrical activity; however, in four of these rejection pathology was noted. Thus, it seems that combined TLI-RATG therapy may be of benefit in the management of transplant recipients, but its use will probably not abolish these patients' requirements for immunosuppressive maintenance measures.

Animals

The effect of ICI 55,897 and clofibrate on platelet function and other tests abnormal in atherosclerosis.

There is considerable evidence that the quantity or quality of plasma lipids influences platelet function tests, and clofibrate reduces high plasma lipids and alters some platelet tests. Clofibrate was accordingly given to patients with vascular disease who were at risk of thrombosis. The heparin thrombin clotting time (HTCT), initially short and thus possibly reflecting increased activation, was regularly returned to normal after about a month's delay. The fibrinogen was also normalized but the initially abnormal anti-thrombic activity became more abnormal. ICI 55,897, an analogue of clofibrate, also normalized the HTCT and the fibrinogen and had no adverse effect on the anti-thrombin levels. This compound has no effect on plasma lipids. If it can be shown that the correction of abnormal tests conveys clinical benefit these findings suggest that ICI 55,897 might clinically be more beneficial than clofibrate. However, direct comparison of clofibrate and ICI 55,897 suggests that clofibrate is more effective in normalizing the HTCT. The mechanism underlying these drug-induced changes are unknown but they cannot be directly related to lipid changes.

Aged

Transatrial repair of ventricular septal defects with reference to their anatomic classification.

A consecutive series of 50 children undergoing elective operations for ventricular septal defect (VSD) is presented. Atriotomy was performed routinely. Repair of the defect through the tricuspid valve was attempted in all cases and achieved in 72 percent. There was a 24 percent incidence of right bundle branch block. All patients improved symptomatically after the operation. The mortality rate was 4 percent. The right atrial route is considered to be preferable as a primary approach and has no disadvantages.

Child

Effect of a diet of polyunsaturated fats on some platelet-function tests.

The fat in the normal diet of 19 apparently well men was partly replaced by linoleic acid. This produced striking changes in many platelet-function tests, suggesting decreased platelet activation. Twenty controls maintaining their normal diet showed no change. It is concluded that normal people have a degree of platelet activation which can be decreased. This may be relevant to the benefits attributed to a diet containing polyunsaturated fats.

Adult

Acute platelet changes after large meals of saturated and unsaturated fats.

Large amounts of saturated fats (S.F.) or unsaturated fats (U.S.F.) were given to healthy volunteers at a single meal. The heparin thrombin clotting-time, which may measure platelet factor 4 released from platelets into the plasma, was shortened after S.F. and prolonged after U.S.F. The antithrombin clotting activity decreased after S.F. and increased after U.S.F. The platelet-count decreased and the platelet volume increased after both S.F. and U.S.F.

Adult