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Biomedical subjects

D Cosgrove

Publications and source records attributed to D Cosgrove.

At least 55 records · Page 3Linked to original sources
PubMed1994

The Royal Marsden Hospital pilot tamoxifen chemoprevention trial.

A pilot randomised placebo controlled trial using tamoxifen in healthy women at increased risk of developing breast cancer, has been undertaken in order to evaluate the problems of accrual, acute symptomatic toxicity, compliance, and safety as a basis for subsequent large national multicentre trials designed to test whether tamoxifen can chemoprevent breast cancer. From October 1986 until June 1993, 2012 healthy women with an increased risk of developing breast cancer, usually because of a strong family history, were randomly allocated to receive tamoxifen 20 mgs/day or placebo for up to 8 years if possible. Accrual remained high in spite of extensive informed consent regarding potential risk. Acute symptomatic toxicity was low for participants on tamoxifen or placebo and compliance remained correspondingly high with a predicted 77% of women on tamoxifen and 82% of women on placebo continuing medication at 5 years. There was a significant increase in hot flushes (34% versus 20%) mostly in premenopausal women (p < 0.005), vaginal discharge (16% versus 4%, p < 0.005), and menstrual irregularities (14% versus 9%, p < 0.005). The requirements for hormone replacement therapy for women on tamoxifen or placebo were the same. Safety monitoring indicates no adverse anti oestrogenic effects of tamoxifen. There was no obvious effect of tamoxifen on bone mineral densities (single photon radial absorption). The fibrinogen and antithrombin III were both lowered, resulting in no observed detrimental effect on the ratio of these clotting factors. There was a significant reduction in the serum cholesterol maintained out to 5 years. Annual pelvic assessment using transvaginal ultrasound indicates an increased incidence of uterine fibromata and benign ovarian cysts.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Another view of the selective model of thymocyte selection.

Thymocyte commitment to the CD4 helper versus CD8 cytotoxic lineage has not been satisfactorily established. Two models have been elaborated: one based on instruction, the other on selection. Most previous results support the instructive model, but our comparison of thymocyte differentiation in MHC class II-, class I- and double-deficient mice provides data challenging it. There exists a significant population of CD4 single positive cells in class II-deficient animals that is intermediate in maturity between CD4+CD8+ and end-stage CD4+CD8- thymocytes and is selected on class I molecules; an equivalent CD8+CD4- population occurs in class I-deficient animals. We propose a selective model entailing two TCR-MHC molecule engagements: the first provokes random down-modulation of either CD4 or CD8 and a degree of differentiation; the second, requiring participation of the appropriate coreceptor, permits end-stage differentiation.

Animals↗
PubMed1993

Do patients with less than 'echo-perfect' results from mitral valve repair by intraoperative echocardiography have a different outcome?

BACKGROUND: Not all valve repairs for mitral regurgitation (MR) have a perfect result, with no MR on postpump intraoperative echocardiography. Although more than 2+ MR by postpump echocardiography has led to second pump runs for further surgery in 6% to 8% of our patients, those left with 1+ or 2+ MR, traditionally an acceptable result, have not previously been evaluated for clinical outcome. METHODS AND RESULTS: Among 530 patients undergoing mitral repair during 1987 to 1989, 76 patients with 1+ or 2+ MR by postpump intraoperative echocardiography were compared with 76 patients who had equivalent age, sex, left ventricular function, and concomitant surgery but who had no MR by postpump echo. In-hospital morbidity measured by the frequency of respiratory complications, strokes, time in intensive care unit, and duration of hospital stay was actually higher in the patients with no MR after repair. Hospital mortality was not significantly different. There were no significant differences in posthospital mortality (4-year survival estimate of 86% in both groups), thromboembolic events, hospitalizations for heart failure, or functional class, although more patients in the group with no MR after repair were using diuretics. There was a trend toward more reoperations in patients with 1+ or 2+ MR compared with those with no MR by intraoperative echocardiography after repair (4-year estimates of freedom from reoperation, 83% versus 94%; adjusted risk ratio, 3.30). CONCLUSIONS: The presence of 1+ or 2+ MR by postpump intraoperative echocardiography does not confer increased morbidity or mortality. However, the trend toward more reoperations suggests the need for close follow-up for possible recurrence of MR. These data support our low threshold for performing further surgery during second pump runs.

Female↗
PubMed1992

Evaluation of the functional equivalence of major histocompatibility complex class II A and E complexes.

Most mice display two conventional major histocompatibility complex class II isotypes, A and E. Several A+E- strains have been observed, but never any that are A-E+. Because of this and because of hints from several lines of functional analysis, it has been proposed that the two isotypes might not operate equivalently. This proposition has not been directly testable until now because of the lack of an E-only strain. We report the production of such mice, exploiting previously created class II-transgenic and class II-"knock-out" lines. A+E-, A-E-, and A-E+ littermates have been compared by a number of parameters. We find that E and A molecules are, for the most part, functionally equivalent. However, subtle differences are seen in their ability to engage CD4 molecules on immature thymocytes, and in the profile of receptors on T cells selected into the periphery.

Animals↗
PubMed1992

The thymic compartment responsible for positive selection of CD4+ T cells.

Our aim was to assess the generality of the observation that positive selection of CD4+ T cells is mediated by MHC class II molecules on epithelial cells of the thymic cortex. By appropriate matings of previously established transgenic and mutant mouse lines, we were able to produce animals that lacked MHC class II molecules; individuals expressing only the class II E complex, but in all the usual thymic compartments; animals that had E molecules in the thymic medulla but not in the cortex; and, reciprocally, individuals expressing the E complex in the thymic cortex but essentially not in the medulla. Those mice which displayed class II molecules in the cortex had normal numbers of CD4+CD8- T cells in the thymus and CD4+ T cells in the periphery, while 'bare' cortex mice were almost devoid of mature CD4 single positive cells. This finding serves to generalize observations from previous studies of similar design but limited to assaying positive selection of T cells which expressed a single transgenic E-restricted TCR or a subset of V beta 6+ TCRs.

Animals↗
PubMed1991

Mice lacking MHC class II molecules.

We have produced mice that lack major histocompatibility complex class II antigens, permitting us to evaluate the role of these molecules in diverse aspects of T and B cell differentiation. The mutant mice show near-complete elimination of CD4+ T lymphocytes from the spleen and lymph nodes; the few remaining CD4-positive cells are preferentially localized to B cell follicles. Surprisingly, substantial numbers of CD4 single-positive cells reside in the thymus; however, these are not mature thymocytes as we currently recognize them. B lymphocytes occur in normal numbers and are capable of terminal differentiation to plasma cells. Nevertheless, several aberrations in the B cell compartment are demonstrable: a lack of germinal centers, fewer IgM+IgD+ cells in certain individuals, reduced production of serum IgG1, and complete inability to respond to T-dependent antigens. In short, the class II-negative mice have confirmed some old ideas about lymphocyte differentiation, but have provided some surprises.

Animals↗
PubMed1991

Resection of inferior vena cava tumor thrombi from renal cell carcinoma.

Renal cell carcinoma is an unusual cancer with the propensity to invade not only the renal vein but to propagate into the inferior vena cava (IVC) as a tumor thrombus. Experience has recently confirmed that MRI will be valuable in evaluating the extent of the tumor thrombus. The surgical techniques used to remove the thrombus are dependent on the extent of the cancer. For lesions involving the infrahepatic IVC, only proximal and distal control of the IVC are necessary. For a thrombus involving the intrahepatic IVC, isolation of the suprahepatic IVC, hepatic circulation, and infrahepatic IVC or cardiopulmonary bypass can be used. For the large thrombus in the supradiaphragmatic IVC or atrium, cardiopulmonary bypass either with or without deep hypothermic circulatory arrest is appropriate. In a review of 48 cases with renal cell carcinoma with IVC tumor thrombi, the tumor thrombus was removed intact in 58 per cent and in multiple fragments ("piece-meal") in 42 per cent of the patients. Cardiac bypass has been used in 26 cases with 22 undergoing deep hypothermic circulatory arrest. The postoperative mortality of 48 cases between 1965 and 1987 was 4 per cent. Removal of the most complicated and extensive renal cell carcinoma tumor thrombi is now technically feasible. In patients with large tumor thrombi, however, the ultimate outlook remains poor in the absence of effective systemic adjuvant therapy.

Carcinoma, Renal Cell↗
PubMed1990

How many tests are required in the diagnosis of palpable breast abnormalities?

Palpable breast nodules in 143 patients attending our primary diagnosis breast clinics were assessed by clinical examination, needle cytology, mammography, ultrasonography and magnetic resonance imaging (MRI). The diagnostic accuracy of all test combinations was compared with the final diagnosis of malignant or benign disease. Two-test combinations increased the sensitivity of diagnosis over that of the individual tests to between 93% and 100% except for MRI/mammography and MRI/cytology. The combinations of three or more tests increased the sensitivity further, but at the expense of an increased false-positive rate. MRI does not appear to have an important role in the primary diagnosis of breast cancer. Mammography is necessary because of the possibility of occult or multifocal disease. Clinical examination was associated with a high false-positive rate. The combination of cytology and ultrasound was best at correctly diagnosing malignancy, but in this series only 42% of patients underwent ultrasound examination. The role of breast ultrasound together with needle aspiration cytology for the diagnosis of malignancy in palpable breast nodules deserves further evaluation.

Adult↗
PubMed1989

Chemoprevention of breast cancer.

The hypothesis that oestrogen is an important promoter of human breast cancer raises the possibility that endocrine intervention could prevent the disease. Various methods of reducing oestrogenic activity have been proposed including dietary control, progestin therapy, and ovarian ablation. Tamoxifen is a synthetic anti-oestrogen of low toxicity with proven anti-proliferative activity in endocrine sensitive breast cancer which makes it an attractive alternative for a trial of endocrine prevention. We have undertaken a double-blind placebo-controlled pilot study to assess the feasibility of mounting a large multicentre study of tamoxifen in the prevention of breast cancer in high risk women. Two hundred women were randomised to tamoxifen or placebo during an 18 month accrual period. Acute toxicity was mild and serial studies of blood lipids, clotting factors, and bone mineral density suggested that no long-term deleterious effects are likely to be seen. It is estimated that 10,000 women would be required with a 10-15 year follow up in order to detect a 25% prevention effect.

Adult↗
PubMed1989

A pilot trial to evaluate the acute toxicity and feasibility of tamoxifen for prevention of breast cancer.

Epidemiological and experimental evidence indicates that oestrogens are involved in the carcinogenic promotion of human breast cancer. We have undertaken a pilot trial of tamoxifen, an anti-oestrogen, compared to placebo given to 200 women at a high risk of developing breast cancer. The results of this trial show that acute toxicity is low and that accrual and compliance are satisfactory. Furthermore, biochemical monitoring of lipids and clotting factors indicate that tamoxifen may reduce the risk of cardiovascular deaths. At this stage no untoward long-term risks have been identified, and it is therefore proposed that a large multicentre trial should be started.

Adult↗
PubMed1989

Randomized clinical trial of fibrin sealant in patients undergoing resternotomy or reoperation after cardiac operations. A multicenter study.

A multicenter study was conducted to test the efficacy and safety of fibrin sealant as a topical hemostatic agent in patients undergoing either reoperative cardiac surgery (redo) or emergency resternotomy. A total of 333 patients from 11 centers in the United States were included in the study. Patients were randomly assigned to initially receive the fibrin sealant or a conventional topical hemostatic agent when such was required during an operation. The end point used to evaluate the agent's efficacy was local hemostasis, the number of bleeding episodes controlled within 5 minutes. The fibrin sealant group from the prospective study was compared with historical matched control subjects for postoperative blood loss, need for resternotomy, blood products received, and hospital stay. It was also compared with historical nonmatched control subjects for the incidence of resternotomy and mortality. The results showed a 92.6% success rate for fibrin sealant in controlling bleeding within 5 minutes of application, compared with only a 12.4% success rate with conventional topical agents (p less than 0.001). Fibrin sealant also rapidly controlled 82.0% of those bleeding episodes not initially controlled by conventional agents. High-volume postoperative blood loss was significantly less (p less than 0.05) in the fibrin sealant group than in the matched controls. Additionally, resternotomy rates after redo operations were significantly lower in the fibrin sealant group (5.6%) than in the nonmatched historical control group (10%) (p less than 0.0089). There were no significant differences in hospital stay or blood products received between the fibrin sealant group and matched historical controls and no difference in mortality between the fibrin sealant group and nonmatched historical controls. There were no documented instances of adverse reactions, transmission of viral infection (hepatitis B, non-A/non-B hepatitis), or human immunodeficiency virus seroconversion. This study shows that fibrin sealant is safe and highly effective in controlling localized bleeding in cardiac operations. Fibrin sealant reduces postoperative blood loss and decreases the incidence of emergency resternotomy. These findings make fibrin sealant a valuable hemostatic agent in cardiac surgery.

Aprotinin↗
PubMed1987

Long-term acid-induced wall extension in an in-vitro system.

When frozen-thawed Avena sativa L. coleoptile and Cucumis sativa L. hypocotyl sections, under tension, are acid-treated, they undergo rapid elongation (acid-extension). The acid-extension response consists of two concurrent phases: a burst of extension which decays exponentially over 1-2 h (ExE), and a constant rate of extension (CE) which can persist for at least 6h. The extension (delta L) is closely represented by the equation: delta L = a-a e(-kt) + C t where a is the total extension of the exponential phase, k is the rate constant for ExE, and c is the rate of linear extension (CE). Low pH and high tension increased a and c, whereas temperature influenced k. The magnitude of the CE (over 50% extension/10 h), the similarity in its time course to auxin-induced growth, and the apparent yield threshold for CE indicate that CE is more likely than ExE to be the type of extension which cell walls undergo during normal auxin-induced growth.

Avena↗
PubMed1986

Systolic anterior motion of the mitral valve after Carpentier ring valvuloplasty for mitral valve prolapse.

Between July 1983 and March 1985, 45 patients with severe mitral regurgitation underwent mitral valvuloplasty with insertion of a semirigid Carpentier ring. No patient had echocardiographic evidence of systolic anterior motion (SAM) preoperatively, whereas 5 patients had this echocardiographic finding postoperatively. All 5 had mitral valve prolapse as their underlying disease process and SAM developed at varying intervals after valvuloplasty. The development of SAM is related to insertion of the semirigid ring, persistence of a redundant anterior mitral leaflet, narrowing of the left ventricular (LV) outflow tract and the Venturi effect. LV and aortic pressure measurements with simultaneous Doppler echocardiography have confirmed the presence of a significant LV outflow tract gradient in these patients. Although all 5 patients are functionally improved after mitral valvuloplasty, the long-term implications of SAM after valvuloplasty are unknown.

Echocardiography↗