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Biomedical subjects

G J Miller

Publications and source records attributed to G J Miller.

At least 163 records · Page 9Linked to original sources
PubMed1993

Fibrinolytic activity, clotting factors, and long-term incidence of ischaemic heart disease in the Northwick Park Heart Study.

Fibrinolytic activity (FA) was measured by dilute blood clot lysis time at entry to the Northwick Park Heart Study in 1382 white men aged 40-64, of whom 179 subsequently experienced episodes of ischaemic heart disease during a mean follow-up period of 16.1 years. There was a significant interaction between age and low FA (p = 0.02) with respect to ischaemic heart disease: a difference of one standard deviation in FA was associated with a difference of about 40% in ischaemic heart disease risk (p = 0.002) in those aged 40-54 at entry. The FA association remained after adjusting for plasma fibrinogen. High fibrinogen concentrations themselves were also associated with ischaemic heart disease, as was high factor VII activity with fatal events. Low FA in younger men may exert a long-term influence by impairing the removal of fibrin deposits that contribute to atherogenesis. Low FA appears to be a leading determinant of ischaemic heart disease in younger men and methods of enhancing fibrinolytic activity, whether by life-style changes or pharmacologically, should be considered.

Adult↗
PubMed1993

Significance of abnormal diploid DNA histograms in localized prostate cancer and adjacent benign prostatic tissue.

To clarify the relationship of DNA ploidy to tumor grade and volume, 32 clinical Stage B prostate cancers, with low and high Gleason scores and small and large tumor volumes, were compared with adjacent histologically normal prostate tissue and with samples from benign prostatic hyperplasia (BPH). All 22 samples from benign glands were diploid, with 2.7 +/- 1.2% tetraploid (4C) cells. Samples from cancer-bearing glands were considered diploid (normoploid) if they had a major diploid (2C) peak and a small 4C peak with the percentage of cells falling within 3 standard deviations of the figure found for BPH. Abnormal ploidy included abnormal diploid (6.3-14.9% 4C), tetraploid (> or = 15% 4C), and aneuploid samples (peaks not at 2C or 4C). Abnormal DNA ploidy was found to be related to tumor volume. All five tumors smaller than 0.4 cm3 and their adjacent benign tissue were normoploid; however, 10 of 13 cancers with volumes of 0.4-1 cm3 had abnormal ploidy (9 abnormal diploid, 1 tetraploid) and 6 of 9 of the adjacent benign tissue samples also were abnormal diploid. All larger tumors (> 1 cm3) showed abnormal ploidy (7 abnormal diploid, 3 tetraploid, 5 aneuploid). For large tumors, abnormal ploidy was present in 10 of 13 of the adjacent benign areas (8 abnormal diploid, 2 benign areas that were clearly aneuploid). Abnormal diploid cancers are intermediate forms between diploid and tetraploid tumors, as defined above. Although they have fewer 4C cells than tetraploid cancers, they have equivalent numbers of hypertetraploid cells (BPH: 1.3 +/- 0.9%; abnormal diploid: 10.8 +/- 5.4%; tetraploid: 11.1 +/- 6.8% hypertetraploid cells). Thus, the authors propose that abnormal diploid cancers represent an early stage in ploidy progression. DNA ploidy abnormalities also occur in benign prostatic tissue adjacent to many prostate cancers, consistent with the concept that human prostatic cancer is a field-change disease.

Aneuploidy↗
PubMed1993

Positive association between self-reported fatty food consumption and factor VII coagulant activity, a risk factor for coronary heart disease, in 4246 middle-aged men.

Raised levels of factor VII coagulant activity (VIIc) have been reported to increase the incidence of CHD. Preliminary evidence from observational and experimental studies suggests that dietary fat intake is positively associated with VIIc. We explored this further in 4,246 men aged 45-69, who were found to be free of major CHD when screened for a primary prevention trial of antithrombotic medication. All men were asked about their consumption of fatty foods and changes in consumption in the last month. In the 9% of men who reported avoidance of fatty foods in the month before interview, age adjusted VIIc was 7.8% of standard (95% CI 5.1-10.6%) lower than in the remainder. Serum cholesterol and body mass index (BMI) were also significantly lower. The extent to which fat consumed in the past month had deviated from usual intake was significantly and positively related with VIIc, serum cholesterol and BMI. Thus, the VIIc difference between those eating much less fatty food than usual and those eating much more than usual was 11% of standard, with those eating their usual amount having an intermediate level. This study adds to the evidence that dietary fat intake influences VIIc and coagulability. The effect is rapid, so that much of the benefit of dietary fat reduction on thrombogenic risk in CHD is likely to occur within a short time. Thus, the results reinforce the value of a low fat diet, even in individuals with advanced atheroma, in whom dietary intervention has sometimes been considered unlikely to be effective.

Antigens↗
PubMed1993

Reconstruction of the humerus with an intramedullary fibular graft. A clinical and biomechanical study.

Nine patients with nonunited humeral shaft fractures were treated by open reduction and internal fixation with an intramedullary fibular bone graft and a compression plate. Fixation of the screws was enhanced by passing them through the fibula as well as the two humeral cortices (quadricortical fixation). Eight of the nine fractures united at an average of 3.5 months. Tests on cadaver bones showed that quadricortical fixation was as strong as methylmethacrylate augmentation and significantly better than bicortical fixation.

Adult↗
PubMed1993

The activation of factor VII in citrated plasma by charged long-chain saturated fatty acids at the interface of large triglyceride-rich lipoproteins.

The prolonged incubation of dilute plasma on ice in the presence of added sulphatide vesicles or the long-chain saturated fatty acids (FA) stearic acid (C18:0) or behenic acid (C22:0) induced a concentration-dependent increase in factor VII coagulant activity (VIIc). The addition of FA at various ratios to human serum albumin showed the micellar non-bound pool to be responsible for this effect, FA bound to the high-affinity or low-affinity binding sites of albumin having no influence on VIIc. Plasma VIIc also increased following addition of behenate-enriched lipoprotein particles produced by incubation of the d < 1.006 g/ml lipoprotein fraction with this FA, or addition of lipoprotein remnants produced by pre-incubation of the d < 1.006 g/ml fraction with lipoprotein lipase. Long-chain saturated fatty acids in the interface of lipoprotein remnants, produced by the interaction of triglyceride-rich lipoprotein particles with lipoprotein lipase, appear to provide a surface that activates the contact system of coagulation and subsequently factor VII.

Anticoagulants↗
PubMed1993

Carbon dioxide embolization and laparoscopic cholecystectomy.

The risk of venous air or CO2 embolization during laparoscopic biliary procedures is unknown. Sixty-one consecutive patients undergoing laparoscopic cholecystectomy at La Crosse Lutheran Hospital/Gundersen Clinic were monitored by precordial Doppler ultrasound and end-tidal capnography to determine the risk of gas embolization. Patients ranged in age from 19 to 77 years (mean, 47 years). No venous embolization was detected by Doppler ultrasound or capnography. The highest end-tidal CO2 ranged from 34 to 53 mm Hg (mean, 41 mm Hg). No patient demonstrated an abrupt change in end-tidal CO2. No significant intraoperative hemodynamic changes occurred, and no postoperative neurologic defects developed. We caution the surgical community to remain alert concerning the possibility of venous gas embolization as newer laparoscopic procedures are developed that may have increased risks of embolization.

Adult↗
PubMed1992

Gemfibrozil reduces plasma prothrombin fragment F1 + 2 concentration, a marker of coagulability, in patients with coronary heart disease.

The effects of gemfibrozil on several indices of haemostatic activity were explored in male patients with coronary heart disease (CHD). Sixty-three of 71 patients completed a crossover study in which gemfibrozil 1,200 mg/day and matching placebo were each taken in randomised order for 2 months in a double-blind manner, separated by a 2-month washout period. Serum cholesterol decreased by an average (95% confidence interval) of 12 (9 to 15)% and non-fasting triglyceride concentration by 43 (34 to 51)% during active treatment. Plasma prothrombin fragment F1 + 2 concentration, a marker of the in vivo rate of generation of thrombin, was 25 (12 to 37)% lower on average while on gemfibrozil than during the placebo phase. Factor VII coagulant activity (VIIc) and antigen concentration, and fibrinopeptide A concentration were not influenced by gemfibrozil in the group overall. However, the VIIc response appeared to be dependent upon the untreated cholesterol level. Hypercholesterolaemic men (cholesterol greater than 6.5 mmol/l) experienced a significant reduction in VIIc averaging 6% of standard during active therapy. Other effects of gemfibrozil were a 5 (2 to 9)% increase in plasma fibrinogen by a gravimetric method, an 11 (8 to 13)% increase in platelet count, and a 6 (2 to 10)% reduction in white cell count. The reduced incidence of CHD following gemfibrozil therapy in hyperlipidaemic patients may arise in part through a reduction in procoagulant activity and thus the risk of an occlusive coronary thrombosis.

Biomarkers↗
PubMed1992

The human prostatic carcinoma cell line LNCaP expresses biologically active, specific receptors for 1 alpha,25-dihydroxyvitamin D3.

The LNCaP prostatic carcinoma cell line was examined for the presence of specific receptors for 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25-(OH)2D3]. Whole cell binding studies identified approximately 2500 high-affinity (Kd = 1.4 x 10(-9) binding sites per cell. Competition studies revealed that these receptors are specific for the 1 alpha,25(OH)2 metabolite. Binding studies using the synthetic androgen R1881 indicate that separate androgen and vitamin D3 receptors exist in LNCaP cells. The vitamin D3 receptors sediment at approximately 3.5S on linear sucrose gradients. The sedimentation coefficient could be shifted with a monoclonal anti-vitamin D3 receptor antibody (9A7 gamma) but not with a monoclonal antibody to the androgen receptor (AN1-15). The receptor/ligand complex elutes from native DNA cellulose at 0.2 M KCl. Northern blot analysis identified an mRNA of approximately 4.6 kilobases which hybridized with a specific vitamin D3 receptor complementary DNA probe (hVDR). In the absence of androgens, 1 alpha,25(OH)2D3 stimulated growth and prostate-specific antigen production by LNCaP cells in a dose-dependent fashion. Dose-response curves indicated that at physiological concentrations (10(-9) M) 1 alpha,25(OH)2D3 was mitogenic, whereas at higher concentrations (10(-8) M) it promotes differentiation. These studies suggest that 1 alpha,25(OH)2D3 could play an important role in the natural history of and response to hormone therapy by prostatic cancer.

Antibodies, Monoclonal↗
PubMed1992

Chemoprevention of prostate cancer: guidelines for possible intervention strategies.

The "natural history" of prostate cancer may bedevil the development of guidelines for chemoprevention interventions. Can strategies be designed to direct agents to those lesions which have the potential to develop localized extension that may become symptomatic or metastatic disease? Of necessity our interventions will focus on the identification and quantification of appropriate biomarkers as intermediate endpoints, although no reliable endpoints for prostate cancer have yet been identified. The reduction of prostate cancer incidence may be the ultimate objective, but a decrease in the progression of microfocal or "latent" cancer may well be just as effective as prevention when the age of the target population and competing causes of death are taken into account. Early intervention strategies must focus on the analysis of the interactions of the chosen chemopreventive agents upon precancerous and cancerous cellular dynamics in the prostate. Whether the requirements of such molecular epidemiology necessitate a more deliberate strategy of Phase II studies or a high risk-high gain strategy of a broad Phase III study is open to debate. Factorial designs for proposed randomized chemoprevention trials may be desirable to test multiple chemopreventive agents simultaneously, provided knowledge of the biochemical synergism of the agents is solid. Stratification of study participants by degree of risk will ameliorate concerns regarding the precision targeting of lesions at different stages in the precancer/cancer continuum.

Androstenes↗
PubMed1992

Alterations in mRNA levels for growth-related genes after transplantation into castrated hosts in oncogene-induced clonal mouse prostate carcinoma.

A clonal mouse prostate carcinoma was established by the introduction of the ras and myc oncogenes via the recombinant retrovirus Zipras/myc 9 using a mouse prostate reconstitution model system. A single-cell suspension derived from an early passage ras+myc-induced carcinoma was inoculated into the flanks of intact or castrated adult male C57BL/6 mice, and tumors were harvested 3 wk postinoculation for northern and Southern blotting. Tumor volume analysis showed that this carcinoma was not dependent on testicular androgens for growth. Southern blot analysis of virus-cell DNA junction fragments revealed that tumor cell populations recovered from both intact and castrated mice were progeny of the same virus-infected cell. Northern blotting showed that mRNA levels for the four growth-related genes transforming growth factor-beta 1 (TGF-beta 1), transforming growth factor-beta 3 (TGF-beta 3), tissue-type plasminogen activator (tPA), and c-myc were significantly elevated in clonal mouse prostate carcinomas grown in castrated hosts. In contrast, androgen receptor mRNA levels were significantly reduced under the same conditions. The response of TGF-beta 1, tPA, and c-myc mRNA levels in the carcinomas grown in castrated hosts was similar to that shown previously in normal rat ventral prostate. However, unlike normal rat ventral prostate after castration, increased numbers of apoptotic cells were not seen in the castrated group relative to the intact group at the time of analysis, indicating that the altered gene expression was not associated with cell death. In addition, testosterone-repressed prostate mRNA number 2 levels, shown previously to be elevated after castration in normal rat ventral prostate, were not increased in the androgen-deprived clonal mouse prostate carcinomas. Therefore, this early passage clonal ras+myc-induced prostate carcinoma demonstrates unique patterns of expression for a set of growth-related genes in an androgen-deprived environment.

Androgens↗
PubMed1992

Expression of c-erb B-2/neu proto-oncogene in human prostatic cancer tissues and cell lines.

Both amplification and overexpression of c-erb B-2/neu have been associated with the progression and possible prognosis of a number of human cancers. In this study, we demonstrated that c-erb B-2/neu may also play an important role in human prostate cancer. Our conclusion is based on the following observations: (1) A monoclonal antibody raised against a peptide sequence from the C-terminal domain of the human c-erb B-2/neu gene product reacted positively with 68.7% (11 of 16) of the human prostatic cancer tissue extracts analyzed by western blot procedure. These results were supported by the immunohistochemical staining of the prostatic cancer specimens; 80% (12 of 15) showed positive staining, primarily around the plasma membranes of the prostatic cancer cells. c-erb B-2/neu oncoprotein was not detectable in normal prostate tissues (five examined by immunohistochemical staining and three by western blotting) or in human benign prostatic hyperplasia (two examined by immunohistochemical staining and six by western blotting) and was expressed less abundantly with lower intensity in "normal" human prostate tissues adjacent to cancerous prostate tissue (5 of 12 examined by immunohistochemical staining). We observed no evidence of c-erb B-2/neu gene amplification in 10 fresh human prostatic cancer specimens examined by Southern blotting and in the cultured human prostatic cancer cell lines PC-3, DU-145, and LNCaP. (2) The c-erb B-2/neu protein was detected in both androgen-receptor-positive (LNCaP) and -negative (PC-3 and DU-145) human prostate cancer cell lines. Positive immunostaining of c-erb B-2/neu protein was found to be associated predominantly with the plasma membranes of PC-3 cells, but was also found to be widespread in the cytoplasmic region of the LNCaP cells and in the perinuclear region of the DU-145 cells. (3) Like prostate-specific antigen (PSA) expression, c-erb B-2/neu mRNA expression was also positively regulated by androgen in androgen-receptor-positive LNCaP cells in vitro and LNCaP tumors in vivo. When LNCaP tumors were grown in castrated male hosts, levels of c-erb B-2/neu and PSA mRNA expression decreased initially, but rebounded at 3 wk to levels comparable to those expressed by tumors maintained in intact adult male hosts.

Blotting, Northern↗
PubMed1992

Lipolysis of triglyceride-rich lipoproteins activates coagulant factor XII: a study in familial lipoprotein-lipase deficiency.

A high factor VII coagulant activity (VIIc), a marker of increased risk of coronary heart disease, is frequently found in types IIb and IV hyperlipidaemia, but its cause is not fully understood. Factor VII can be activated by factor XIIa, generated from factor XII upon activation of the contact system of coagulation. Ten patients with familial lipoprotein-lipase (LPL) deficiency and 10 healthy control subjects were therefore compared to explore the hypothesis that high concentrations of unesterified fatty acids (UFA), released from triglyceride-rich lipoproteins by LPL, are a source of factor XII activation and hence the increased VIIc that is observed post-prandially and in non-LPL-deficient hypertriglyceridaemic states. Mean plasma cholesterol and triglyceride concentrations were, respectively, 1.5- and 19-fold higher in the patients than controls, due to increases in very-low-density lipoproteins and chylomicrons. The concentration and composition of plasma UFA were similar in both groups. In conformity with the hypothesis, VIIc was not increased in the LPL-deficient group, despite their massive hypertriglyceridaemia. Furthermore, when the patients' plasma was treated with LPL, factor XII was activated promptly and substantially, whereas no similar effect was observed in the controls. These results suggest that high concentrations of circulating triglyceride-rich lipoproteins will increase VIIc in the presence of LPL.

Adult↗
PubMed1992

Immunohistochemical localization of PGF2 alpha receptor in the rat ovary.

As a step towards understanding the role of prostaglandin F2 alpha (PGF2 alpha) in ovarian function, a rabbit antiserum against purified PGF2 alpha receptor (PGF2 alpha-R) was produced. This report details the use of this antiserum in immunohistochemical staining of ovaries of non-pregnant and pregnant rats to ascertain which cell types, in vivo, possess PGF2 alpha-R. In non-pregnant rats, three ovarian cell subpopulations contain immunoreactive PGF2 alpha-R. These include: a subpopulation of the cells found in corpora lutea, a subpopulation of the thecal cells surrounding secondary and mature (Graafian) follicles, and a subpopulation of primary and secondary interstitial cells. The ovarian tissues and cell types in which immunoreactive PGF2 alpha-R cannot be demonstrated include: the serosa overlying the ovary and its vessels, the coelomic epithelium and its underlying cortical stroma, medullary stroma and vessels, granulosa cells of primary, secondary and mature follicles, the oocyte, and the blood vessels and stroma within corpora lutea. PGF2 alpha-R immunohistochemical staining of corpora lutea from non-pregnant animals was examined both prior to the start of luteolysis and during luteolysis. During luteolysis, cells undergoing apoptosis stained for the presence of PGF2 alpha-R. PGF2 alpha-R immunohistochemical staining was also examined in corpora lutea during pregnancy and until 4 days postpartum. The major findings here were the apparent large increase in staining intensity of granulosa-lutein cells during pregnancy, and the loss of PGF2 alpha-R immunopositivity of the granulosa-lutein cells during the postpartum period. In summary, three ovarian cell subpopulations, all of which can secrete steroids, possess immunoreactive PGF2 alpha-R.

Animals↗
PubMed1992

Androgen sensitivity and gene expression in ras + myc-induced mouse prostate carcinomas.

We established an androgen-sensitive cell line (BR31-5) from a ras + myc-induced mouse prostate carcinoma and used this cell line together with a previously reported transplantable androgen-independent mouse prostate carcinoma to investigate patterns of expression for apoptosis-related genes in an androgen-deprived environment. Single cell suspensions derived from the BR31-5 cell line were inoculated into the flank of intact or castrated adult male C57BL/6 mice and tumors were harvested 12 days post-inoculation for Northern blotting. A transplantable androgen-independent prostate cancer was also inoculated into intact or castrated mice and tumors harvested 21 days later. Tumor volume analyses showed that BR31-5 carcinomas were androgen-sensitive. Northern blotting showed that mRNA levels for two apoptosis-related genes, transforming growth factor-beta 1 and c-myc, were significantly elevated to a similar extent in carcinomas grown in castrated hosts compared to intact hosts for both the androgen-sensitive BR31-5 and androgen-independent carcinomas. Levels of mRNA for tissue type plasminogen activator, shown previously to be elevated in androgen-independent carcinomas following growth in castrates, were also increased in BR31-5 carcinomas under similar androgen-deprived conditions but to a lesser extent. Interestingly, testosterone repressed prostate mRNA No. 2 levels shown previously to be similar in both the intact and castrated groups for androgen-independent carcinomas were significantly increased in the castrated group compared to the intact group for BR31-5 carcinomas. Therefore, specific patterns of expression for apoptosis-related genes may be able to discriminate androgen-sensitive and androgen-independent prostate cancer under androgen-deprived conditions.

Androgens↗
PubMed1992

Environmental influences on hemostasis and thrombosis. Diet and smoking.

High levels of factor VII coagulant activity (VIIc) and fibrinogen concentration are independently associated with an increased risk of acute coronary heart disease in middle-aged men. Studies have, therefore, been undertaken to determine the responsiveness of these hemostatic factors to changes in diet and smoking habit. Plasma VIIc increases acutely with an increase in total fat intake, but fibrinogen is unaffected. In the general community, men who have a high total fat intake for their body size tend to have a high VIIc level. Changes in the dietary ratio of saturated to polyunsaturated fat of up to 14 days' duration have no effect on factor VIIc or fibrinogen (there are conflicting reports on the influence of dietary very-long-chain polyunsaturated fatty acids on fibrinogen concentration). Cigarette smokers have a higher fibrinogen concentration than do nonsmokers, but their levels slowly revert toward those of nonsmokers when the habit is relinquished.

Adult↗