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Biomedical subjects

G J Miller

Publications and source records attributed to G J Miller.

At least 127 records · Page 7Linked to original sources
PubMed1996

Incidence of hypertension and non-insulin dependent diabetes mellitus and associated risk factors in a rapidly developing Caribbean community: the St James survey, Trinidad.

OBJECTIVE: To compare the incidence rates of hypertension and non-insulin dependent diabetes mellitus in relation to ethnicity and other characteristics in a rapidly developing community. DESIGN: Prospective surveillance of a total community for five years. SUBJECTS: Cohort of 2491 men and women aged 35 to 69 years (79% response), of African, Indian and "other' (mainly Afro-European) descent. RESULTS: During surveillance, secular increases occurred in fasting blood glucose concentrations in both sexes and in body mass index (BMI) in men, with apparent secular reductions in systolic blood pressure in both sexes. Incidence rates of hypertension did not differ significantly with ethnicity, ranging between 33 and 41 per 1000 person-years in men and between 27 and 32 per 1000 person-years in women. In men, the incidence of diabetes (per 1000 person-years) in Indians (24) was significantly higher than in Africans (13) and others (11). In women, the diabetic incidence was similar to that for men in Indians (23) and Africans (14), but in others was twice that in men (21). In both sexes, weight gain was an important risk factor for hypertension, whereas risk of diabetes increased with BMI at baseline. The increased risk of diabetes in Indians among men was independent of baseline BMI and blood glucose. CONCLUSION: Apart from the increased risk of diabetes in Indians, ethnicity had no significant influence on incidence rates of hypertension and diabetes in Trinidad. Secular increases in blood glucose in both sexes and in BMI in men probably contributed to the concurrent increase in mortality from coronary heart disease in this community.

Adult↗
PubMed1996

Stable expression of the nuclear vitamin D receptor in the human prostatic carcinoma cell line JCA-1: evidence that the antiproliferative effects of 1 alpha, 25-dihydroxyvitamin D3 are mediated exclusively through the genomic signaling pathway.

The secosteroid hormone 1 alpha, 25-dihydroxyvitamin D3 [1,25-(OH)2D3] has been found to regulate the growth and differentiation of human prostate cancer cells, although the precise mechanisms mediating these effects have not been defined. 1,25-(OH)2D3 is capable of acting through both nongenomic signaling pathways involving a membrane-associated receptor and genomic pathways involving the nuclear vitamin D receptor (VDR). The primary purpose of this study was to directly evaluate the role of the nuclear VDR in mediating the growth inhibitory effects of 1,25-(OH)2D3 on human prostate cancer cells. The cell line JCA-1 was used because it fails to express detectable number of VDRs and is not measurable affected by 1,25-(OH)2D3 in growth studies. These cells were stably transfected with a wild-type VDR complementary DNA construct producing the following results: 1) the expression of high affinity nuclear VDRs, 2) the dose-dependent inhibition of growth by 1,25-(OH)2D3, and 3) a significant increase in 24-hydroxylase up-regulation by 1,25-(OH)2D3 compared to that in controls. These data indicate that nuclear VDR expression is sufficient to mediate the antiproliferative effects of 1,25-(OH)2D3 on prostate cancer cells. In addition, because the stereoisomer 1 beta, 25-dihydroxyvitamin D3 failed to block these antiproliferative effects, we conclude that nongenomic mechanisms of action are not requisite for growth inhibition by 1,25-(OH)2D3.

Base Sequence↗
PubMed1996

Increased activation of the haemostatic system in men at high risk of fatal coronary heart disease.

The haemostatic system was examined in 2951 men aged 50 to 61 years, clinically free of cardiovascular disease, who were ranked according to a risk score for fatal coronary heart disease (CHD). Risk was judged from their serum cholesterol concentration, systolic blood pressure, body mass index and smoking habit. The status of the factor VII-tissue factor pathway was estimated from the plasma levels of factor VII coagulant activity, factor VII antigen and activated factor VII. Activation of factor IX was assessed from the plasma concentration of factor IX activation peptide. Activity within the common pathway was measured as the plasma concentrations of prothrombin fragment 1 + 2 and fibrinopeptide A. All 6 markers of haemostatic status were positively and statistically significantly associated with risk, providing further evidence for a hypercoagulable state in men at high risk for fatal CHD. Plasma fibrinogen and serum triglyceride concentrations were also graded positively with risk.

Biomarkers↗
PubMed1996

Postprandial activation of coagulant factor VII by long-chain dietary fatty acids.

Factor VII coagulant activity (FVIIc) is associated with an increased risk of fatal ischaemic heart disease (IHD). Several reports have suggested that dietary fat intake or hypertriglyceridaemia are associated with elevated levels of FVII. This study demonstrates that an intake of long-chain fatty acids sufficient to induce postprandial lipaemia in healthy subjects leads to a substantial elevation in both FVIIc and the concentration of FVII circulating in the activated form. Such an increase in FVIIc could not be induced by medium-chain triglycerides. These results suggest that the consumption of a sufficient amount of long-chain triglycerides to induce postprandial lipaemia induces the activation of FVII.

Adult↗
PubMed1996

Molecular cloning and characterization of human FGF8 alternative messenger RNA forms.

Three alternatively spliced mRNA isoforms of the human fibroblast growth factor-8 (FGF8) gene, expressed in a prostatic carcinoma cell line, have been isolated as cDNA clones and characterized by DNA sequencing. The clones, designated FGF8a, FGF8b, and FGF8e, differ from each other at the NH2-terminal region of the mature proteins and share extensive nucleotide sequence homology in the protein coding region to the corresponding mouse cDNA isoforms that were previously reported. FGF8a and FGF8b exhibit identical amino acid sequences to those of their murine counterparts. FGF8e displays partial sequence variation from the corresponding mouse clone only in the extra exon sequence found in this isoform in both species. There is extensive sequence diversity between FGF8 (human) and Fgf8 (murine) genes in the 3'-untranslated region of the mRNAs. Northern blot analyses revealed FGF8 mRNA expression only in fetal kidney tissue among the various fetal and adult human tissues tested. The reverse transcription-PCR amplification method, however, detected FGF8 mRNA expression in adult prostate, kidney, and testes (the tissues that were tested) and in all normal and tumor prostatic epithelial cell lines examined; although expression of both FGF8a and FGF8b was seen in kidney and testes, FGF8b appeared to be the predominantly expressed species in the prostatic tissue and cell lines analyzed by reverse transcription-PCR. To address the biological effect of specific isoform expression, NIH3T3 cells were transfected with a eukaryotic expression vector containing cDNA for FGF8a, FGF8b, or FGF8e. Consistent with previous reports on differences in the transforming potential of mouse FGF8 isoforms, human FGF8b was found to induce marked morphological transformation to NIH3T3 cells and strong tumorigenicity of the transfected cells in nude mice. Human FGF8a and FGF8e were moderately transforming in NIH3T3 cells, and the transfected cells were moderately tumorigenic in vivo. These results document the production of three alternatively spliced FGF8 mRNAs in human tissues and the transforming and tumorigenic potential of their protein products. Moreover, these data, combined with the tissue-specific expression of these isoforms, suggest that they may have different biological functions.

Alternative Splicing↗
PubMed1995

Combined use of aspirin and warfarin in primary prevention of ischemic heart disease in men at high risk.

The combination of aspirin and warfarin is likely to be more effective than either agent alone in the prevention of ischemic heart disease (IHD), but its practical value also crucially depends on a low incidence of serious bleeding. The occurrence of bleeding of different degrees of severity is being established in the Thrombosis Prevention Trial of primary prevention in men aged 45-69 years at increased risk of IHD, in which 75 mg aspirin and warfarin dosed to an international normalized ratio of 1.5 are used in a factorial design. The annual risk of serious bleeding, i.e., requiring transfusion or surgery, may be about 1 in 500 for those on active treatment, whether this consists of both aspirin and warfarin or either alone. Less serious degrees of bleeding are significantly increased by the combination of aspirin and warfarin compared with either alone and by either alone compared with placebo. The risk of serious bleeding is probably acceptable if low dosages are used.

Aged↗
PubMed1995

The short- and long-term effects of methotrexate on the rat skeleton.

Both clinical and laboratory studies have shown that the chemotherapy drug, Methotrexate (MTX), has adverse short-term effects on bone. There are no studies that demonstrate the long-term response of bone to MTX. The purpose of this study was to determine the short- and long-term effects of MTX on bone volume, turnover, mineralization and strength. Three-month-old Sprague-Dawley rats were randomly assigned to a control (CTL) or MTX group and were given either daily MTX or saline injections for two separate 5-day courses (5 on/9 off/5 on). Fluorochrome compounds were injected prior to killing to label actively mineralizing bone surfaces. One CTL and MTX group were killed at 30, 80 and 170 days after treatment. Both femurs and tibiae were harvested for cancellous and cortical bone histomorphometry and biomechanical testing (torsion). Standard cancellous and cortical histomorphometric parameters were measured from undecalcified, methyl-methacrylate-embedded sections from the right proximal tibia and tibial and femoral diaphyses. The contralateral femur and tibia were torsionally loaded to failure and standard mechanical parameters were measured. All bone responses were statistically analyzed using a two-way ANOVA followed by Duncan's multiple comparison procedure (significance: p = 0.05). Cancellous bone volume was significantly lower in the MTX-treated group at 80 and 170 days. Cancellous mineralizing surface and longitudinal bone growth were significantly depressed at all time points yet mineral apposition rate was only depressed at the 170-day point. Cancellous osteoclast surface was increased at all time points for the MTX-treated animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1995

Computer simulation of the probability of detecting low volume carcinoma of the prostate with six random systematic core biopsies.

OBJECTIVES: Six random systematic core biopsies (SRSCB) of the prostate (biopsies from apex, middle, and base of each lobe) have been commonly used in detection of prostate carcinoma. The objective of this study was to verify the validity of the SRSCB technique in detecting cancer in prostates with low-volume tumor (less than 6 cc). METHODS: We developed a computer model of the prostate to simulate the SRSCB technique. The data for development of this model were taken from 159 radical prostatectomy specimens in which 112 patients had tumor volumes measured and in which 91 prostates had tumors with volumes less than 6 cc (by whole-mount sectioning). RESULTS: The simulation shows that only 20.3% of the simulated prostates, with total aggregate tumor volume between 0.034 and 5.1 cc, had a tumor distribution for which the SRSCB technique has a 95% probability of detecting the tumor. In fact, 26.8% had a tumor distribution that was completely disjointed from the six recommended biopsy regions. To compare these results with other possible occurrence, various biases for the angle of biopsy and the distribution of cancer foci were incorporated into the model. Study results should be viewed with the understanding that any simulated model has its limitations. In our simulated model, the shape of the simulated tumor foci (spherical) does not represent all the possible shapes of prostate cancer. However, these results indicate that detection of cancer with biopsies taken from the apex, middle, and base of each lobe of a prostate with tumor volumes of less than 6 cc may not be as effective as it is in prostates with larger tumor volumes or patients with an abnormal digital rectal examination. The study of bias models suggests that the distributional pattern of cancerous foci can have a significant impact on the effectiveness of a given biopsy strategy. CONCLUSIONS: We concluded that future attempts to improve systematic biopsy strategies for detection of low-volume cancer should include biomechanical characteristics of prostate cancer, including gland volume and tumor distribution. Driven by the conclusions from this idealized model, we have developed a three-dimensional model of the prostate gland from its whole-mount histologic maps. It is anticipated that this continuing investigation will lead to realistic guidelines for improving biopsy techniques.

Biopsy↗
PubMed1995

Salvage radical prostatectomy after failed transperineal cryotherapy: histologic findings from prostate whole-mount specimens correlated with intraoperative transrectal ultrasound images.

OBJECTIVES: This study evaluates the potential for salvage radical prostatectomy after failure of transrectal ultrasound (TRUS)-guided percutaneous cryosurgical ablation of the prostate. An additional purpose was to determine the accuracy of intraoperative TRUS to delineate the extent of freeze destruction that results from cryosurgery. METHODS: Six patients with biopsy-confirmed, Stage T3 prostate cancer underwent salvage radical prostatectomy 3 to 10 months after failing prostate cryosurgery. Zones of freeze destruction (resolving coagulative necrosis) and residual adenocarcinoma were mapped on the coverslips of whole-mount sections. Histologically proven zones of freeze destruction correlating to successfully treated prostatic tissue were compared to the hypoechoic ice ball treatment zones seen on intraoperative TRUS images. RESULTS: The whole mounts were found to contain necrotic areas of cryodestruction that appeared much smaller than predicted by intraoperative ultrasound. Each of the cases also contained residual viable adenocarcinoma. All patients are alive and clinically free of localized disease 0.5 to 12 months after salvage radical prostatectomy. CONCLUSIONS: Salvage radical prostatectomy offers an effective treatment option in patients who have failed transperineal cryosurgery of the prostate. Intraoperative TRUS predicted that the entire prostate would show freeze destruction. Whole-mount analysis, however, revealed areas of remaining unaffected adenocarcinoma and normal prostatic parenchyma. TRUS, therefore, overstimates the area of prostatic tissue destroyed by extreme cold. This finding challenges the assumption that the entire prostate is lethally frozen when its boundaries are included within the hypoechoic ice ball witnessed on TRUS.

Aged↗
PubMed1995

Lipoproteins and thrombosis: effects of lipid lowering.

Evidence continues to accrue for disturbances in coagulation, fibrinolysis and platelet behaviour in hyperlipidaemic states, which together might constitute a prethrombotic state. Lipid lowering by diet or drug therapy appears to ameliorate these disturbances, thus providing one possible mechanism whereby such treatment reduces the risk of coronary heart disease in addition to its effects on atherogenesis.

Blood Coagulation↗
PubMed1995

The effect of training on equine metacarpal bone breaking strength.

Right third metacarpal bones (n = 24) from Thoroughbreds, 24 to 48 months old and in race training, were tested to failure in 3 point bending. The neutral load axis was estimated and the distance from the axis to the outer dorsal cortical surface measured. Mid-diaphyseal dorsopalmar and lateromedial outer cortical and medullary diameters were measured. Breaking strength, cortical area and area moment of inertia were also calculated. Significant correlations were demonstrated between months in training and dorsopalmar bone diameter, cortical area and area moment of inertia. Significant linear models were illustrated between the same 3 variables and number of months in training. It was concluded that increased duration of training significantly enlarges dorsopalmar bone diameter, cortical area and area moment of inertia. Training did not affect metacarpal bone breaking strength as determined by 3 point bending.

Age Factors↗
PubMed1995

A common variant in the gene for lipoprotein lipase (Asp9-->Asn). Functional implications and prevalence in normal and hyperlipidemic subjects.

Subjects with combined hyperlipidemia (CHL) were screened for mutations in the lipoprotein lipase (LPL) gene by single-strand conformational polymorphism, and a previously reported G-->A DNA sequence change in exon 2, causing substitution of Asp by Asn at position 9, was identified in 2 individuals. Because this substitution destroys a recognition site for Taq I, pooling of DNA samples, amplification, and digest with Taq I allowed the rapid screening of 1563 healthy individuals and patients of Dutch, Swedish, English, and Scottish origin. In the general populations of all four countries, healthy carriers of the mutation were detected at a frequency of 1.6% to 4.4% (mean, 3.0%; 95% confidence interval, 2.0% to 4.0%). The frequency of carriers was roughly twice as high (range, 4.0% to 9.8%) in selected patients with CHL or type IV hyperlipoproteinemia or in subjects with angiographically assessed atherosclerosis; the frequency was consistently higher in each patient group compared with its matched control group. In 773 healthy men from two general practices in the United Kingdom, 25 carriers and 2 homozygotes for the mutation were identified. In these 27, plasma triglyceride but not plasma cholesterol levels were significantly higher than in noncarriers (2.25 versus 1.82 mmol/L, P < .02), and this difference was maintained in three subsequent annual measurements. Postheparin LPL activity data were available for some carriers and for 7 of 9 individuals from the patient groups, and 6 of 6 individuals from the control groups had LPL activity that was lower than the respective group mean. In vitro mutagenesis and transient expression in COS cells showed that compared with the LPL-Asp9 construct, LPL-Asn9 activity and mass were reduced by 20% to 30% in the culture media. Overall however, LPL-Asn9 had only slightly reduced specific activity (by 18%). Thus, although the precise mechanism of the effect is unclear, the data strongly suggest that the LPL-Asn9 variant is associated with and may play a direct role in predisposing carriers to develop hypertriglyceridemia.

Adult↗
PubMed1995

Heterogeneity in intratumor distribution of p53 mutations in human prostate cancer.

Prostatic carcinoma from 65 patients have been examined for the occurrence of point mutations in the p53 tumor suppressor gene locus within the region of exons 5 to 8. Overall, only a small fraction of tumors (12.3%) was found to contain p53 mutations. No significant correlation was detected between the presence of the mutant gene and either tumor volume or histopathological grade. However, metastatic prostatic tumors are found to display a higher percentage (21.4%) of p53 mutations compared with primary adenocarcinomas (9.8%). Analysis of the topographical distribution of the p53 mutant genotype revealed two remarkable findings. First, multifocal tumors within a prostate appear to differ in harboring the mutant gene, and second, evidence is obtained for intratumor heterogeneity in the distribution of the mutant p53 allele. Together these findings appear to explain, at least in part, why there has been a wide discrepancy in the reported detection frequency of p53 mutations in prostate cancer specimens. It appears that the outcome of mutation analysis would depend not only on which tumors but also which regions of the tumors are included in the study. Furthermore, the observed heterogeneous topographical distribution of the mutation, if confirmed to be unique to prostate cancer, may have important implications in the understanding of the biology of prostate carcinogenesis.

Adenocarcinoma↗
PubMed1995

The effects of quality and timing of venepuncture on markers of blood coagulation in healthy middle-aged men.

Effects of the quality and the time of venepuncture on factor VII coagulant activity (VIIc) and the concentrations of fibrinogen, prothrombin fragment 1 + 2 (F1 + 2) and fibrinopeptide A (FPA) were sought in 2665 men, of whom 2334 were re-examined after about one year. Venepunctures were categorised as satisfactory, not fully satisfactory or unsatisfactory according to pre-defined criteria. Neither the quality nor timing of the venepuncture influenced VIIc or fibrinogen concentration. However, at baseline and re-examination F1 + 2 and FPA were increased on average by about 9% and 45% respectively when venepunctures were not fully satisfactory, and by about 11% and 100% when unsatisfactory. Plasma collected after 1500 h had slightly but significantly lower levels of F1 + 2 and FPA than samples taken earlier, possibly due to circadian rhythm. The results emphasise the need for careful surveillance of the venepuncture procedure and the value of FPA when using F1 + 2 as a marker of risk of thrombosis.

Antigens↗
PubMed1995

Effects of running on the torsional strength, morphometry, and bone mass of the rat skeleton.

Intensity and duration effects of weight-bearing exercise on the rat skeleton were investigated. Eighty-four 3-month-old female Sprague-Dawley rats were assigned to control and nine exercise groups. Exercised rats were run on a treadmill for either 30, 60, or 90 min.d-1 at low (Vo2max approximately 55%), medium (VO2max approximately 65%), or high (VO2max approximately 75%) intensity 4 d.wk-1 for 10 wk. Rat femurs, tibias, and vertebrae were harvested for torsional mechanical tests, bone density assessment, and morphometry. Our results indicate exercise has a significant effect (P < 0.05) on the femoral mechanical response (energy absorbed and twist angle), tibial morphometry (cortical bone area and thickness), and tibial and vertebral bone density measurements but had no effect (P > 0.05) on bone strength when compared with control values. Higher intensity exercise decreased tibial and femoral torque (P < 0.05). Long duration exercise increased tibial and femoral stiffness and decreased twist angle and energy absorbed (P < 0.05). These results indicate bone adapts to its loading environment by increasing bone mineral density, increasing cortical bone area, increasing stiffness, decreasing energy absorbed, and decreasing twist angle. High-intensity exercise decreased the maximum force the bone could withstand, whereas long duration exercise made the bone more brittle.

Absorptiometry, Photon↗