Biomedical subjects

G J Miller

Publications and source records attributed to G J Miller.

At least 91 records · Page 5Linked to original sources

PubMed1998

CD44 and CD44v6 downregulation in clinical prostatic carcinoma: relation to Gleason grade and cytoarchitecture.

BACKGROUND: Altered expression of CD44 has been implicated in tumor progression and metastasis in multiple neoplasms. METHODS: CD44 expression in archival tissues of prostate carcinoma was examined by immunohistochemistry with monoclonal antibodies against core CD44 and the RNA splice variant CD44v6 (v6). RESULTS: Core CD44 expression was reduced in the majority of primary neoplastic foci (n = 94) and loss of expression correlated with increasing Gleason grade. Staining for v6 was absent in most carcinomas and metastases. Expression of core CD44 in pelvic lymph node (n = 27) and bone metastases (n = 21) was significantly reduced. In addition, CD44 expression correlated with cytoarchitecture. Tall columnar tumor cells typically stained positively, yet more rounded cells forming cribiform structures or nests showed reduced expression. All cases of high-grade prostatic intraepithelial neoplasia were positive for core CD44 yet, there was decreased expression in cribiform and micropapillary variants. CONCLUSIONS: The majority of clinically relevant human prostatic carcinomas and metastases downregulate expression of CD44. Additional studies to determine whether CD44 cell surface expression relates to clinical outcome independent of other established clinicopathologic risk factors are warranted.

Alternative Splicing↗

PubMed1998

Postprandial lipaemia and haemostatic factors.

Factor VII activity (FVIIc), a reported risk factor for fatal coronary heart disease, increases transiently after a fat-rich meal. The response shows dose-response characteristics and peak FVIIc and triglyceride concentrations above fasting levels tend to be positively associated. The mechanism is incompletely understood, but appears to require factor IX and the presence in plasma of lipoprotein products of lipolytic activity. Factor XII is not apparently essential. The increase in FVIIc is due to raised activated factor VII (FVIIa) activity, but is not associated with increased thrombin production or changes in fibrinolytic activity. The response of FVIIa appears independent of the proportions of saturated, monounsaturated and polyunsaturated fatty acids in the dietary fat, although dietary stearic acid may be less effective than myristic acid. However, in one study in which deliberate efforts were made to force an increase in plasma free stearic acid, its plasma level was positively associated with postprandial FVIIc. Because FVIIa initiates the thrombotic response to rupture of an atheromatous plaque, a raised postprandial level may represent a transient rise in the likelihood of a clinically significant coronary thrombosis.

Animals↗

PubMed1998

Computer modeling of prostate biopsy: tumor size and location--not clinical significance--determine cancer detection.

PURPOSE: Sampling error is an inherent problem of prostate biopsy, and the determination of clinical significance based on biopsy results is problematic. We quantify the dimensions of these problems by computer simulation. MATERIALS AND METHODS: We constructed 3-dimensional solid computer models of 59 autopsy prostates containing clinically undetected prostate cancer, and performed simulations of the standard prostate biopsy method. RESULTS: Biopsy simulation detected 19 tumors from the 59 prostates, the majority of which were in the most accessible portion of the prostate, the posterior peripheral zone. Using 0.5 cc or greater tumor volume or less than 0.5 cc and Gleason sum 7 or greater as criteria of significance, the model detected 58% (11 of 19) significant tumors and 20% (8 of 40) insignificant tumors. With 0.25 cc or greater tumor volume or less than 0.25 cc and Gleason sum 7 or greater as criteria 15 of 29 significant (52%) and 4 of 30 insignificant (13%) tumors were detected. Among significant tumors defined by either volume criterion there was a statistical difference between detected and undetected tumors in terms of mean tumor volume and mean ratio of tumor volume-to-prostate volume. Among insignificant tumors defined by either criterion there was no such difference. CONCLUSIONS: As much as 20 to 40% of currently detected prostate cancer may be histologically insignificant, as 4 of 19 cancers were detected when 0.25 cc was used as volume determinant of clinical significance and 8 of 19 were detected when 0.5 cc volume was used. These tumors are detected randomly. On the other hand, perhaps only one-half to three-fourths of clinically significant prostate cancers are being detected, and then only because the volume and anatomic location make them hard to miss.

Adult↗

PubMed1998

W64R mutation in beta-3-adrenergic receptor gene and weight in a large population sample.

We have investigated the W64R (Trp64Arg) mutation in the beta-3-adrenergic receptor in 2270 healthy British males aged 50-61 y. The frequency of the rare R allele was 0.07 (95% confidence interval (CI) 0.06-0.08). The men showed an absence of association between W64R genotype and weight or height, both in the whole sample and in each quintile of the body mass index (BMI), and there was no association with tendency to gain weight. The W64R heterozygous state appears not to be a major contributing factor to obesity in the general population.

Alleles↗

PubMed1998

Associations of protein C and protein S with serum lipid concentrations.

Difficulties in the laboratory measurement of protein C and protein S levels cause problems in the diagnosis of deficiency states in individual patients and may complicate estimation of the prevalence of these states in the general population. Some difficulties may be due to unappreciated influences affecting the measured levels of proteins C and S. We measured protein C activity and antigen, total and free protein S antigen, and serum total cholesterol, high-density cholesterol and triglyceride in a community-based study of 150 adults (73 male, 77 female), age range 23-80 years. Participants were identified from the list of a single general practice by stratified random sampling within sex and decade of age. Protein C activity and antigen were strongly associated with serum lipids, mean levels increasing by approximately 0.25 u/ml as total cholesterol and triglyceride concentration each rose from the 5th to 95th centile. Total protein S antigen concentration was associated with total cholesterol, the mean rising by over 0.1 u/ml as total cholesterol increased from the 5th to the 95th centile, whilst a similar rise in triglyceride was associated with an increase in mean free protein S of more than 0.3 u/ml. Overall, physiological variation in total cholesterol and triglyceride concentration was associated with significant variation in protein C and protein S levels, independent of age and sex, suggesting that it is important to take serum lipids into account when investigating patients for protein C or protein S deficiency. Failure to do so may be misleading in some circumstances.

Adult↗

PubMed1998

Effects of diet composition on coagulation pathways.

Total dietary fat intake is an important determinant of factor VII coagulant activity, a hemostatic risk factor for fatal ischemic heart disease in middle-aged men. This association has a long-term effect by which a high-fat diet increases plasma factor VII antigen concentration, and an acute effect whereby a small proportion of factor VII is converted from its proenzyme to active serine protease for several hours postprandially. In adults whose usual diet is rich in long-chain saturated fatty acids, postprandial activation of factor VII occurs irrespective of the fatty acid composition. The underlying mechanism appears to require lipolysis and the presence of another coagulant protein, factor IX. There is limited evidence that factor VII activation after a meal rich in polyunsaturated fatty acid is blunted when the background diet also has a high content of polyunsaturated fatty acid. Meals rich in medium-chain triacylglycerols do not induce factor VII activation. The effects of dietary enrichment with n-3 fatty acids on factor VII are uncertain. All studies have been confined to the fasting state, and only one suggested changes consistent with factor VII activation. Fibrinogen concentration, another major hemostatic risk factor for ischemic heart disease, is uninfluenced by dietary fat content or composition, the one exception being inconsistent reports of a reduction after dietary enrichment with n-3 fatty acids. Overall, the evidence so far indicates that total dietary fat intake is more important than dietary fat composition for factor VII and by implication its attendant risk of fatal ischemic heart disease in high-risk populations.

Adult↗

PubMed1998

Plant monoterpenes do not raise plasma high-density-lipoprotein concentrations in humans.

BACKGROUND: Low plasma concentrations of HDLs are associated with an increased risk of coronary artery disease. Two uncontrolled studies suggested that plant monoterpenes may have substantial HDL-cholesterol-elevating activity in humans. Each study used a proprietary mixture of 6 monoterpenes in olive oil. OBJECTIVE: The present study was undertaken to test more rigorously the hypothesis that monoterpenes raise HDL concentrations in men with hypoalphalipoproteinemia. DESIGN: A double-blind, placebo-controlled crossover design was used. Twenty-four men aged 58-68 y (x: 62.3 y) with plasma HDL cholesterol <1.1 mmol/L, plasma triacylglycerols <3.5 mmol/L, and plasma total cholesterol <5.5 mmol/L at recruitment were randomly assigned to 6 capsules daily of a proprietary mixture of 6 monoterpenes in olive oil or 6 capsules daily of olive oil alone for 24 wk, followed by a washout period of 8 wk, and then the alternative capsules for 24 wk. RESULTS: Five men dropped out. In the others, compliance was excellent as judged by capsule counts and urinary menthol glucuronide concentrations. No significant effects were observed on plasma HDL-cholesterol or apolipoprotein A-I concentrations, nor on plasma triacylglycerol, LDL-cholesterol, or apolipoprotein B concentrations. CONCLUSIONS: Plant monoterpenes have no HDL-elevating activity of potential value for coronary artery disease prevention.

Aged↗

PubMed1998

Postprandial effects of an oleic acid-rich oil compared with butter on clotting factor VII and fibrinolysis in healthy men.

BACKGROUND: Factor VII coagulant activity (FVII:c) is associated with an increased risk of fatal ischemic heart disease, is correlated with plasma triacylglycerol concentration, and increases after a meal rich in long-chain fatty acids. OBJECTIVE: We planned to compare effects of meals rich in oleate and butter fat with those of a low-fat meal on FVII:c and fibrinolytic activity. DESIGN: A crossover design was used to compare the postprandial effects on coagulant and fibrinolytic activities in 12 men of 3 high-fat (95 g) meals--high oleate, butter, and oleate + medium-chain triacylglycerols (oleate+MCT)--with an isoenergetic low-fat meal (18 g MCT). The oleate+MCT blend was used to mimic the ratio of long-chain to shorter-chain fatty acids in butter. RESULTS: Neither the amount nor type of fat consumed influenced plasminogen activator inhibitor 1 or t-plasminogen activator activities or D-dimer concentration. FVII:c increased by 12.5% (95% CI: 4.6%, 20.5%) after the high-fat meals at 3 h and by 6.7% (95% CI: 1.6%, 11.7%) at 7 h and changed 7 h after the low-fat meal by -14.3% (95% CI: -3.3%, -25.4%). The responses to the high-fat meals did not differ. Measurements of activated FVII (FVIIa), FVII zymogen, and activated FXII (FXIIa) concentrations made after the low-fat and high-oleate meals showed a significant increase in FVIIa only after the high-oleate meal. CONCLUSIONS: The results of this study confirm that FVII:c falls after a low-fat meal and suggests that postprandial activation of FVII occurs rapidly after a fat-rich meal without involving an increase in FXIIa.

Adolescent↗

PubMed1998

Analysis of the association of a heat shock protein70-1 gene promoter polymorphism with myocardial infarction and coronary risk traits.

Heat shock proteins (HSP) are induced during coronary ischaemia, and abnormal expression of one HSP gene may cause hypertension in rats. We examined association of a promoter polymorphism in the major stress-inducible hsp70 gene (hsp70-1 or HSP70A1) on chromosome 6 (p21.3) with coronary disease traits. This C-->A base substitution (AAACCCC) is at nucleotide position-110 in the heat shock transcription factor binding site (heat shock element, HSE). The first study sample (ECTIM), recruited from Belfast and three centers in France, consisted of 578 myocardial infarction cases and 698 age-matched controls. The frequency of the A-110 allele was 0.381 (95% CI = 0.35-0.41) and 0.384 (95% CI = 0.36-0.41) in cases and controls respectively. Homozygotes for the rarer A-110 allele had a higher BMI (27.3 kg/m2 +/- 3.9) compared with homozygotes for the common C-110 allele (26.3 kg/m2 +/- 3.3). The rarer homozygotes were shorter and heavier than the common homozygotes. A follow-up study involved 1431 healthy, middle aged men from the UK (NPHS II group). The frequency of the A-110 allele was 0.385 (95% CI = 0.37-0.40), and there was no association of genotype with BMI. Thus there appears to be no strong association of the Hsp70-1 promoter polymorphism with risk of myocardial infarction, BMI or any coronary disease traits analysed here.

Adult↗

PubMed1998

Inventory accuracy in 60 days.

This article describes a program for increasing basic inventory record accuracy. The program can be implemented in 60 days, and its cost is likely to be free when the benefits are taken into account. The hardest part is selling people on the need to improve accuracy and keeping them motivated during the implementation.

Accounting↗

PubMed1998

Morphological analysis and classification of latent prostate cancer using a 3-dimensional computer algorithm: analysis of tumor volume, grade, tumor doubling time and life expectancy.

PURPOSE: We estimate the potential clinical significance of prostate cancers found at autopsy provided the individual had lived to the projected lifespan based on life expectancy tables. MATERIALS AND METHODS: We used 3-dimensional computer models of 59 autopsy prostates that contained clinically undetected carcinoma to determine tumor volumes. Using doubling times of 2, 3, 4 and 6 years, carcinoma volumes at autopsy were extrapolated through patient projected lifespans. The carcinomas were then classified as clinically insignificant or significant according to Mayo Clinic criteria. RESULTS: In 13 patients less than 60 years old, using doubling times of 2, 3, 4 and 6 years, clinically significant tumors were identified in 13 (100%), 10 (77%), 7 (54%) and 7 (54%), respectively. In 46 patients 60 years old or greater significant tumors were identified in 32 (70%), 22 (48%), 21 (46%) and 18 (39%), respectively. A statistical difference (p <0.0001) was found between the mean tumor volume (0.20 +/- 0.10 cc) of 43 organ confined carcinomas and the mean tumor volume (3.26 +/- 3.58 cc) of 16 extracapsular tumors. No capsule perforation was found in tumors with Gleason sums of 4 or less. However, capsule perforation was present in 8 of 31 tumors (25.8%) with Gleason sums of 5 or 6, and 8 of 11 tumors (72.7%) with Gleason scores of 7 or 8. CONCLUSIONS: Prostatic carcinomas that remain clinically insignificant throughout life are likely to have doubling times greater than 4 years. The subset of carcinomas that emerge as clinically significant are likely to have doubling times less than 3 years. Therefore, an accurate method to measure doubling time at diagnosis could, provide an objective indicator to guide clinical management.

Adult↗

PubMed1998

Activation of the coagulant pathway in cigarette smokers.

The effects of chronic cigarette smoking on the coagulation system were examined in 2964 men aged 50 to 61 years and clinically free of cardiovascular disease. Factor VII activity (VIIc), factor VII antigen (VIIag), prothrombin fragment 1+2 (F1.2), fibrinopeptide A (FPA) and fibrinogen were measured in all participants, and activated factor VII (VIIa), factor IX activation peptide (IX pep) and factor X activation peptide (X pep) in a large sub-sample. The levels of all indices except FPA differed significantly between non-smokers, ex-smokers and current smokers. After adjustment for other conventional cardiovascular risk factors, mean VIIc was raised slightly by 3% in ex-smokers and current smokers as compared with non-smokers, owing to increases in VIIa and VIIag. Plasma IX pep, X pep, F1.2 and fibrinogen concentration were highest in current smokers, intermediate in ex-smokers and lowest in non-smokers. These findings accord with the increased risk of arterial thrombosis in smokers.

Blood Coagulation↗

PubMed1998

Sex differences in the determinants of fibrinolytic activity.

Impaired whole blood fibrinolytic activity (FA), measured by the dilute clot lysis time (DCLT), is associated with first episodes of ischaemic heart disease (IHD) in the Northwick Park Heart Study in men, especially under 55 years, and in women. In a community-based study to investigate possible determinants of the DCLT, and therefore to assess which fibrinolytic components might be predictors of first IHD events, we measured fibrinolytic variables in a sub-sample of 150 healthy adults (73 males, 77 females) randomly selected from a single general practice. Most of the variance in DCLT (68% in men, 63% in women) was explained by tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor type-1 (PAI-1) activities. In multiple regression analysis there was a significant difference in the strength of the association of t-PA activity with DCLT in men compared to women (test for interaction p = 0.05), the association of t-PA activity with DCLT being significant in males but not in females. Plasma PAI-1 activity was strongly associated with DCLT in both sexes. There was no independent association of DCLT with plasma fibrinogen, t-PA antigen, other fibrinolytic inhibitors, body mass index, serum lipids or C-reactive protein. Plasma PAI-1 activity in females and both t-PA and PAI-1 activities in males are the main determinants of whole blood FA measured by DCLT. It is therefore likely that these modulators of the plasma fibrinolytic system are associated with the onset of first clinical episodes of IHD. Elevated levels of t-PA antigen were positively associated with DCLT after adjustment for age and sex and therefore indicate impaired rather than enhanced FA. Further studies of the association of FA with risk of IHD should include not only "global" measures but also assessment of t-PA and PAI-1 activities, particularly as our results suggest that their associations with IHD may differ in men and women.

Adult↗

PubMed1998

Very low activated factor VII and reduced factor VII antigen in familial abetalipoproteinaemia.

Abetalipoproteinaemia is a rare disorder of apolipoprotein B metabolism associated with extremely low plasma concentrations of triglyceride. To discover whether the general positive association between factor VII and triglyceride levels extends to this condition, 5 patients were compared with 18 controls. All patients had a triglyceride below 100 micromol/l. Plasma unesterified fatty acid concentration was normal. Although factor IX activity was only slightly reduced (mean 88% standard) and factor IX antigen was normal, mean activated factor VII in patients was strikingly reduced to 34% of that in controls, a level similar to that found in haemophilia B. The patients' mean factor VII activity and factor VII antigen were also significantly reduced to 54% and 63% of those in controls, respectively. Mean factor XI activity and tissue factor pathway inhibitor activity were reduced in patients to 70% and 75% of control values respectively, while factor XII, factor XI antigen, factor X, prothrombin and protein C were normal.

Abetalipoproteinemia↗

PubMed1998

Detection of abnormal E-cadherin expression by simulated prostate biopsy.

PURPOSE: Sampling error is an inherent problem of prostate biopsy. Consequently the determination of whether a given carcinoma is clinically significant based on biopsy results is problematic. We assess the dimensions of sampling error and, thereby, provide insight into the potential value of prognostic markers applied to needle biopsies. MATERIALS AND METHODS: We constructed 3-dimensional computer models of 21 prostatectomy specimens, including outlines of carcinomas, regions of abnormal E-cadherin expression and individual Gleason patterns. The 6 random systematic core biopsy technique and modifications were simulated using a computer algorithm. RESULTS: In 6 of 21 cases the area of abnormal E-cadherin expression and/or high grade carcinoma was not sampled on 6 random systematic core biopsy. The areas missed were either small or inconsistently under sampled regions of the prostate. Modifying the placement of biopsy needles improved the detection of these features. In addition, percent tumor in the needle appeared to be well correlated to percent tumor in the prostate (r = 0.891, r2 = 0.642). CONCLUSIONS: To avoid underestimating the aggressiveness of prostatic carcinoma at least 6 biopsies should be taken from each patient. A more extensive sampling is probably not warranted in all patients but it may prove useful in those in whom extent of disease is unclear or whose general health makes treatment decisions difficult. A reliable estimate of tumor volume in the prostatectomy specimen can be made based on relative amount of tumor in the biopsy specimen on an individual basis.

Aged↗

PubMed1997

Histological and biomechanical evaluation of calcium phosphate coatings applied through surface-induced mineralization to porous titanium implants.

The purpose of this pilot study was to evaluate surface-induced mineralization (SIM) as a potential technique to apply ceramic coatings to metal orthopaedic implants. Cylindrical titanium porous-coated implants were either coated by SIM or plasma-spray (PLS) techniques with calcium phosphate, or left uncoated (CTL). The implants were bilaterally implanted into the intramedullary canal of the proximal femur of 24 adult New Zealand white rabbits segregated into the following groups: PLS/CTL, SIM/CTL, and SIM/PLS. After 6 weeks in vivo, biomechanical and histologic evaluations were completed. Biomechanically, SIM had consistently greater mechanical interlock than PLS implants. However, CTL implants had greater mechanical interlock than both PLS and SIM. The small sample size prevented statistical evaluation and definitive biomechanical conclusions. Histologically, SIM and PLS had significantly greater ingrowth than CTL implants (p < 0.05). The SIM coating technique produced similar ingrowth characteristics as standard PLS coatings, yet may prevent osteolysis by providing a stronger, more reliable, covalent bond between the ceramic and metal.

Alloys↗

PubMed1997

Comparison of ras activation in prostate carcinoma in Japanese and American men.

BACKGROUND: Comparative studies of point mutations in K-, N-, and H-ras oncogenes were performed on prostate carcinoma from Japanese and American patients to clarify the racial difference. METHODS: We probed for mutations in 70 Japanese and 31 American specimens using polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) analysis and immunohistochemistry for ras p21. RESULTS: Within the 70 Japanese specimens, eight mutations in codon 12 of K-ras (five GGT-->GTT transversions and three CGT-->GAT transitions) and one mutation in codon 12 of the N-ras gene (a GGT-->GTT transversion) were confirmed, whereas the American samples yielded only one definable mutation, a GGT-->GAT transition, in codon 12 of K-ras. CONCLUSIONS: The frequency of ras gene mutations in clinical carcinoma in Japanese men was higher than that in American men. It is suggested that there may be fundamental differences in the etiology of prostate carcinoma in Japan and the United States, perhaps based on genetics and/or environmental factors.

Adenocarcinoma↗

PubMed1997

Rapid microwave-stimulated fixation of entire prostatectomy specimens. Biomed-II MPC Study Group.

Conventional fixation of large solid surgical specimens is a slow process. Consequently, autolytic damage to tissues may occur if the fixative does not reach the central part of the specimen in time. However, as there is also a time relationship between formalin fixation and antigen masking, fixation for too long can also be detrimental. In seeking the optimum balance for fixation, microwave irradiation might be of assistance. This study set out to evaluate methods for fixing entire prostate glands within a brief period of time, using microwave-stimulated formalin fixation. The results show that entire prostates can be optimally fixed if formalin is present throughout the tissue as the temperature is increased by microwave irradiation. This is achieved by injecting the fixative into the prostate at multiple sites immediately following prostatectomy. The technique described ensures standardization of a critical step during tissue processing, leading to uniform microscopic results with both routine and immunohistochemical stains. It is a simple, rapid method, suitable for routine diagnostic use. Using this modified approach, DNA of much larger sizes can be extracted from paraffin-embedded material, which could expand the possibilities for molecular analysis.

Cadherins↗