Biomedical subjects

D G Miller

Publications and source records attributed to D G Miller.

At least 55 records · Page 3Linked to original sources

PubMed1992

Urinary prostate specific antigen levels: role in monitoring the response of prostate cancer to therapy.

We have shown that prostate specific antigen (PSA) levels can be as readily obtained from voided urine as from serum samples. This procedure was found to give stable and reproducible results. PSA analyses were performed on voided urine collected from 42 patients with benign prostatic hypertrophy (BPH), 27 with stage D2 prostate cancer and 57 after radical prostatectomy. The 42 BPH samples had a mean urinary PSA level of 216 ng./ml., which did not correlate with estimated prostate size. For 4 of 5 patients with stage D2 disease who presented before hormonal therapy urinary PSA levels were greater than 50 ng./ml. For 22 stage D2 patients seen after initiation of hormonal therapy the majority had low urinary PSA levels. After initiation of hormonal therapy in most cases low urinary PSA levels were found in conjunction with high serum PSA values. However, in other cases we found high urinary PSA with low serum PSA levels. Of 43 patients who underwent radical prostatectomy for stages A to C disease it was noteworthy that 77% had elevated urinary PSA levels, while only 33% had elevated serum levels. Therefore, close to 80% of these patients have prostate tissue remaining locally after this operation.

Antigens, Neoplasm↗

PubMed1992

Tunicamycin treatment of CHO cells abrogates multiple blocks to retrovirus infection, one of which is due to a secreted inhibitor.

Chinese hamster ovary (CHO) cells are resistant to infection by all of the major classes of murine retroviruses and are partially resistant to infection by gibbon ape leukemia virus. Treatment of CHO cells with the glycosylation inhibitor tunicamycin rendered these cells susceptible to infection by retroviral vectors with ecotropic, xenotropic, and amphotropic host ranges and increased the titer of gibbon ape leukemia virus pseudotyped vectors 10-fold. Vectors having a polytropic host range did not infect CHO cells in the presence or absence of tunicamycin, showing that the effect of tunicamycin was specific and related to the pseudotype of the vector. We present evidence for three mechanisms of resistance to infection: lack of viral receptors on CHO cells, the presence of nonfunctional receptors which can be made functional by treatment with tunicamycin, and the secretion of a protein factor that blocks retroviral infection of CHO cells. Several criteria indicate that the secreted inhibitor is not an interferon, and secretion of this factor was not detected in several other cell lines that were examined.

3T3 Cells↗

PubMed1991

Modulation of the cancer susceptibility measure, adenosine diphosphate ribosyl transferase (ADPRT), by differences in low-dose n-3 and n-6 fatty acids.

Adenosine diphosphate ribosyl transferase (ADPRT) is related to oxidants, and lower values for ADPRT in white cells suggest increased cancer susceptibility. Ordinarily, oxidants are generated intracellularly via metabolism of n-6 fatty acids common in western diets. However, n-3 fatty acids in fish oils might limit oxidants via competitive inhibition of key enzymes, elevate ADPRT, and lower cancer risk. In this controlled trial, 47 women were assigned either lecithin (an n-6 fatty acid, 7.2 g daily) or eicosapentaenoic acid-docosahexaenoic acid (n-3 fatty acids, 1.5 g daily) for six weeks, and 45 women completed all four visits. After six weeks, ADPRT increased by 9.3 +/- 10.8% (SD) for the n-3 fatty acid group relative to the n-6 fatty acid group. For the subset of 39 women with good compliance, ADPRT increased by 20.9 +/- 11.1% (nonparametric p = 0.039). This increase persisted after adjustment for regression to the mean. The trial suggests a "normalizing" effect of low-dose n-3 fatty acids on the ADPRT measure.

Disease Susceptibility↗

PubMed1991

Goniotomy technique for removal of anterior chamber intraocular lenses.

Removal of an anterior chamber intraocular lens is often impeded by formation of peripheral anterior synechiae around one or more of the lens haptics. We describe a method of lysing adhesions under direct visualization through a contact gonioprism lens. This method is relatively atraumatic to vital anterior-chamber-angle structures.

Anterior Chamber↗

PubMed1990

Mitogenic induction of ornithine decarboxylase in human mononuclear leukocytes: relationships with adenosine diphosphate ribosyltransferase.

1. Relationships between ornithine decarboxylase (ODC) and adenosine diphosphate ribosyl transferase (ADPRT) in human mononuclear leukocytes (HML) were tested by statistical comparisons of their values in a group of 46 people, and by use of inhibitors of ADPRT. 2. ODC was assayed following exposure of HML, for 20 hr, to mitogens [phytohemagglutinin (PHA) and pokeweed mitogen]; ADPRT was measured following exposure of HML to H2O2 (100 microM) for 1 hr (activated ADPRT), and in parallel cultures without H2O2 (constitutive ADPRT). 3. Significant correlations were found between ODC and ADPRT values; the effects of smoking disturbed the correlations. PHA induction of ODC was negatively influenced by age (standardized beta coefficient = -2.95, P = 0.005), while age also influenced ADPRT values negatively in non-smokers (for H2O2 activated ADPRT, standardized beta coefficient = -2.74, P less than 0.008). 4. Inhibitors of ADPRT, nicotinamide, caffeine and benzamide inhibited the induction of ODC by PHA in a concentration-dependent manner, in the range (0.6-10 mM) known to inhibit ADPRT.

Age Factors↗

PubMed1990

Isoenzyme(s) of glutathione transferase (class Mu) as a marker for the susceptibility to lung cancer: a follow up study.

Glutathione transferase are divided into three classes: Alpha, Mu and Pi. Isoenzyme(s) from one of these classes, class Mu, is dominantly inherited and can be determined by activity measurements directed towards the substrate trans-stilbene oxide. The frequency of this phenotype has been measured in patients with bronchial carcinoma and in control subjects matched for age and smoking history. After combining an earlier study from our laboratory (Carcinogenesis, 7, 751-753, 1986) with the additional material presented here (control smokers, n = 114, lung cancers, n = 125) non-cancer smokers had an increased number of subjects who expressed class Mu isoenzymes (58.3% of total n = 192) compared with lung cancer patients (36.6% of total n = 191; P less than 0.0001). The pathology of lung tumors related to the lack of class Mu isoenzymes which occurred most frequently in patients with adenocarcinomas. It is concluded that the gene expressing class Mu isoenzymes may be a host determinant of genetic susceptibility to lung cancer among smokers.

Adenocarcinoma↗

PubMed1990

Involutional entropion of the upper lid.

Involutional entropion is an inturning of the eyelid margin caused by changes of lid tissues due to aging. Two patients with the uncommon finding of involutional entropion of the upper lid were treated with surgery based on the principles used to treat common lower lid entropion. The causes of lower lid entropion include increased horizontal and vertical lid laxity, and correcting these same factors in the upper lid resulted in a satisfactory repair of the entropion. Treatment of involutional entropion in the upper lid is compared and contrasted with that of the lower lid.

Aged↗

PubMed1990

Gene transfer by retrovirus vectors occurs only in cells that are actively replicating at the time of infection.

Previous reports have shown that retrovirus infection is inhibited in nonreplicating (stationary-phase [hereafter called stationary]) cells. Infection of stationary cells was shown to occur when the cells were allowed to replicate at times up to a week after infection, suggesting that an unintegrated retrovirus could persist in a form that was competent to integrate after release of the block to replication. However, those studies were complicated by the use of replication-competent virus, which can spread in the infected cells. We have used a replication-defective retrovirus vector to compare the efficiency of gene transfer in stationary and replicating rat embryo fibroblasts. In agreement with previous results, gene transfer was inhibited 100-fold in stationary versus replicating cells. In contrast to previously reported results, the block to infection could not be relieved by stimulating stationary cells to divide at times from 6 h to 10 days after infection. Thus, for successful retroviral infection, the infected cells must be replicating at the time of infection. These results have important implications for the use of retroviral vectors for gene transfer.

Animals↗

PubMed1990

Oxidative stress, DNA repair, and cancer susceptibility.

For several years, our laboratory has been interested in evaluating if DNA repair capacity in peripheral human mononuclear leukocytes (HML) might be utilized as a marker of susceptibility to cancer. We have tested our hypothesis by using two different estimates of DNA repair, namely, unscheduled DNA synthesis (UDS) and ADP-ribosyl transferase (ADPRT) activity. Both UDS and ADPRT are sensitive to regulation by oxidative stress, and these parameters are suppressed in patients with cancer of the breast, colon, or lung, or with the genetic predisposition to develop it. Here we have considered interindividual variation in prooxidant-induced DNA repair in HML by analyzing ADPRT responses in regard to (1) constitutive ADPRT levels, (2) the levels of DNA damage induced by different prooxidant generating systems, (3) the type of oxygen radical generated, and (4) the role of antioxidant defenses. Only the constitutive level of ADPRT responses could explain the variation observed on 50 subjects. These data support a regulatory role for endogenous host factor variation in ADPRT and the likelihood of involvement of genetic factors.

Adult↗

PubMed1990

Acquired oculomotor-abducens synkinesis.

The authors present a rare case of bilateral aberrant oculomotor regeneration following severe head trauma with the unusual finding of unilateral palpebral fissure widening on abduction with normal lateral rectus function (oculomotor-abducens synkinesis). The findings do not match the usual syndromes of either acquired oculomotor synkinesis or acquired Duane's retraction syndrome and seem to represent a unique case of aberrant regeneration involving the third and sixth cranial nerves.

Abducens Nerve↗

PubMed1989

Ornithine decarboxylase in resting human mononuclear leucocytes: evidence for an endogenous inhibitor.

1. Ornithine decarboxylase (ODC) was measured in human mononuclear leucocytes (HML) by retention of putrescine on cation exchange paper. 2. The method was validated with unstimulated HML, phytohemagglutinin-stimulated HML, and a commercial preparation of ODC. The average enzyme activity of unstimulated HML (50 samples) was 22.6 +/- 7.3 pmol/hr 10(7) cells, with 29 values less than 5 pmol/hr 107 cells. 3. The results show that an endogenous inhibitor or inactivator of ODC exists in unstimulated HML: enzyme activity in extracts of mitogen-stimulated cells were inhibited by extracts of unstimulated cells (37-55%) inhibition under the conditions used.

Cation Exchange Resins↗

PubMed1989

DNA repair synthesis in individuals with and without a family history of cancer.

The influence of family history on DNA repair synthesis, unscheduled DNA synthesis (UDS), was assessed in volunteers with or without a family history of cancer. UDS, following treatment of mononuclear leukocytes with N-acetoxy-2-acetylaminofluorene, was measured as the incorporation of [3H]thymidine into DNA in the presence of hydroxyurea. The positive family history group (n = 71) had an average of 2.4 first-degree relatives with cancer, defined as any major cancer, excluding skin cancer: 31 participants reported that cancer occurred in both their parents. The "no family history' comparison group (n = 29) had no family history of cancer through the second degree. There was a significant reduction in UDS in cells from individuals with family history, compared to those with no family history (P greater than 0.002). This relationship was not explained by factors known to influence UDS, such as age, smoking or hypertension. We conclude that reduced UDS in mononuclear leukocytes is associated with a family history of any major cancer, and is not confined to a history of cancer of any single organ site. This conclusion is further supported by the observation that individuals (n = 13) with parents who had an earlier onset of cancer (less than 60 years) also had a significantly lower DNA repair synthesis than those (n = 18) whose parents had later diagnosis of cancer (greater than 60 years).

Acetoxyacetylaminofluorene↗

PubMed1989

Adenosine diphosphate ribosyl transferase responses to a standardized dose of hydrogen peroxide in the mononuclear leukocytes of patients with a diagnosis of cancer.

Mononuclear leukocytes from 151 patients with cancer of various organs and from 467 apparently cancer-free individuals were exposed, in vitro, to H2O2 (100 microM) and the effects of the exposure on the activity of adenosine diphosphate ribosyl transferase (ADPRT) were determined. First, the reproducibility of this test procedure was established as satisfactory, by comparing the results of assays performed independently by two investigators, and by measuring ADPRT in cells from two individuals over a 9-week period. The test data were analyzed by multiple linear regression, and the correlation of cancer diagnosis, age, sex and smoking habits with ADPRT values was determined. The strongest correlate was cancer diagnosis. We considered categorizing ADPRT values as high and low, with a cut-off value that would substantially distinguish cancer from cancer-free individuals. When a cut-off value of 1200 c.p.m. TCA ppt [3H]NAD+/5 x 10(5) cells was applied to the complete test material, it was found that ADPRT values from cancer patients were more frequently below the cut-off than values from disease-free individuals: the relative risk estimate (odds ratio) was 13.8. When a similar analysis was done on values from lung cancer patients and smoking disease-free individuals, the odds ratio was 73.5. However, a cut-off value of 2000 c.p.m. TCA ppt [3H]NAD+/5 x 10(5) cells was most effective in distinguishing lung cancer patients (the largest cancer group, n = 96) from smoking non-cancer individuals: that value provided better sensitivity (85%) and specificity (81%) than other cut-off values tested in the range 1200-2000 c.p.m. Further, in the case of lung cancer, possible effects of anatomical site, and of staging and pathology on ADPRT values was analyzed by the chi-squared test: no significant associations were found. These data support the value of the ADPRT test in detecting early stage lung cancer regardless of location or pathological type.

Adult↗

PubMed1989

The nonspecific esterases of human mononuclear leukocytes metabolize arylamine carcinogens and steroids esters.

The presence of non-specific esterases in various leukocyte subfractions of whole blood is well established, but no endogenous substrates or function for these esterases have been identified. Here we report on the metabolism of N-acetoxy-2-acetylaminofluorene (NA-AAF) and beclomethasone-17-21-dipropinate (BDP) in viable human mononuclear leukocytes (HML). Conversion of NA-AAF to DNA binding intermediates and BDP to beclomethasone-17-monopropionate by a common esterase was demonstrated and then further characterized by a broad spectrum of effectors including well-established inhibitors and substrates for the nonspecific esterases. Two esters, beta estradiol-17-propionate and alpha naphtyl propionate, competitively inhibited this esterase activity. Together, these data identify at least one isozyme of A- or B-classes of HML nonspecific esterases as being responsible for the metabolism of NA-AAF and BDP. That HML nonspecific esterases may be functionally involved in arylamine carcinogenes (i.e. as it may relate to immune function) and in the endogenous production of steroids from their naturally occurring esters emphasizes the importance of continuing their characterization.

2-Acetylaminofluorene↗

PubMed1989

Protein-restricted diets in diabetic nephropathy.

Low-protein diets in nondiabetic renal failure may slow the progressive loss of renal function in some patients, but few studies have detailed the nutritional consequences of these diets in patients with diabetic nephropathy. We studied 7 patients with insulin-dependent diabetes mellitus and chronic renal insufficiency [mean +/- SEM creatinine clearance (S, U): 28.3 +/- 6.5 ml/min (0.47 +/- 0.11 ml/s x 1.73/A)] for 15 weeks who were prescribed a diet of 0.6 g protein/kg ideal body weight. Midarm muscle circumference (24.1 +/- 1.8 at onset vs. 24.5 +/- 1.5 cm at completion), triceps skinfold thickness (21.6 +/- 3.1 vs. 21.0 +/- 1.5 mm), body weight (71.8 +/- 4.1 vs. 71.2 +/- 4.6 kg), and serum albumin [3.0 +/- 0.1 vs. 3.2 +/- 0.1 g/dl (30 +/- 1 vs. 32 +/- 1 g/l)] remained stable. Based on urinary nitrogen excretion, diet diaries overestimated the degree of dietary protein restriction; there was good adherence to the diet as evidenced by a reduction in urinary urea nitrogen (average 32%). Blood glucose control was maintained despite increased carbohydrate intake. On average, creatinine clearance did not change significantly, but proteinuria diminished slightly (1.8 +/- 0.2 vs. 1.5 +/- 0.6 g/day). These results indicate that 0.6 g/kg/day protein diets did not cause protein depletion in insulin-dependent diabetic patients. Longer-term studies are indicated to assess more fully the efficacy of these dietary regimens in reducing proteinuria or benefiting diabetic nephropathy.

Adult↗

PubMed1988

Relationship between the covalent binding of N-acetoxy-2-acetylaminofluorene to DNA and a steroidal esterase activity in human mononuclear leukocytes.

A method for the quantitative assessment of steroidal esterase activity in viable human mononuclear leukocytes (HML) has been developed. It is based on estimating the conversion of [3H]beclomethasone-17,21-dipropionate (BDP) to beclomethasone-17-monopropionate (BMP) using TLC on silica gel 60 F-254 plates developed in a solvent system of chloroform/methanol (97:3, v/v). The cell assay procedure was dependent on BDP concentration, incubation time and cell concentration. The steroidal esterase activity was completed for by N-acetoxy-N-acetyl-2-aminofluorene (NA-AAF) and completely inhibited by 100 microM paraoxon. When [3H]NA-AAF binding to DNA was used as an indicator of HML esterase (deacylase) activity, BDP functioned as a substrate inhibitor. Parallel estimations of BDP metabolism and NA-AAF binding to DNA indicated striking correlations in the interindividual variations (r = 0.62, P less than 0.001) and in relation to the menstrual cycle events of a healthy female. Hence, these data indicate that both BDP and NA-AAF are metabolized by the same non-specific steroidal esterase present in HML.

2-Acetylaminofluorene↗

PubMed1988

Effects of cumene hydroperoxide on adenosine diphosphate ribosyl transferase in mononuclear leukocytes of patients with adenomatous polyps in the colon.

We have studied the effects of plasma and of cumene hydroperoxide (CUM) on adenosine diphosphate ribosyl transferase (ADPRT) from mononuclear leukocytes (HML) of patients with colonic adenomatous polyps (n = 22), with colonic hyperplastic polyps (n = 5) and with neither type of polyp (controls) (n = 6). ADPRT was measured after incubation of HML with plasma alone (termed the plasma value), and with plasma plus CUM (50 microM) (the activated value); the difference elicited by CUM was termed the induced value. There was no significant difference in values between the control and hyperplastic polyp groups: these were combined for further analysis. The plasma (P = 0.038), activated (P = 0.009) and induced (P = 0.0024) values of the combined group all differed significantly from those of the adenoma group. At low exposures, CUM stimulated both ADPRT and unscheduled DNA synthesis and, at higher exposures, inactivated both. Pretreatment of HML with vitamin E protected against these effects of CUM, while pretreatment with diamide (which depletes GSH) accentuated the effects. This study demonstrates a differential reaction of ADPRT in patients harboring colonic adenomas and suggests that the origin of this difference may lie in cellular responses to oxidative stress.

Benzene Derivatives↗

PubMed1988

Hydrogen peroxide induced adenosine diphosphate ribosyl transferase (ADPRT) response in patients with inflammatory bowel disease.

The sample population in this initial case control study of the adenosine diphosphate ribosyl transferase (ADPRT) response of inflammatory bowel disease patients included: 23 patients with ulcerative colitis (UC)-active and inactive, 13 patients with Crohn's disease (CD)-active and inactive, 14 first degree relatives of UC and CD patients, and 19 age-matched controls. Adenosine diphosphate ribosyl transferase activity was determined after one hour incubation with 1% plasma (the constitutive value) or with 1% plasma and 100 microM H2O2 (the activated value) with the resulting difference designated as the induced value. Statistically significant decrease in ADPRT activity was found for the constitutive, activated and induced values in human mononuclear leucocytes of UC and CD patients, compared with controls. The values in the first degree relatives of UC and CD patients were not significantly different from either the control or disease populations, indicating an intermediate ADPRT response. These results may be related to the nature of the immunological response of IBD patients and comparable with similar findings in other diseases with known DNA repair deficiencies--for example, colon cancer.

Adult↗