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Biomedical subjects

D R Miller

Publications and source records attributed to D R Miller.

At least 145 records · Page 8Linked to original sources
PubMed1989

Induction of terminal differentiation-resistant epidermal cells in mouse skin and in papillomas by different initiators during two-stage carcinogenesis.

Carcinogen treatment of normal mouse epidermal cells causes some cells, if cultured under the appropriate conditions, to continue to proliferate instead of terminally differentiate, forming foci at 37 degrees C in medium with a calcium level above 0.1 mM. We have examined these Calcium (Ca)-resistant cells formed in the skin of SENCAR mice after treatment with the carcinogen initiator 7,12-dimethylbenz[a]anthracene (DMBA) followed by tumor promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA). Although in our previous studies TPA promotion initially increased the size but reduced the number of foci caused by the carcinogen initiator N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), TPA promotion of DMBA-treated mice increased the size but had no effect on the number of foci. Papillomas resulting from DMBA plus TPA treatment contained many rapidly growing Ca-resistant cells, corroborating our earlier results with MNNG. Permanent cell lines prepared from papilloma-derived foci formed squamous cell carcinomas in nude mice after relatively short periods in culture. These data provide further evidence that Ca-resistant cells may be papilloma (and perhaps carcinoma) precursors in vivo. In addition, since TPA tends to reduce the number of early Ca-resistant cells caused by MNNG but not by DMBA, this may at least partially explain why treatment with DMBA plus TPA is much more effective in producing papillomas in SENCAR mice than is treatment with MNNG plus TPA.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1989

Reversal of neutropenia with methotrexate treatment in patients with Felty's syndrome. Correlation of response with neutrophil-reactive IgG.

We evaluated the clinical and hematologic response to methotrexate (MTX) in 4 women with Felty's syndrome (FS) who had had neutropenia for 1-3 years. Since immune complexes or antineutrophil antibodies are implicated in the pathogenesis of the neutropenia of FS, we also measured both direct and indirect levels of neutrophil-reactive IgG. All 4 patients showed a prompt and dramatic increase in neutrophil counts within 1-2 months of starting MTX therapy. In 3 patients, the symptoms of arthritis also improved; in the fourth patient, arthritis worsened. Recurring infections ceased in 3 patients. Neutrophil-reactive IgG levels, which were elevated in all patients prior to treatment, decreased toward normal while the patients were receiving MTX therapy. We conclude that MTX is effective in treating the neutropenia of FS, in part by lowering neutrophil-reactive IgG.

Aged↗
PubMed1989

Bolus administration of esmolol for the treatment of intraoperative myocardial ischaemia.

We report the successful treatment with esmolol of intraoperative myocardial ischaemia associated with concurrent hypertension and tachycardia, in a patient with risk factors for coronary artery disease undergoing peripheral vascular surgery. The pathophysiology of myocardial ischaemia, and the therapeutic role of beta blocking drugs are briefly reviewed. Esmolol, a short-acting cardioselective beta blocking drug, was administered in a bolus of 1.5 mg.kg-1, and resulted in prompt resolution of the haemodynamic abnormalities, with concomitant restitution of the ST segments to isoelectric baseline. We conclude that bolus administration of esmolol is practical and can be effective for the treatment of intraoperative myocardial ischaemia.

Adrenergic beta-Antagonists↗
PubMed1989

Recovery of induced mutations for X chromosome-linked muscular dystrophy in mice.

We have used elevated levels of plasma creatine phosphokinase activity to identify muscular dystrophy phenotypes in mice and to screen the progeny of chemical mutagen-treated male mice for X chromosome-linked muscular dystrophy mutations. We were not successful in identifying heterozygous carriers of these induced muscular dystrophy mutations in greater than 8000 progeny. However, we were highly successful in identifying three additional alleles of the characterized mdx locus. These alleles of mdx were recovered from various mutagen-treated males and they occur on an X chromosome that carries flanking markers that allow us to follow the mutations in genetic crosses and in the development of corresponding mutant stocks. These alleles have been designated as mdx2Cv, mdx3Cv, and mdx4Cv. Preliminary data show that mice with mdx2Cv and mdx3Cv mutations have muscular dystrophic phenotypes that do not grossly differ from the characterized mdx mutation. These additional mdx mutations expand the value of mouse models of X chromosome-linked muscular dystrophy and potentially define additional sites of mutation that impair dystrophin expression.

Animals↗
PubMed1989

Breast cancer before age 45 and oral contraceptive use: new findings.

The relation between the risk of breast cancer before 45 years of age and oral contraceptive use was examined in a case-control study conducted in New York, Philadelphia, Baltimore, and Boston from 1983 to 1986 of 407 patients with breast cancer and 424 controls. With allowance for confounding, for ever use, the multivariate relative risk estimate was 2.0 (95% confidence interval (CI), 1.4-2.9). For less than 10 years of use, the estimate approximated 2.0 in all categories of duration, including less than three months; for 10 or more years of use it was 4.1 (95% CI, 1.8-9.3). The association was apparent in virtually all subgroups examined, including younger and older women, and women at low and high underlying risk of breast cancer. Contrary to some previous reports, the association was not stronger for use before a first term pregnancy or at an early age. The results suggest that oral contraceptive users, particularly those with very long durations of use, may be at increased risk of breast cancer. However, information bias, particularly for short-term use, could not be ruled out. There may also have been selection bias if oral contraceptive users were under more intensive medical surveillance. It has not been possible to reconcile the findings of the various studies to date, including the authors' earlier results showing no association. The latter results were derived from data collected using methods almost identical to those used in the present study.

Adult↗
PubMed1989

Acquired immune deficiency syndrome (AIDS). Indications for abdominal surgery, pathology, and outcome.

Thirty-six major abdominal operations were performed on 35 Acquired Immune Deficiency Syndrome (AIDS) patients (33 men, two women). Twenty-two elective operations were indicated for diagnosis of abdominal or retroperitoneal mass (6), incomplete bowel obstruction (5), intra-abdominal infection (4), biliary symptoms (3), thrombocytopenia (3), and toxic megacolon (1). Fourteen emergency operations were for perforated viscus or peritonitis (11), massive gastrointestinal bleeding (2), and cecal volvulus (1). In 5 of 22 (23%) elective operations AIDS was unknown to the treating physicians until diagnosed by the surgical pathology; in contrast, all 14 emergency operations were in patients who had a known diagnosis of AIDS. The operative findings were related to AIDS in 34 of 36 (94%) operations. Cytomegalovirus was the most common pathogen, isolated or identified microscopically in 11 patients (eight emergency and three elective operations). Mycobacterial infections presented as retroperitoneal adenopathy or splenic abscess in six patients. Non-Hodgkins lymphoma was the most common malignancy found, presenting as an abdominal mass (4), bowel obstruction (3), or with gastrointestinal bleeding (2). Kaposi's sarcoma was diagnosed at laparotomy in four patients. The 1-month operative mortality rate for elective operation was 9% (2 of 22) and 46% (6 of 13) in emergencies. Postoperative complications included 1 reoperation for sepsis caused by inadequately resected CMV colitis; 1 pancreatic fistula; 1 wound dehiscence, and 2 minor wound infections.

Abdomen↗
PubMed1989

Early response to induction therapy as a predictor of disease-free survival and late recurrence of childhood acute lymphoblastic leukemia: a report from the Childrens Cancer Study Group.

The Childrens Cancer Study Group (CCSG) CCG-160 protocol series was designed to evaluate prognostic factors in acute lymphoblastic leukemia (ALL). Patients were assigned to one of three prognostic groups based upon initial WBC count and age. To determine the optimal duration of therapy, CCG-160 patients completing 2 years of treatment in continuous remission were randomized ("late randomization") to discontinue therapy or receive another year of maintenance therapy. The prognostic significance of early response to induction therapy, as measured by the percentage of lymphoblasts in the day-14 bone marrow (d14 BM) aspirate, was evaluated in 2,516 children. For 1,490 patients with complete data, the status of the d 14 BM was a highly significant predictor of disease-free survival (DFS) by univariate and multivariate analysis (P less than .0001). The observed/expected (O/E) failure rate in patients with d14 M1 (less than 5% blasts), M2 (4% to 25% blasts), or M3 (greater than 25% blasts) BM rating who were subsequently M1 on day 28 or day 42, was .87, 1.59, and 2.30, respectively (P less than .0001). Patients with M2 or M3 d14 BM were more likely to have L2 ALL (modified French-American-British [FAB] morphologic classification), P less than .001. The significance of the d14 BM rating persisted after correction was made for WBC count and clinical prognostic groups using current CCSG criteria, except in infants less than 12 months of age. The d14 BM was also the most significant predictor of DFS in 975 patients after late randomization at 2 years following diagnosis. The O/E failure rate in patients with d14 M1, M2, or M3 BM was .88, 1.78, and 2.02, respectively (P = .0002, trend). Other significant predictors of late relapse were prognostic groups (P = .0003, trend) and initial WBC count (P = .004, trend). Predictive for both early and late relapse of ALL, early response should be monitored closely and alternative treatment regimens should be considered for slow responders.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Three versus five years of maintenance therapy are equivalent in childhood acute lymphoblastic leukemia: a report from the Childrens Cancer Study Group.

Childrens Cancer Study Group protocol 141 (CCG-141), a randomized trial, was designed in part to compare 3 v 5 years of maintenance therapy, to evaluate the role of late reinduction, and to identify factors that predict relapse after 3 years of continuous complete remission (CCR) in acute lymphoblastic leukemia (ALL). Of 880 patients entered on study, 827 (94%) achieved complete remission and 499 (56.7%) were in CCR after 3 years of maintenance therapy. Boys were required to have negative testicular biopsies before randomization. A total of 481 patients were eligible for the duration of therapy phase of the study. Of the 310 (64.4%) randomly assigned patients, 101 were entered on regimen A: discontinue therapy; 105 on regimen B: reinduction for 4 weeks, then discontinue therapy; and 104 on regimen C: continue maintenance therapy for 2 more years, then discontinue. After a median follow-up of over 72 months, no significant differences in disease-free survival (DFS) or survival were noted in the three regimens. At 6 years from randomization, 93.0%, 89.1%, and 89.1% of patients on regimens A, B, and C, respectively, remained in CCR. Isolated CNS or overt testicular relapses were not significantly different in any of the study regimens. Isolated testicular relapse after a negative biopsy occurred in only two of 137 randomized males (1.5%). DFS (P = .10) and survival (P = .83) were not significantly different for all boys and girls randomized to regimens A, B, or C. The relapse rate was higher in boys than in girls randomized to discontinue therapy (11% v 4%), but the difference was not statistically significant (P = .14). Except for the presence of occult testicular leukemia (TL) in males, no other factors were identified that predicted for adverse events after 3 years of CCR. We conclude that prolongation of maintenance therapy beyond 3 years does not improve survival or decrease the risk of relapse.

Adolescent↗
PubMed1988

In vivo behavior of murine epidermal cell lines derived from initiated and noninitiated skin.

The in vivo behavior of cell cultures derived from normal and carcinogen-treated mouse epidermis was studied by implanting the cultures in a s.c. vascularized bed protected by a silicone chamber. Cells derived from normal adult mouse epidermis as well as cells derived from tumor-promoter-treated skin were unable to grow in these systems. Conversely, cell lines derived from skin initiated with single doses of N-methyl-N'-nitro-N-nitrosoguanidine or 9,10-dimethyl-1,2-benzanthracene proliferated in these chambers, reforming an epithelial structure. The type of structure in the chambers varied, ranging from formation of almost normal epithelia to atypical invasive behavior. The variable in vivo behavior among the different cell lines may be attributed to the initiation agent, the number of passages of the cultures, random genetic events, the strain of mouse, or a combination of these factors. Most of the cell types used in this study and all the cell lines that were able to grow in these chambers were selected for resistance to Ca-induced terminal differentiation. However, resistance to terminal differentiation according to the Ca2+ switch does not always correlate with the ability to grow in the chambers, since cell lines derived from spontaneous foci of resistance failed to grow in this system. These studies showed some of the possibilities of the SC silicone chambers to study the histogenic potential of cell lines derived from carcinogen-treated epidermis. This system also appears suitable to study the complex relationship between epidermal cells and specialized (dermal) stroma.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1988

Major upper gastrointestinal tract bleeding. Relation to the use of aspirin and other nonnarcotic analgesics.

In a hospital-based case-control study, the risk of a first episode of major upper gastrointestinal tract bleeding in subjects now known to be predisposed was assessed in relation to the use of nonnarcotic analgesics. For aspirin use within the week before the onset of symptoms, the rate ratio estimates, adjusted for potential confounding, were 15 (95% confidence interval, 6.4 to 34) for regular use (at least four days a week) and 5.6 (confidence interval, 2.7 to 12) for occasional use. For aspirin use discontinued at least one week earlier, the estimate was 1.6 (confidence interval, 0.6 to 4.2). There was no evidence that acetaminophen use increased the risk. For the regular use of other analgesics in the week before onset, the adjusted rate ratio estimate was 9.1 (confidence interval, 2.7 to 31); there were insufficient data to evaluate occasional use. The findings suggest that the risk of bleeding is increased substantially by aspirin, even when used occasionally. With the exception of acetaminophen, other nonnarcotic analgesics may also increase the risk, but they remain to be evaluated individually.

Acetaminophen↗
PubMed1988

Effects of anesthetic induction on myocardial function and metabolism: a comparison of fentanyl, sufentanil and alfentanil.

Anaesthetic induction may induce myocardial ischaemia. A prospective randomized trial was instituted to compare the effect on ventricular function and myocardial metabolism of induction with fentanyl (FEN) or its analogues sufentanil (SUF) or alfentanil (ALF) in 96 patients undergoing elective coronary artery bypass grafting (CABG). Haemodynamic, metabolic (coronary sinus oxygen and lactate extraction) and gated ventriculographic measurements were made awake pre-induction (PRE), after induction (IND) and after intubation (INT). Induction was performed with FEN 75 micrograms.kg-1, SUF 15 micrograms.kg-1 or ALF 125 micrograms.kg-1 and metocurine. Fentanyl induction was associated with the greatest stability of mean arterial pressure (MAP), cardiac performance, and systolic function without associated myocardial lactate production. SUF produced the greatest depression of systolic function (p less than 0.05) but without haemodynamic instability or myocardial lactate production in all but one patient. Induction with ALF produced the greatest reduction in MAP (p less than 0.05) associated with the greatest decrease in diastolic compliance (p less than 0.05) and 50 per cent incidence of myocardial lactate production (p less than 0.05) with no significant change in coronary blood flow or myocardial oxygen consumption.

Alfentanil↗
PubMed1988

Intermediate-term survival results in clinically understaged prostate cancer patients following radical prostatectomy.

To determine the natural history of clinically understaged prostatic cancer patients who were followed without adjuvant therapy for at least 6 years after radical prostatectomy we reviewed the clinical courses of 21 patients (1 with clinical stage A and 20 with clinical stage B disease). All patients underwent radical retropubic prostatectomy and 9 had pathological stage C disease (6 with capsular penetration only and 3 with seminal vesicle invasion). A total of 12 patients had pathological stage D1 disease by virtue of positive nodes on permanent sections after frozen sections were read as negative. Among the patients with pathological stage C disease 67 per cent were free of recurrence 6 years after radical prostatectomy. Of the patients with seminal vesicle invasion 33 per cent had recurrence compared to 17 per cent of those with capsular penetration only. Among the 12 stage D1 cancer patients 75 per cent were free of recurrence at 6 years. In both groups patients who were followed beyond 7 years had a diminished survival free of tumor owing to late tumor recurrences. The results indicate that the intermediate survival rates free of tumor in patients with clinically understaged A or B prostatic cancer are remarkably good without adjuvant therapy. However, survival without recurrence appears to decrease after 7 years. All patients who failed treatment did so distantly; no patient failed with local recurrence alone. These results may be important in the evaluation of adjuvant therapy protocols currently under investigation for patients with clinically understaged prostate cancer.

Adenocarcinoma↗
PubMed1988

Methodologic considerations for investigating the diet-cancer link.

Evidence from human ecological studies and experimental animal studies suggest that a number of dietary factors may have a role in the etiology of cancers of various sites. When associations are examined within populations on the level of the individual, they often weaken or disappear. Although in some cases the suspect nutrient may have no real carcinogenic effect, it is proposed that there are at least three important methodologic problems that could prevent the observation of a true association between dietary factors and human cancer. First, diet assessment methods are inadequate to estimate true exposure with sufficient accuracy and precision especially over long periods. Second, use of retrospective diet assessment methods in case-control study designs can often introduce an important bias. Third, sufficient within-study-group contrasts are often lacking. These problems are discussed in interpreting recent cancer studies of diet, and recommendations are made for future research.

Diet↗