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Biomedical subjects

R Miller

Publications and source records attributed to R Miller.

At least 361 records · Page 20Linked to original sources
PubMed1996

Relation of prediagnostic serum estrogen and androgen levels to breast cancer risk.

To evaluate the relation of serum sex hormones to breast cancer risk, we conducted a prospective nested case-control study using the Breast Cancer Serum Bank (Columbia, MO). This bank included serum from 3375 postmenopausal women free of cancer and not taking replacement estrogens when they donated blood between 1977 and 1987. Of these, 71 were diagnosed subsequently with breast cancer. For each case, two women alive and free of cancer at the age of the case's diagnosis and matched to the case on age and on date and time of day of blood collection were selected as controls. The median age of subjects at blood collection was 62 years, and the time from blood collection to diagnosis ranged from less than 1 to 9.5 years, with a median of 2.9 years. Postmenopausal women with elevated serum levels of total and non-sex hormone-binding globulin-bound E2 were at an increased risk of developing breast cancer. For non-sex hormone-binding globulin-bound E2, risks were elevated 4-5 fold for women in the upper three quartiles relative to those in the lowest quartile. Although breast cancer was not related to estrone or estrone sulfate concentration, the ratio of estrone sulfate to estrone was significantly inversely associated with risk, suggesting that women who develop breast cancer may be less able to metabolize estrone to its less active form. Serum testosterone was significantly positively associated with postmenopausal breast cancer; the relative risk for women in the highest versus the lowest quartile was 6.2 (95% confidence interval, 2.0-19.0). Our results support the hypothesis that prediagnostic serum estrogens and androgens are related to the subsequent diagnosis of breast cancer in postmenopausal women.

Adult↗
PubMed1996

Low-cost high-resolution fast spin-echo MR of acoustic schwannoma: an alternative to enhanced conventional spin-echo MR?

PURPOSE: To determine whether unenhanced high-resolution T2-weighted fast spin-echo MR imaging provides an acceptable and less expensive alternative to contrast-enhanced conventional T1-weighted spin-echo MR techniques in the diagnosis of acoustic schwannoma. METHODS: We reviewed in a blinded fashion the records of 25 patients with pathologically documented acoustic schwannoma and of 25 control subjects, all of whom had undergone both enhanced conventional spin-echo MR imaging and unenhanced fast spin-echo MR imaging of the cerebellopontine angle/internal auditory canal region. The patients were imaged with the use of a quadrature head receiver coil for the conventional spin-echo sequences and dual 3-inch phased-array receiver coils for the fast spin-echo sequences. RESULTS: The size of the acoustic schwannomas ranged from 2 to 40 mm in maximum dimension. The mean maximum diameter was 12 mm, and 12 neoplasms were less than 10 mm in diameter. Acoustic schwannoma was correctly diagnosed on 98% of the fast spin-echo images and on 100% of the enhanced conventional spin-echo images. Statistical analysis of the data using the kappa coefficient demonstrated agreement beyond chance between these two imaging techniques for the diagnosis of acoustic schwannoma. CONCLUSIONS: There is no statistically significant difference in the sensitivity and specificity of unenhanced high-resolution fast spin-echo imaging and enhance T1-weighted conventional spin-echo imaging in the detection of acoustic schwannoma. We believe that the unenhanced high-resolution fast spin-echo technique provides a cost-effective method for the diagnosis of acoustic schwannoma.

Adult↗
PubMed1995

Structure-activity relationships of the antimalarial agent artemisinin. 2. Effect of heteroatom substitution at O-11: synthesis and bioassay of N-alkyl-11-aza-9-desmethylartemisinins.

A novel class of artemisinin analogs, N-alkyl-11-aza-9-desmethylartemisinins 17-29, were synthesized via ozonolysis and acid-catalyzed cyclization of precursor amides 5-16. These amides were prepared through condensation of an activated ester of the known intermediate acid 2 with the corresponding primary amine. The analogs were tested in vitro against W-2 and D-6 strains of Plasmodium falciparum and found in some cases to be more active than artemisinin. A comparison of the in vitro testing methods of Milhous and Makler was conducted and gave similar relative antimalarial activities for these artemisinin analogs. Log P values were determined for most of the compounds, but no apparent correlation between log P and in vitro activity was found.

Animals↗
PubMed1995

Effects of recombinant dimeric TNF receptor on human inflammatory responses following intravenous endotoxin administration.

Effects of dimeric TNF receptor (p80) Fc (TNFR:Fc) on acute phase responses were evaluated in 18 volunteers given endotoxin (4 ng/kg i.v.). Subjects were randomized to receive either placebo (n = 6), low dose TNFR:Fc (10 mg/m2 i.v., n = 6), or high dose TNFR:Fc (60 mg/m2 i.v., n = 6). TNFR:Fc blocked plasma TNF bioactivity (p = 0.001) and increased, in a dose-ordered fashion, TNF immunoactivity (p < 0.001). TNFR:Fc decreased secondary cytokine levels including IL-1 beta (p = 0.007), IL-8 (p < 0.001), IL-1 receptor antagonist (p < 0.001), granulocyte-CSF (p = 0.03), and growth regulated peptide-alpha (p = 0.001) but not macrophage inflammatory protein-1 alpha or IL-10. Low dose, but not high dose, TNFR:Fc blunted or delayed the release of epinephrine and cortisol (p < or = 0.026). Despite the absence of plasma TNF bioactivity, high dose TNFR:Fc was less immunosuppressive than low dose TNFR:Fc as measured by cytokine and stress hormone responses. Endotoxin-related symptoms were not altered by TNFR:Fc and the febrile response was delayed but not diminished (p = 0.004). Increases in cardiac index (72 +/- 19%) and heart rate (60 +/- 10%) and decreases in systemic vascular resistance index (47 +/- 7%) were unaltered by TNFR:Fc. These data suggest that the inflammatory response to endotoxin can escape from high levels of circulating TNF-blocking activity and redundant pathways, independent of circulating TNF, can sustain inflammation and clinical responses caused by acute endotoxemia.

Animals↗
PubMed1995

Psychotropic drug use in Sydney nursing homes.

OBJECTIVE: To determine the pattern of use of psychotropic drugs in Sydney nursing homes. DESIGN: Survey of data from medical records of residents and interviews with residents and staff. SETTING: Central Sydney Health Area, June to December 1993. PARTICIPANTS: All residents of 46 of the 47 nursing homes in the western sector of the health area. MAIN OUTCOME MEASURES: Psychotropic drugs used regularly or as required. Degree of cognitive impairment and depression rated on interview with residents, using Mini-Mental State Examination and Geriatric Depression Scale. Behavioural disturbances reported by staff. RESULTS: Most residents (58.9%) were taking one or more psychotropic drugs regularly and another 7% were prescribed these drugs as required. Neuroleptics were taken regularly by 27.4% and as required by a further 1.4% (at least one dose in the previous four weeks), but doses were equivalent to more than 100 mg/day of chlorpromazine for only 8.8%. Neuroleptics were more likely to be given to residents with greater cognitive impairment and more disturbed behaviour. Other psychotropic drugs in regular use were: benzodiazepines (32.3%); hypnotics (26.6%); antidepressants (15.6%); and anxiolytics (8.6%). At least half of antidepressant doses were subtherapeutic. Of 874 residents who responded to a depression questionnaire, 30% scored as significantly depressed; one-third of these were taking antidepressants. CONCLUSIONS: The percentage of residents in Central Sydney nursing homes who were taking neuroleptics, hypnotics or anxiolytics is among the highest reported from geriatric institutions around the world. Prescribing practices in Australian nursing homes need to be reviewed.

Aged↗
PubMed1995

Synthetic phosphopeptide from rhodopsin sequence induces retinal arrestin binding to photoactivated unphosphorylated rhodopsin.

A synthetic heptaphosphopeptide comprising the fully phosphorylated carboxyl terminal phosphorylation region of bovine rhodopsin, residues 330-348, was found to induce a conformational change in bovine arrestin. This caused an alteration of the pattern of limited proteolysis of arrestin similar to that induced by binding phosphorylated rhodopsin or heparin. Unlike heparin, the phosphopeptide also induced light-activated binding of arrestin to both unphosphorylated rhodopsin in disk membranes as well as to endoproteinase Asp-N-treated rhodopsin (des 330-348). These findings suggest that one function of phosphorylation of rhodopsin is to activate arrestin which can then bind to other regions of the surface of the photoactivated rhodopsin.

Amino Acid Sequence↗
PubMed1995

Preclinical evaluation of LU 79553: a novel bis-naphthalimide with potent antitumor activity.

LU 79553 is a novel bis-naphthalimide which is highly cytotoxic in vitro with EC50 (concentration required for 50% inhibition of growth) ranging from 2 x 10(-7) to 5 x 10(-10) M. A number of studies were conducted to examine its antitumor activity in human xenograft models. In addition, we wanted to explore the possible schedule dependency of LU 79553 cytotoxicity in these xenograft models. Complete regression of MX-1 (mammary carcinoma) xenografts was observed when LU 79553 was administered i.v. daily for 5 doses at 20 mg/kg (2 cycles starting on Days 6 and 20) or every 3 days for 2 doses at 55 mg/kg (2 cycles starting on Days 6 and 13) or every 7 days for 4 doses. Complete regression was also seen in the MX-1 model when tumors were staged at 1-2 g prior to the initiation of treatment. Regressions (complete or partial) were observed in the LX-1 (lung), CX-1 (colon), DLD (colon), and LOX (melanoma) xenograft models. A significant increase in the median survival time of OVCAR-3- (ovarian carcinoma) bearing mice was noted in LU 79553-treated animals (treated/control = 195%). The excellent activity of this compound in such a wide variety of tumor types suggests LU 79553 merits further investigation in clinical trials.

Amides↗
PubMed1995

Flanking and intragenic sequences regulating the expression of the rabbit alpha-globin gene.

Despite their descent from a common ancestral gene and the requirement for coordinated, tissue-specific regulation, the alpha- and beta-globin genes in many mammals are regulated in distinctly different ways. Unlike the beta-globin gene, the rabbit alpha-globin gene is transiently expressed at a high level without an added enhancer in transfected erythroid and non-erythroid cells. By examining a series of alpha/beta fusion genes, we show that internal sequences of the rabbit alpha-globin gene (within the first two exons and introns) are required along with the 5' flank for this enhancer-independent expression. Furthermore, deletion of the introns of the alpha-globin gene, or replacement by introns of the beta-globin gene, results in severely decreased expression of the transfecting genes. Hybrid constructs between segments of the alpha-globin gene and a luciferase gene confirm that internal alpha-globin sequences are needed for high level production of RNA in transfected cells. The flanking and internal sequences implicated in regulation of the rabbit alpha-globin gene coincide with a prominent CpG-rich island and may comprise an extended promoter (including both flanking and intragenic sequences) that is active in transfected cells without an enhancer.

Animals↗
PubMed1995

Availability of thrombolytic therapy in rural Newfoundland and Labrador.

OBJECTIVE: To determine the availability of thrombolytic therapy in rural Newfoundland and Labrador. DESIGN: Self-administered questionnaire mailed to staff at health care facilities. Respondents were sent two reminders by mail, and questionnaires not returned were completed through telephone interviews. SETTING: Rural health care facilities, including hospitals, 24-hour clinics and satellite clinics. PARTICIPANTS: All chief medical officers, nursing supervisors and administrators in the 34 government-funded rural health care facilities in Newfoundland and Labrador. OUTCOME MEASURES: Number of facilities offering thrombolytic therapy to patients with acute myocardial infarction (AMI) in 1992. For each facility: number of patients presenting with AMI during that year, number of these patients who received thrombolytic therapy, number of staff trained in advanced cardiac life support, travel time to the nearest referral centre, population served and number of beds. RESULTS: Of the 34 rural health care facilities in Newfoundland and Labrador, 91% (31/34) responded to the survey. Thrombolytic therapy was offered in 93% (13/14) of the rural hospitals, 22% (2/9) of the 24-hour clinics and none of the single-physician satellite clinics. In 1992, 390 patients with AMI presented to these health care facilities; 39% of these patients presented to facilities that did not offer thrombolytic therapy. CONCLUSIONS: Thrombolytic therapy has been successfully introduced in many of the rural and isolated health care facilities in Newfoundland and Labrador. An important factor in this success is continuing medical and nursing education on the effectiveness of thrombolytic therapy and the skills needed to provide it. Cost-effectiveness data are needed to determine whether it is reasonable to offer this therapy in isolated, low-volume clinics. More research on the outcomes in patients receiving thrombolytic therapy in rural facilities is also needed.

Humans↗
PubMed1995

Use of the minimal function for partial structure development in direct methods.

The shake-and-bake procedure, which is based on the minimal function, has been tested and shown to be extremely effective in molecular-fragment recycling applications. Correctly positioned fragments as small as 5% of the scattering power of the structure typically have a 50% chance of producing a solution in a single recycling trial. While starting models for tangent-formula recycling methods normally require an average r.m.s. displacement error of less than approximately 0.25 A from the refined structure to ensure an adequate chance of success, the shake-and-bake method often tolerates r.m.s. model errors well in excess of 0.5 A. Tests indicate that the new method can outperform traditional tangent-formula procedures in difficult structural applications involving multiple copies of pseudosymmetrically related molecules or low-resolution data.

Cholesterol Esters↗
PubMed1995

A model for estimating individualized valproate clearance values in children.

To evaluate the population pharmacokinetics of valproic acid in children, 97 steady-state serum valproate concentration measurements were gathered during normal, routine, outpatient care of 52 children with epilepsy (1.2-16 years of age). Levels were obtained from patients receiving valproate monotherapy (49%) or valproate with concomitant carbamazepine (32%), phenytoin (11%), or phenobarbitone (8%). A one-compartment model was used to fit the data with the Nonlinear Mixed Effects Model (NONMEM) computer program. The final model for clearance (L/hr) was CL = [EXP (0.022WT-1.38)] X M, where EXP = the base of the natural logarithm, WT = patient weight (kg) and M = a scaling factor for concomitant medication with a value of 1 for patients on valproate monotherapy and 1.61 for those receiving concomitant carbamazepine. Although phenytoin and phenobarbitone also were expected to increase valproate clearance, this could not be demonstrated, possibly because of the small number of samples taken from patients receiving these agents. Weight-adjusted values of valproate clearance decreased with increasing age. The actual mean value of 0.021 L/hr/kg for children taking monotherapy was slightly higher than values shown in most previously published reports, whereas the mean value of 0.028 L/hr/kg for patients taking concomitant carbamazepine was similar to those found previously in children taking other antiepileptic drugs.

Administration, Oral↗