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Biomedical subjects

W H Miller

Publications and source records attributed to W H Miller.

At least 127 records · Page 7Linked to original sources
PubMed1992

Reverse transcription polymerase chain reaction for the rearranged retinoic acid receptor alpha clarifies diagnosis and detects minimal residual disease in acute promyelocytic leukemia.

The characteristic t(15;17) of acute promyelocytic leukemia (APL) fuses the retinoic acid receptor alpha (RAR-alpha) gene on chromosome 17 to a gene on chromosome 15 called PML, a putative transcription factor. This distinct translocation results in a fusion mRNA detected by Northern analysis. Two cDNAs have been isolated that differ in the extent of 3' PML nucleic acid sequence contained. This study describes a reverse transcription polymerase chain reaction (RT-PCR) assay for the PML/RAR-alpha fusion transcript, which amplifies PML/RAR-alpha mRNA from APL cells with either reported breakpoint. DNA sequencing of the predominant RT-PCR products from 6 patients showed identical RAR-alpha exonic breakpoints and two PML breakpoints. This RT-PCR assay was positive in leukemic cells from 30/30 APL patients with the molecular rearrangement confirmed by cytogenetics or Northern analysis. In leukemic cells of patients with a morphologic diagnosis of APL lacking the t(15;17) by routine cytogenetics, a positive RT-PCR assay predicted clinical response to all-trans-retinoic acid (RA) therapy. Dilutional studies with leukemic cells that express (NB4) or do not express (HL-60) a PML/RAR-alpha fusion mRNA reveal that this RT-PCR assay detects the transcript from as little as 50 pg of total RNA. In APL cells from 5/6 patients treated with RA alone, a complete response by clinical and cytogenetic criteria accompanied a persistently positive RT-PCR assay. This preceded relapse by 1-6 months. RT-PCR for PML/RAR-alpha mRNA provides a more-sensitive test for the t(15;17) than routine cytogenetics or Northern analysis. This molecular rearrangement detected by RT-PCR best defines this RA-responsive malignancy. The RT-PCR assay for the PML/RAR-alpha transcript yields important diagnostic and prognostic information in the management of APL patients.

Base Sequence↗
PubMed1992

Dermatologic disorders of Chinese Shar Peis: 58 cases (1981-1989).

A retrospective study on the skin diseases of Chinese Shar Peis was conducted over a 9-year period. Skin disease was found in 58 (49.2%) of the 118 dogs studied. Folliculitis was the most common clinical finding (43 of 58 dogs). In 6 dogs, there was no apparent reason for the folliculitis; however, it was secondary to allergic dermatitis, demodicosis, IgA deficiency, or hypothyroidism in the other dogs. Approximately 20% of the dogs had more than one of these disorders. Serum IgA concentration was measured in 7 dogs and was low in all 7.

Animals↗
PubMed1992

Evaluation of an allergy screening test for use in atopic dogs.

An in-office allergy screening kit was evaluated for its repeatability, sensitivity, and specificity in 21 atopic dogs. Results of this testing were compared with results of a full regionalized allergy test offered by the same manufacturer. Results of the screening kit were repeatable and had high specificity but poor sensitivity. The kit as presently marketed is of questionable value as a diagnostic aid for use in dogs with atopy.

Animals↗
PubMed1992

Continuous treatment with all-trans retinoic acid causes a progressive reduction in plasma drug concentrations: implications for relapse and retinoid "resistance" in patients with acute promyelocytic leukemia.

Although all-trans retinoic acid (RA) induces complete remission in a high proportion of patients with acute promyelocytic leukemia (APL), all groups have described clinical relapses despite continued RA treatment. This finding suggests that resistance to the cytodifferentiating effects of the retinoid had been acquired. To investigate potential mechanisms of clinical resistance to RA, we serially evaluated the clinical pharmacology of the drug in APL patients treated with this agent. Leukemic cells from patients relapsing from RA treatment were cultured in the presence of RA and examined for evidence of morphologic maturation. We also studied messenger RNA expression of the newly described gene product of the (15;17) translocation in APL, PML/RA receptor-alpha (PML/RAR-alpha). Serial pharmacokinetic studies showed that continuous daily RA treatment was associated with a marked decrease in plasma drug concentrations at the time of relapse compared with the initial day of therapy. Doubling the RA dose in six patients failed to reinduce response at the time of relapse and also failed to significantly augment plasma RA concentrations. However, leukemic cells obtained at the time of relapse from four patients retained in vitro sensitivity to the differentiating activity of RA (10(-6) mol/L). No change was observed in the pattern of PML/RAR-alpha expression assessed by Northern blot analysis at the time of relapse compared with pretreatment in two patients who were tested. These results indicate that clinical relapse and "resistance" to continuous treatment with all-trans RA in APL is associated with progressive reduction of plasma concentrations, potentially to levels below those that sustain differentiation of leukemic cells in vivo. Long-term success of this treatment will require the development of strategies that circumvent this pharmacologic phenomenon.

Carrier Proteins↗
PubMed1992

Chronic mental illness and perinatal outcome.

A retrospective review of pregnant women admitted to a state psychiatric facility and to an acute university psychiatric unit compares various characteristics of the two populations. No major significant differences were noted in demographic, psychiatric, or obstetric characteristics. It was hypothesized that the patients from the state facility would have a better perinatal outcome secondary to an opportunity for closer prenatal follow-up. No differences were noted in perinatal outcomes between the two facilities. Significantly poorer perinatal outcomes were noted in the combined group of psychiatric patients when compared were noted in the combined group of psychiatric patients when compared with the state of Oregon's birth-outcome statistics. The importance of prenatal care in this high-risk population is discussed, and specific recommendations are offered.

Adult↗
PubMed1992

An intercomparison of neutron dosimeters and detectors for in-containment dosimetry.

To improve the methodology for assessing neutron dose at Union Electric's Callaway Nuclear Power Plant, an intercomparison of neutron detectors and dosimeters was performed. Seven different neutron detectors and dosimeters were tested in four different neutron fields utilizing facilities at the Missouri University Research Reactor and at the Southwest Radiation Calibration Center at the University of Arkansas. In general, all results agree within a factor of 2 in predicting the neutron dose equivalent. It was concluded that measurements of dose in containment should utilize the Tissue-Equivalent Proportional Counter (TEPC), the Bonner-sphere system, and the proton recoil spectrometer to accurately assess the neutron dose. These data can then be used to provide correction factors for more traditionally used dosimeters in containment, such as thermoluminescent dosimeters and survey meters.

Neutrons↗
PubMed1992

Perinatal substance abuse.

This article reviews medical, obstetrical, and neonatal complications of perinatal substance abuse. The psychological and social issues commonly encountered in drug-abusing pregnant women are also discussed. Treatment considerations that take into account the complex biopsychosocial parameters are presented.

Adolescent↗
PubMed1992

Retinoic acid and its rearranged receptor in the etiology and treatment of acute promyelocytic leukemia.

All-trans retinoic acid can induce complete remissions in patients with acute promyelocytic leukemia. The balanced chromosomal translocation t(15;17)(q22;q12-21) of this malignancy is now known to involve the nuclear retinoic acid receptor-alpha (RAR-alpha) on the long arm of chromosome 17 and a novel gene on the long arm of chromosome 15, designated PML (previously called myl). A unique fusion mRNA, PML/RAR-alpha, is produced. Paradoxically, this rearrangement of RAR-alpha results in clinical sensitivity to retinoic acid. Despite its efficacy, retinoic acid therapy has side effect, including a syndrome of hyperleukocytosis and respiratory distress in some patients. Remissions induced and maintained by continuous all-trans-retinoic treatment are not durable in most of these patients. Retinoic acid therapy for acute promyelocytic leukemia represents a unique example where a molecular defect may be involved both in the pathogenesis and treatment of a malignancy.

Animals↗
PubMed1992

Ras oncogene point mutation: an infrequent event in bronchioloalveolar cancer.

Ras oncogene point mutation, primarily activating the K-ras gene, has been reported in approximately one third of lung adenocarcinomas. This identifies a subset of early stage tumors clinically associated with smoking and an aggressive clinical course. Because of these findings, this study was undertaken to determine the occurrence of ras point mutations in bronchioloalveolar carcinoma. This uncommon form of lung adenocarcinoma is usually indolent but can sometimes present as a rapidly growing, multifocal tumor. Twenty tumor samples obtained at thoracotomy were examined for H-ras, K-ras, and N-ras oncogene mutational activation involving codons 12, 13, or 61. This was performed by an oligonucleotide hybridization technique following polymerase chain reaction amplification of these specific sequences. K-ras point mutation involving codon 12 was observed in two tumors, but not in the adjacent histologically benign lung tissue. These mutations were confirmed by direct sequencing of these polymerase chain reaction products. Both patients were smokers, had stage I tumors, and remain disease-free at 27 and 40 months postoperatively. No H-ras or N-ras point mutations were found. These findings suggest that ras activation is an infrequent event in bronchioloalveolar carcinoma. We speculate that ras activation is not a common transformational event in this form of lung adenocarcinoma.

Adenocarcinoma, Bronchiolo-Alveolar↗
PubMed1992

Comparison of the clinical efficacy of two commercial fatty acid supplements (EfaVet and DVM Derm Caps), evening primrose oil, and cold water marine fish oil in the management of allergic pruritus in dogs: a double-blinded study.

Twenty dogs with atopy or idiopathic pruritus were treated in a double-blinded clinical trial with computer-randomized and computer-generated sequences of 4 fatty acid-containing products: evening primrose oil, cold water marine fish oil, DVM Derm Caps, and EfaVet. Each dog received each product for a 2-week period. Five of 20 dogs (25%) had a good-to-excellent reduction in their level of pruritus with at least 1 of the products: evening primrose oil (2 dogs), DVM Derm Caps (1), EfaVet (1), DVM Derm Caps and cold water marine fish oil (1). Only 1 dog experienced a side effect (loose stools). Clinical response to fatty acid supplements appeared to be quite individualized, and independent of age, breed, sex, weight, duration of disease, specific diagnosis, or number of positive intradermal test reactions.

Animals↗
PubMed1992

Nonsteroidal management of canine pruritus with amitriptyline.

Thirty-one dogs with nonlesional pruritus were treated with amitriptyline (1 mg/kg orally q12h) to determine its efficacy in the management of canine allergic pruritus. Seventeen dogs were known to be atopic, 8 were presumed to be atopic, and 6 had pruritus of undetermined etiology. Pruritus was virtually eliminated in 5 (16.1%) dogs, reduced by approximately 50% in another 5 (16.1%) dogs, and not changed in the remaining 21 dogs. Side effects were uncommon.

Amitriptyline↗
PubMed1991

Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor, PML.

A unique mRNA produced in leukemic cells from a t(15;17) acute promyelocytic leukemia (APL) patient encodes a fusion protein between the retinoic acid receptor alpha (RAR alpha) and a myeloid gene product called PML. PML contains a cysteine-rich region present in a new family of apparent DNA-binding proteins that includes a regulator of the interleukin-2 receptor gene (Rpt-1) and the recombination-activating gene product (RAG-1). Accordingly, PML may represent a novel transcription factor or recombinase. The aberrant PML-RAR fusion product, while typically retinoic acid responsive, displays both cell type- and promoter-specific differences from the wild-type RAR alpha. Because patients with APL can be induced into remission with high dose RA therapy, we propose that the nonliganded PML-RAR protein is a new class of dominant negative oncogene product. Treatment with RA would not only relieve this inhibition, but the activated PML-RAR protein may actually promote myelocyte differentiation.

Amino Acid Sequence↗
PubMed1991

Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid).

BACKGROUND AND METHODS: Patients with acute promyelocytic leukemia have a characteristic (15;17) translocation, with a breakpoint on chromosome 17 in the region of the retinoic acid receptor-alpha (RAR-alpha). Since this receptor has been shown to be involved with growth and differentiation of myeloid cells in vitro, and since recent clinical studies have reported that tretinoin (all-trans-retinoic acid) induces complete remission in patients with acute promyelocytic leukemia we studied the effects of tretinoin on cellular maturation and molecular abnormalities in patients undergoing the induction of remission with this agent. RESULTS: Eleven patients with acute promyelocytic leukemia were treated with tretinoin administered orally at a dose of 45 mg per square meter of body-surface area per day. Nine of the 11 patients entered complete remission. In two patients, complete remission was preceded by striking leukocytosis that then resolved despite continued drug treatment. Serial studies of cellular morphologic features, cell-surface immunophenotypic analysis, and fluorescence in situ hybridization with a chromosome 17 probe revealed that clinical response was associated with maturation of the leukemic clone. All patients who responded to treatment who were tested by Northern blot analysis had expression of aberrant RAR-alpha. As patients entered complete remission, the expression of the abnormal RAR-alpha message decreased markedly; however, it was still detectable in several patients after complete morphologic and cytogenetic remission had been achieved. CONCLUSIONS: Tretinoin is a safe and highly effective agent for inducing complete remission in patients with acute promyelocytic leukemia. Clinical response to this agent is associated with leukemic-cell differentiation and is linked to the expression of an aberrant RAR-alpha nuclear receptor. Molecular detection of the aberrant receptor may serve as a useful marker for residual leukemia in patients with this disease.

Administration, Oral↗
PubMed1991

Parapituitary meningioma in a dog with pituitary-dependent hyperadrenocorticism.

A dog with constitutional and cutaneous signs of hyperadrenocorticism had central visual impairment caused by an intracranial mass. Irradiation of the presumed pituitary mass did not improve the dog's condition. At necropsy, the intracranial mass was not of pituitary origin, but rather, was a parapituitary meningioma.

Adrenocortical Hyperfunction↗