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Biomedical subjects

J A Miller

Publications and source records attributed to J A Miller.

At least 73 records · Page 4Linked to original sources
PubMed1998

A comparison of efficacy of sargramostim (yeast-derived RhuGM-CSF) and filgrastim (bacteria-derived RhuG-CSF) in the therapeutic setting of chemotherapy-induced myelosuppression.

A randomized, double-blind, multicenter study in 181 afebrile cancer patients with ANC levels < 500/microL receiving myelosuppressive chemotherapy was undertaken to compare sargramostim (yeast-derived recombinant human granulocyte-macrophage colony-stimulating factor, RhuGM-CSF) and filgrastim (bacteria-derived recombinant human granulocyte colony-stimulating factor, RhuG-CSF) in the treatment of chemotherapy-induced myelosuppression. Patients received daily subcutaneous (SC) injections of either agent until ANC levels reached at least 1500/microL. There was no statistical difference between treatment groups in the mean number of days to reach an ANC of 500/microL, but the mean number of days to reach ANC levels of 1000/microL and 1500/microL was approximately one day less in patients receiving filgrastim. Fewer patients in the sargramostim arm were hospitalized, and they had a shorter mean length of hospitalization, mean duration of fever, and mean duration of i.v. antibiotic therapy compared with patients who received filgrastim. Both growth factors were well tolerated. No patient was readmitted to the hospital after growth factor was discontinued. Sargramostim and filgrastim have comparable efficacy and tolerability in the treatment of standard-dose chemotherapy-induced myelosuppression in community practice.

Adult↗
PubMed1998

Enhancement of achievement and attitudes through individualized learning-style presentations of two allied health courses.

This investigation analyzed the effects of the instructional resource Programmed Learning Sequence (PLS) on the achievement and attitudes of college students and correlated the findings with the individuals' learning styles. The subjects were enrolled in Sonography I and Cross-Sectional Anatomy in a college of health-related professions. Both classes were administered the Productivity Environmental Preference Survey to identify learning-style strengths, and alternately presented with lessons using a PLS in a book format and traditional lectures. The sonography class also was exposed to a PLS in multimedia computer format. The Semantic Differential Scale measured the students' attitudes comparing the instructional methods experienced, and class examinations measured content mastery. In both classes, examination scores were significantly higher (effect size for the sonography class was 1.42; for the anatomy class, 0.63) and students' attitude scores were significantly higher when PLS rather than the traditional method was used. In the sonography class, achievement was significantly higher with the book PLS than with the computer PLS (effect size, 1.11). Significant correlations emerged between learning-style elements and achievement: students who preferred learning with the book PLS required more quiet in the environment than did those who preferred the computer PLS; students who preferred learning traditionally and with the computer PLS required more light than those preferring the book PLS; and students who preferred learning with an authority figure favored the traditional method. Examination of the data for other correlations between learning-style preferences and attitudes using the book PLS also revealed many other significant findings, demonstrating its ability to accommodate diverse styles.

Adolescent↗
PubMed1998

Soluble proteins modified with acetaldehyde and malondialdehyde are immunogenic in the absence of adjuvant.

Recent studies have shown that the alcohol metabolites malondialdehyde and acetaldehyde can combine to form a stable adduct (MAA) on proteins. This adduct has been detected in the livers of rats chronically consuming ethanol, and serum antibodies to MAA have been observed at significantly higher concentrations in ethanol-fed when compared with pair-fed or chow-fed control rats. More recently, preliminary studies have strongly suggested that the MAA adduct is capable of stimulating antibody responses to soluble proteins in the absence of adjuvants. The antibodies produced recognize either the MAA epitope or the carrier protein itself. Therefore, it was the purpose of this study to examine the potential immunogenicity of MAA-modified exogenous proteins in the absence of adjuvants. Balb/c mice were immunized in the presence or absence of adjuvant with different concentrations of unmodified or MAA-modified proteins. The antibody response to both the MAA epitope and unmodified protein epitopes were determined by ELISA. In the absence of adjuvant, significant antibody responses were induced to both the MAA epitope and nonmodified protein epitopes. Smaller immunizing doses of MAA-protein conjugate favored the production of antibodies to nonmodified proteins, whereas larger doses induced a strong anti-MAA response. In studies to begin determining a mechanism for the specificity of the response in the absence of adjuvants, peritoneal macrophages were found to bind and degrade MAA-adducted proteins through the use of a scavenger receptor. This indicated that MAA-adducted proteins may be specifically taken up and epitopes presented to the humoral immune system in the absence of adjuvants. Importantly, these are the first data showing that an alcohol-related metabolite can induce an antibody response in the absence of adjuvant and suggesting a mechanism by which antibody to the MAA adduct or its carrier (exogenous or endogenous) proteins may be generated in vivo.

Acetaldehyde↗
PubMed1997

Prolonged production of NADPH oxidase-corrected granulocytes after gene therapy of chronic granulomatous disease.

Little is known about the potential for engraftment of autologous hematopoietic stem cells in human adults not subjected to myeloablative conditioning regimens. Five adult patients with the p47(phox) deficiency form of chronic granulomatous disease received intravenous infusions of autologous CD34(+) peripheral blood stem cells (PBSCs) that had been transduced ex vivo with a recombinant retrovirus encoding normal p47(phox). Although marrow conditioning was not given, functionally corrected granulocytes were detectable in peripheral blood of all five patients. Peak correction occurred 3-6 weeks after infusion and ranged from 0.004 to 0.05% of total peripheral blood granulocytes. Corrected cells were detectable for as long as 6 months after infusion in some individuals. Thus, prolonged engraftment of autologous PBSCs and continued expression of the transduced gene can occur in adults without conditioning. This trial also piloted the use of animal protein-free medium and a blood-bank-compatible closed system of gas-permeable plastic containers for culture and transduction of the PBSCs. These features enhance the safety of PBSCs directed gene therapy.

Adolescent↗
PubMed1997

Putative folding pathway of insulin-like growth factor-I.

Insulin-like growth factor-I (IGF-I) has three disulfide bonds and refolding of the fully reduced molecule generates varying ratios of correctly (PII) and incorrectly (PI) folded forms via several intermediates. All of the intermediates have the disulfide bond between Cys18 and 61 formed, indicating that formation of this disulfide is the first step in refolding. In order to further understand the refolding pathway, two intermediate froms, PIII with the additional disulfide Cys(6/47) formed and PIIIa with Cys(6/48) formed, were isolated. The oxidation of the remaining Cys48 and 52 in PIII and Cys47 and 52 in PIIIa would lead to PI and PII, respectively; however, air oxidation of these resulted in a rapid reshuffling into other intermediates as well as folding into the fully oxidized forms, and this occurred whether refolding was started with PIII or PIIIa. When oxidation occurred in the presence of an excess of oxidized glutathione, the predominant species generated were various glutathione adducts regardless of the initial intermediate form, indicating that formation of the last disulfide bond is not a favorable process relative to disulfide exchange when excess disulfides from oxidized glutathione are present. Interestingly, if 80 microM copper sulfate, an oxidant, is added to the refolding buffer, PIII resulted in formation of the PI form alone, whereas PIIIa resulted in the PII form alone. It was concluded from these results that the intermediate forms of IGF-1 can rapidly reshuffle between different disulfide structures, and that formation of the last disulfide bond is not as favorable a process as the conversion to other intermediates. The oxidation to form the last disulfide bond in PIII or PIIIa is accelerated and hence the interconversion to other intermediates is kinetically minimized only in the presence of copper sulfate. It appears, therefore, that the two intermediate forms, PIII and PIIIa, are the precursors of the corresponding fully oxidized forms, but their conversions are not energetically a favorable process.

Chromatography, High Pressure Liquid↗
PubMed1997

Efficacy of hyaluronic acid/nonsteroidal anti-inflammatory drug systems in preventing postsurgical tendon adhesions.

Tendon adhesion is acknowledged to be a function of both an overwhelming inflammatory response at the surgical site and the loss of physical separation that is normally present between the tendons and the synovial sheath. Adhesions bind the flexor tendons to each other and to surrounding structures, interfering with their normal gliding function. The clinical result of adhesion formation following flexor tendon surgery is poor digital function. This study investigated the effect of intraoperative treatments of high viscosity absorbable gels made of various combinations of hyaluronic acid and nonsteroidal anti-inflammatory drugs, on adhesion formation in a leghorn chicken flexor tendon model. Forty-eight mature, white leghorn chickens were used to verify the surgical model and to test five different gel treatments. The gels were formed from: 2% sodium hyaluronate in phosphate buffered saline alone or combined with 1 mg/mL tolmetin sodium; 1 mg/mL naproxen sodium; 0.216 g/mL calcium acetate; or 0.216 g/mL calcium acetate plus 1 mg/mL naproxen sodium. The gels were applied by injecting 0.2 mL of the specified composition into the intrasheath space near the conclusion of the surgical procedure. Gross and histological evaluations were conducted to analyze the efficacy. All of the treatments significant reduced the extent and severity of postsurgical tendon adhesion in this animal model as compared with the control (no gel treatment) (p < 0.05). The combination of naproxen sodium and calcium acetate in a high viscosity sodium hyaluronate carrier was the most effective composition. The combination of a high viscosity gel and nonsteroidal anti-inflammatory drugs appears to maintain the natural separation between the tendons and their sheaths and decrease the tissue inflammatory response through mediating two of the major stimuli in adhesion formation.

Animals↗
PubMed1997

Quantitation of vascular endothelial growth factor mRNA levels in human breast tumors and metastatic lymph nodes.

In situ hybridization analysis provides a means to qualitatively study the heterogeneity of primary tumors and metastases based on the types of genes transcribed. In this study, we have tested some parameters for quantitative analysis of in situ hybridizations with paraffin-embedded human breast tumors and measured mRNA levels for the angiogenic protein, vascular endothelial growth factor (VEGF). VEGF mRNAs were highly tumor specific, with the highest levels near necrotic regions within the tissues (0.1 to 2.7 dpm/mm2). Normal cells within the tissue sections did not have detectable levels of VEGF mRNA. For comparison, tumor levels of c-myc (4 to 46 dpm/mm2) and glyceraldehyde-3-phosphate dehydrogenase mRNAs (48 to 214 dpm/mm2) were measured. The mRNAs for both of these genes were more broadly expressed across the tissue sections. The hybridization pattern for VEGF mRNAs was consistent with hypoxia-induced VEGF mRNA steady-state levels and supports the hypothesis that oxidative stress regulates VEGF expression in breast tumors.

Biomarkers, Tumor↗
PubMed1997

Randomized trial comparing the tolerability of sargramostim (yeast-derived RhuGM-CSF) and filgrastim (bacteria-derived RhuG-CSF) in cancer patients receiving myelosuppressive chemotherapy.

A prospective, randomized, double-blind, multicenter study in cancer patients receiving myelosuppressive chemotherapy was undertaken to evaluate and compare the tolerability of sargramostim (yeast-derived recombinant human granulocyte-macrophage colony-stimulating factor, RhuGM-CSF) and filgrastim (bacteria-derived recombinant human granulocyte colony-stimulating factor, RhuG-CSF) in the prophylaxis or treatment of chemotherapy-induced neutropenia. In all, 137 evaluable patients received sargramostim (300 micrograms; 193 mg/m2) or filgrastim (481 mg; 7 mg/kg) once daily by self-administered s.c. injection, usually beginning within 48 h after completion of chemotherapy. With the exception of a slightly higher incidence of grade 1 fever (< 38.1 degrees C) with sargramostim, there were no statistically significant differences in the incidence or severity of local or systemic adverse events possibly related to the growth factors. Although the study was not designed to evaluate efficacy directly, there also were no statistically significant differences between treatment groups in total days of growth factor therapy, days of hospitalization, or days of i.v. antibiotic therapy during the treatment period. Both sargramostim and filgrastim were comparably well tolerated when given by s.c. injection in this group of patients, and no clinically significant differences between the growth factors were demonstrated.

Chi-Square Distribution↗
PubMed1997

Disparate effects of antidiabetic drugs on arterial contraction.

Type II diabetic patients and others with insulin resistance are at risk for development of hypertension characterized by elevated peripheral vascular resistance and loss of insulin's normal vasodilating activity. Oral antidiabetic drugs have recently been recognized to have disparate effects on arterial pressure in such patients and in related rodent models. Sulfonylureas (e.g., glyburide), which stimulate insulin secretion, have been reported either to increase or not to affect arterial pressure, whereas nonsulfonylurea agents with insulin-sensitizing properties, the biguanide metformin and various thiazolidinediones (eg, pioglitazone), have been reported to decrease arterial pressure in humans and rodents. To help elucidate these disparate effects, we investigated these agents for direct actions on arterial vascular contractility and its sensitivity to insulin. Preincubation of intact rat tail arterial tissue rings for 2 hours with known therapeutically effective antidiabetic concentrations of metformin and pioglitazone significantly attenuated the force of contractions produced by either potassium (membrane depolarization) or norepinephrine ([NE] adrenergic receptor activation). Glyburide did not influence these contractions. Preincubation with metformin also induced an attenuating (vasodilating-like) action of insulin on arterial tissue rings contracted by potassium. Conversely, glyburide induced an accentuating action of insulin on potassium-mediated contractions. These results are consistent with measures of vascular function obtained in the past after oral administration of the drugs, which suggested but did not prove that they may exert direct effects on arterial vascular contractility. Thus, metformin and thiazolidinediones may decrease arterial pressure partly by direct vasorelaxant mechanisms, with metformin having an additional effect of inducing vasorelaxation by insulin. In contrast, sulfonylureas may directly induce a paradoxical vasoconstrictor response to insulin.

Animals↗
PubMed1997

Angiotensin converting enzyme gene polymorphism and renal hemodynamic function in early diabetes.

An insertion/deletion (I/D) of the human angiotensin converting enzyme (ACE) gene is a major determinant of circulating ACE levels. Recent studies suggest that the ACE I/D polymorphism may influence the risk of developing nephropathy in patients with insulin dependent diabetes mellitus (IDDM), although the mechanism responsible for the effect is unknown. Since an early increase in glomerular filtration rate (GFR) may also be a risk factor for the development of diabetic nephropathy, we sought to determine if the ACE I/D polymorphism influenced renal hemodynamic function in patients with IDDM. Genomic DNA was obtained from 39 normotensive male and female patients with uncomplicated IDDM (mean duration 3.4 years; range 1 to 6 years), and from 20 non diabetic control subjects. The ACE I/D polymorphism was determined using the polymerase chain reaction. Subjects were divided into three groups based on their ACE genotype. Values for GFR, renal plasma flow (ERPF), filtration fraction, and renal vascular resistance were determined in both groups using classic inulin and paraaminohippurate clearance techniques. Blood glucose was maintained between 4 to 6 mmol/liter in the patients with IDDM using a modified euglycemic clamp technique. Mean values for GFR were significantly greater in patients homozygous for the I allele (143 +/- 7 ml/min/1.73 m2) compared to patients homozygous for the D allele (121 +/- 3 ml/min/1.73 m2, P < 0.01), while the mean GFR values for the heterozygous patients were intermediate. ERPF was also significantly greater in patients homozygous for the I allele (850 +/- 103 ml/min/1.73 m2) compared to patients homozygous for the D allele (672 +/- 31 ml/min/1.73 m2, P < 0.04), while there were no differences in the values for mean arterial pressure, glycosylated hemoglobin, or albumin excretion rates amongst the groups. There was no dominant effect of the ACE gene I/D polymorphism in the control group. These results suggest that: (1) the ACE gene I/D polymorphism influences glomerular filtration and renal plasma flow rates in patients with early uncomplicated IDDM; and (2) differences in renal hemodynamic function do not appear to explain the protection against the development of diabetic nephropathy offered by the I allele.

Adult↗
PubMed1997

The electrophilic, mutagenic and tumorigenic activities of phenyl and 4-nitrophenyl vinyl ethers and their epoxide metabolites.

The metabolism and mutagenicity of phenyl and 4-nitrophenyl vinyl ethers (PVE and NPVE) and their epoxide metabolites, phenoxyoxirane (PO) and 2'-(4-nitro-phenoxy)oxirane (NPO), were studied including reactions with DNA and tests for carcinogenicity. PVE and NPVE were epoxidized in dry acetone by dimethyldioxirane to give high yields (95%) of the pure epoxides. The epoxides are unstable in aqueous media and in 0.1 N phosphate buffer, pH 7.4, at 37 degrees C; they had half-lives of 2.7 min (PO) and 4.4 min (NPO). These times were reduced to 1.9 min (PO) and 2.5 min (NPO) in the presence of isotonic (154 mM) chloride ion. In neutral phosphate buffer these epoxides hydrolyze to form glycolaldehyde and the corresponding phenols; in the presence of chloride ion, chloroacetaldehyde and several unknown compounds are also formed. Glycolaldehyde was also found as a hydrolysis product of the presumed epoxides generated in the hepatic microsomal oxidation of PVE and NPVE. PO and NPO reacted with DNA to form adducts that depurinated in weak acid to form 7-(2'-oxoethyl)guanine and N(2),3-ethenoguanine. PO was weakly mutagenic in Salmonella typhimurium TA1535 while NPO was much more mutagenic under the same conditions. PO and NPO were found to have mutagenic half-lives that matched their chemical half-lives. PO and NPO were found to be tumorigenic in the skin of mice after single or five initiating doses followed by multiple doses of phorbol ester (TPA). NPO was a stronger tumor initiator than PO. NPO had appreciable activity as an initiator of hepatoma formation in infant male B6C3F1 mice. Thus PO and NPO are electrophilic, mutagenic and tumorigenic metabolites of their corresponding phenyl vinyl ethers.

Animals↗
PubMed1997

Fetal alcohol exposure and temporal vulnerability regional differences in alcohol-induced microencephaly as a function of the timing of binge-like alcohol exposure during rat brain development.

In humans, microcephaly (small head for body size) is a common feature of fetal alcohol syndrome. An analogous measure, termed microencephaly (small brain for body size), can be used for evaluating the detrimental effects of the differential timing of alcohol exposure on brain development in animal model systems. Timed-pregnant rats were exposed to binge-like alcohol during either the first 10 days (first trimester equivalent) or second 10 days of gestation (second trimester equivalent), or the combination of first and second trimesters equivalent for prenatal treatments. Offspring from some of the animals exposed to alcohol during the combined first and second trimesters equivalent were raised artificially from postnatal day (P) 4 through P9 (part of the third trimester equivalent), and also received binge-like alcohol during this period, producing animals that were exposed to alcohol during all three trimesters equivalent. Offspring from untreated dams were also raised artificially and received alcohol only from P4 to P9, thus creating animals that were exposed to alcohol only during part of the third trimester equivalent. All pups were perfused on P10. Appropriate controls (nutritional and normally reared) were used for every alcohol treatment combination. Peak blood alcohol concentrations were not different among the treatment groups for a given sampling time. Significant somatic growth deficits occurred in offspring exposed to alcohol for the equivalent of all three trimesters, compared with offspring exposed to alcohol during other periods. Brain growth in offspring also was significantly affected by the timing of alcohol exposure. The whole brain, forebrain, and cerebellum to body weight ratios of pups exposed to alcohol during the third trimester had more significant brain growth deficits than pups in groups exposed to alcohol during other times of brain development. Although alcohol exposure during the third trimester had a significant detrimental impact on overall brain growth, significant differences in temporal vulnerability were also found for the brainstem to body weight ratios. Offspring of dams exposed to alcohol during the first trimester had the same magnitude of deficit as those exposed to alcohol during the third trimester, and those two groups were significantly deficient compared with the groups exposed to alcohol at other times, suggesting some differential vulnerability of this region to alcohol-induced injury at different times of development. This study is the first thorough examination of microencephaly and gross regional vulnerability of the developing brain as related to temporal factors of alcohol exposure in an animal model system, and the results support and expand on the findings of the available clinical literature. Furthermore, our results substantiate claims that the cessation of alcohol before the third trimester can lessen the severity of some alcohol-related birth deficits.

Alcoholic Intoxication↗