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Biomedical subjects

H Miller

Publications and source records attributed to H Miller.

At least 55 records · Page 3Linked to original sources
PubMed1998

Treatment of Felty's syndrome with the haemopoietic growth factor granulocyte colony-stimulating factor (G-CSF).

Felty's syndrome (FS) (rheumatoid arthritis with neutropenia and splenomegaly) has a poor prognosis, largely because of the high risk of severe infection. Granulocyte colony-stimulating factor (G-CSF) is an emerging treatment for chronic neutropenia. We prospectively monitored its use in eight patients with recurrent infections or who required joint surgery. Significant side-effects were documented in five, including nausea, malaise, generalized joint pains, and in one patient, a vasculitic skin rash. In two patients treatment had to be stopped, and in these cases G-CSF had been started at full vial dosage (300 micrograms/ml filgrastim or 263 micrograms/ml lenograstim) alternate days or daily. G-CSF treatment was continued in three patients by restarting at reduced dose, and changing the proprietary formulation. G-CSF raised the neutrophil count, reduced severe infection, and allowed surgery to be performed. A combined clinical and laboratory index suggested that long-term treatment (up to 3.5 years) did not exacerbate the arthritis. Once on established treatment, it may be possible to use smaller weekly doses of G-CSF to maintain the same clinical benefit. One of the three patients whose FS was associated with a large granular T-cell lymphocytosis showed a reduction in this subset of lymphocytes during G-CSF treatment.

Adjuvants, Immunologic↗
PubMed1997

Kinetics of DNA polymerase I (Klenow fragment exo-) activity on damaged DNA templates: effect of proximal and distal template damage on DNA synthesis.

Mutagenic DNA adducts have been analyzed with respect to the rate of nucleotide insertion opposite the modified base, extension from that "mispair", and nucleotide insertion preference. To complement and extend these studies we have investigated the long-range effects of DNA adducts on DNA polymerase activity. To address this question, primer extension reactions were performed using DNA polymerase I, Klenow fragment exo-. Templates containing 7,8-dihydro-8-oxoguanine, dG-C8-aminofluorene, dG-C8-(acetylamino)fluorene, and the model abasic site, tetrahydrofuran, were used for these studies, and the steady-state kinetics of correct nucleotide insertion were determined at positions (-2), (-1), (+1), (+2), (+3), and (+5) with respect to the template lesion. The kinetics of primer extension by Klenow fragment exo- at template positions 3' to the lesion showed only a small inhibitory effect, <3-fold, even for the strongly blocking lesion, dG-C8-(acetylamino)fluorene, indicating that Klenow fragment exo- activity is not greatly affected by lesions in the single-stranded portion of the template-primer. In contrast, a dramatic decrease in the frequency of primer extension was observed at template sites 5' to the site of adduction. Inhibition of polymerase activity decreased as the distance from the lesion increased; however, a relatively large effect was seen at the (+2) and (+3) positions for dG-C8-(acetylamino)fluorene and tetrahydrofuran. For these blocking lesions, the effect on extension 5 bases from the lesion was greatly reduced. We conclude from these studies that DNA damage at positions remote from the site of the lesion affects DNA polymerase function.

DNA Damage↗
PubMed1997

Mutations in the region encoding the central domain of helper component-proteinase (HC-Pro) eliminate potato virus X/potyviral synergism.

Coinfection of tobacco plants with potato virus X (PVX) and any of several members of the potyvirus group causes a synergistic disease characterized by a dramatic increase in symptom severity correlated with a 3- to 10-fold increase in the accumulation of PVX in the first systemically infected leaves. We have recently shown that PVX/potyviral synergistic disease is mediated by expression of potyviral 5'-proximal sequences encoding P1, helper component-proteinase (HC-Pro), and a fraction of P3 (termed P1/HC-Pro sequence). Here we report the effect of mutations in this potyviral sequence on the induction of synergistic disease. Three transgenic tobacco lines expressing the tobacco etch potyvirus (TEV) P1/HC-Pro sequence with mutations within the P1 coding region were not impaired in their ability to mediate synergism when infected with PVX. In contrast, two of three transgenic lines with mutations in the HC-Pro coding region were unable to induce the synergistic increases in either symptom severity or PVX accumulation. Loss of synergistic function was associated with mutations within the region encoding the central domain of HC-Pro, while the ability to induce synergism was retained in a transgenic line expressing HC-Pro with an alteration in the amino-terminal "zinc-finger domain." In coinoculation experiments, a TEV mutant lacking the sequence encoding the zinc-linger domain of HC-Pro induced a typical synergistic response in interaction with PVX. The results indicate that the zinc-finger domain comprising the first 66 amino acid residues of HC-Pro is dispensable for induction of synergistic disease and transactivation of PVX multiplication, while regions within the central domain of HC-Pro are essential for both of these responses.

Binding Sites↗
PubMed1997

Does severity of ischemic coronary disease correlate with erectile function?

An association between diminution in the quality of male sexual function and ischemic coronary disease has been suggested. Patients with ischemic heart disease who underwent coronary angiography participated in this study which aimed to document the impact of the extent of coronary disease upon sexual function in 40 patients (mean age 56.6 y). The 11-questions accepted questionnaire addressing sexual drive, erectile function, and ejaculation was used. Information regarding, age, medications, hypertension, diabetes, relevant risk factors, medical history, and the number of occluded coronary vessels was retrieved from the patients' records. A statistically significant correlation was demonstrated between erectile function and the number of coronary vessels involved. Patients with one-vessel disease had more (P < 0.04) and firmer erections (P < 0.001) with fewer difficulties in achieving an erection (P < 0.007) than men with two- or three-vessel disease. Age, diabetes, and hypertension also had a negative effect on the quality of the erection (P < 0.05) in all patients.

Adult↗
PubMed1997

Prenatal cocaine exposure and mother-infant interaction: implications for occupational therapy intervention.

The literature from multiple disciplines on in utero cocaine exposure and mother-infant interaction and attachment was examined for possible relationships and implications for occupational therapists. Maternal cocaine use and neurobehavioral deficits in neonates prenatally exposed to cocaine may result in interactional difficulties between mother and infant. Knowledge of child development, sensory regulation, and infant cues will enable therapists to assist the mother in creating positive interactive experiences between herself and her child.

Animals↗
PubMed1996

Kinetic mechanism of the 3'-->5' proofreading exonuclease of DNA polymerase III. Analysis by steady state and pre-steady state methods.

DNA polymerase III holoenzyme is the major replicative enzyme in Escherichia coli. An important component of the high-fidelity DNA synthesis that is characteristic of DNA polymerase III holoenzyme is the 3'-->5' proofreading exonuclease activity resident in the epsilon subunit. Steady state and pre-steady state conditions have been used to determine equilibrium and Michaelis constants for substrate binding and the rate constant for cleavage by purified epsilon subunit. The steady state kinetic constants are K(m) = 16 +/- 6 microM and kcat = 210 +/- 23 s-1 for degradation of single-stranded DNA by epsilon. These steady state values are in agreement with the rate constants determined for excision of the 3' nucleotide of a dT10 oligomer under pre-steady state conditions. Using a simple two-step model, E + Dn reversible E.Dn-->E + Dn-1, we find K = 12 microM and kf = 280 s-1 for the dT10 substrate. In these experiments, epsilon subunit acts in a distributive manner and product release is not the rate-limiting step. Activity of the epsilon subunit on paired DNA oligonucleotides with zero to three mismatches at the 3' terminus indicates that an additional step is required in the mechanism. In the scheme Dn reversible Dn* + E reversible E.Dn*-->E + Dn-1, the 3' terminus undergoes a conformational change or "melts" before the DNA is a substrate for epsilon subunit. With this additional step, the values for binding of activated substrate and cleavage are the same as those for single-stranded DNA. The kinetics for exonucleolytic degradation of single-stranded, paired, and mispaired oligonucleotides support the model that the rate-limiting step in exonucleolytic proofreading of DNA by epsilon subunit is the DNA-melting step.

Base Composition↗
PubMed1996

The mammalian DNA polymerase delta--proliferating cell nuclear antigen--template-primer complex: molecular characterization by direct binding.

Three direct assays, polyacrylamide gel electrophoresis-band mobility shift, agarose gel electrophoresis-band mobility shift, and nitrocellulose filter binding, were established to study complexes formed among mammalian DNA polymerase delta (pol delta), proliferating cell nuclear antigen (PCNA), and synthetic oligonucleotide template-primers. In all contexts, complex formation requires simultaneous presence of pol delta, PCNA, and template-primer. Moreover, we showed in one such assay that the complex formed contains each molecular component. Nuclease protection experiments demonstrate that complex formation protects template from degradation by DNase I. The mass determined for the pol delta.PCNA.template-primer complex was about 267 kDa, consistent with the participation of one molecule of pol delta, two or three molecules of PCNA and one molecule of template-primer. PCNA alone behaved as a trimer (mass determined to be about 87 kDa). Complex could be manipulated enzymologically. Measurement of off rates demonstrates directly that PCNA stabilizes the pol delta.template-primer complex.

Amino Acid Sequence↗
PubMed1996

Clearance of chylomicron remnants in normolipidaemic patients with coronary artery disease: case control study over three years.

OBJECTIVE: To test the hypothesis that subjects who clear chylomicron remnants slowly from plasma may be at higher risk of coronary artery disease than indicated by their fasting plasma lipid concentrations. DESIGN: Case control study over three years. SETTING: An 800 bed general municipal hospital. SUBJECTS: 85 normolipidaemic patients with coronary artery disease selected prospectively and matched with 85 normolipidaemic subjects with normal coronary arteries on angiography. INTERVENTIONS: All subjects were given a vitamin A fat loading test which specifically labels intestinal lipoproteins with retinyl palmitate. MAIN OUTCOME MEASURE: Postprandial lipoprotein metabolism. RESULTS: The area below the chylomicron remnant retinyl palmitate curve was significantly increased in the coronary artery disease group as compared with the controls (mean 23.4 (SD 15.0) v 15.3 (8.9) mumol/l.h; 95% confidence interval of difference 4.37 to 11.82). CONCLUSION: Normolipidaemic patients with coronary artery disease had significantly higher concentrations of chylomicron remnants in plasma than normolipidaemic subjects with normal coronary vessels. This may explain the mechanism underlying the susceptibility to atherosclerosis of coronary artery disease patients with normal fasting lipid values. As diet and drugs can ameliorate the accumulation of postprandial lipoproteins in plasma, the concentration of chylomicron remnants should be measured in patients at high risk of coronary artery disease.

Adult↗
PubMed1996

IFN-alpha-mediated suppression of low-affinity FC(epsilon) receptors on Peyer's patch lymphocytes and augmentation of soluble CD23: implications for IgE responses.

The ability of interleukin (IL)-6 or interferon-alpha (IFN-alpha) to regulate expression of low-affinity Fc(epsilon) receptor (CD23) and serum levels of CD23 was studied in benzylpenicilloyl-keyhole limpet hemocyanin-sensitized BALB/c mice at the peak of a hapten-specific immunoglobulin E (IgE) antibody-forming cell (AFC) response. These responses are analogous to those observed in human atopic disease. To induce peak IgE responses, mice were injected intraperitoneally with BPO-KLH (10 micrograms) in aluminum hydroxide gel (alum) on days 0, 21, and 42. On day 44, mice were injected subcutaneously with IL-6 (100-1000 U) or IFN-alpha (1000-10,000 U). On day 46, numbers of CD23+ lymphocytes in Peyer's patches (PP), mesenteric lymph nodes (MLN), and spleen and levels of soluble CD23 in serum were determined (flow microfluorimetry and enzyme-linked immunosorbent assay, confirmed by competition assay). Data are expressed as percent total cells or as optical density at 490 nm. IFN-alpha treatment strongly suppressed (up to 100%) numbers of CD23+ cells exclusively in PP (i.e., numbers of CD23+ cells in MLN and spleen were unchanged) whereas serum levels of soluble CD23 were dramatically increased (60%). IL-6 treatment had no effect on either numbers of CD23+ lymphocytes or on serum levels of soluble CD23. The data suggest that the mechanism(s) by which IFN-alpha, but not IL-6, regulates IgE responses involves suppression of CD23 expression on lymphocytes in PPs and supports a central role for these organs in regulation of IgE responses in vivo.

Animals↗
PubMed1996

Hyperreactio luteinalis associated with pregnancy: a case report and review of the literature.

Hyperreactio luteinalis is a condition associated with bilateral and, in rare cases, unilateral ovarian enlargement due to theca lutein cysts. Hyperreactio luteinalis is a benign condition, usually found incidentally at cesarean section, which can appear anaplastic and lead to unnecessary ovarian resection. A 21-year-old Hispanic woman, G2P1, presented at 19 weeks with a singleton pregnancy, bilaterally enlarged ovaries, and a normal beta hCG. Over the next four months, her ovaries increased 75% in size with the right ovary becoming entrapped in the pelvis. The patient underwent a primary low transverse cesarean section. The ovaries had an anaplastic appearance and on frozen section revealed multiple benign theca lutein cysts. There are 51 reported cases of hyperreactio luteinalis associated with a normal pregnancy in the literature. It is estimated that approximately 60% of the cases of hyperreactio luteinalis unassociated with trophoblastic disease occur with normal singleton pregnancy. There are multiple benign ovarian lesions including hyperreactio luteinalis that can mimic ovarian neoplasms. Accordingly, it is important to exclude these from the differential diagnosis via a wedge biopsy and frozen section to avoid unnecessary surgical excision.

Adult↗
PubMed1996

In rats, atrial natriuretic peptide secretion is regulated differently in the right and left atria.

Recent studies have suggested the secretion of Atrial Natriuretic Peptide (ANP) is regulated by receptor mediated activation of protein kinase C, which causes the autocrine release of prostaglandins. Prostaglandins stimulate ANP secretion via the adenylate cyclase second messenger system. This report examined the response of right and left atrial ANP secreting cells to the three endothelin isopeptides and to cyclooxygenase inhibition. Our results show that right atrial ANP secretion is stimulated by endothelin 1 and 2 but not 3. In addition, right atrial ANP secretion is reduced by inhibition of cyclooxygenase. In contrast, left atrial ANP secretion is stimulated by endothelin 2 and 3 but not 1. Inhibition of cyclooxygenase did not affect left atrial ANP secretion. These results show the regulation of ANP secretion is different between the two atrial chambers. Right atrial cells appear to contain the prostaglandin-mediated response to protein-kinase C activation, whereas left atrial cells regulate ANP secretion differently.

Animals↗