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R L Miller

Publications and source records attributed to R L Miller.

At least 37 records · Page 2Linked to original sources
PubMed2000

The inhibitory effect of the imidazoquinolinamine S-28828 on the pathogenesis of a type II adenovirus in turkeys.

In this study we show that a type I-IFN inducing compound, S-28828, modulated the pathogenesis of an avian type II adenovirus in turkeys. By itself, S-28828 induced a strong reaction in the spleen characterized by hyperplasia of the red and white pulps as well as an increase in lymphoid cell aggregations. Oral administration of S-28828 before the time of virus inoculation suppressed significantly (P<0.05) the replication of hemorrhagic enteritis virus (HEV) in turkeys. Two doses of 5 or 50 mg of S-28828 administered at 2 days before and at the day of virus inoculation inhibited HEV-induced pathological and histopathological lesions. Virus-induced apoptosis and reduced IgM-surface expression of B cells were suppressed by low dose S-28828 treatment. These results are of interest because mammalian adenoviruses were shown to be resistant to antiviral effects of type I IFN, the major effector cytokine induced by S-28828.

Adenoviridae Infections↗
PubMed2000

Evaluation of a model of the cochlear neural membrane. I. Physiological measurement of membrane characteristics in response to intrameatal electrical stimulation.

To understand the auditory neural response to electrical stimuli similar to those used in a cochlear implant, it will be necessary to understand the neural refraction and summation response kinetics. Evidence exists indicating that the cell soma may alter the auditory neural response kinetics and could be the site of conduction failure for excitation initiated on the peripheral process. There is, however, reason to believe that the excitation site in some healthy, type I neurons and in pathological, type III neurons is the central process of the cell. To characterize the neural response to activation at a controlled central process site, cat auditory neurons were stimulated with an intrameatal electrode, and the summation and refraction response kinetics were measured. This approach was used to: (1) characterize the behavior of the neural response to central process excitation; (2) make comparisons between intrameatal excitation at a known central site and scala tympani excitation at an unknown site; and (3) provide membrane characterization free from the possible alteration of membrane kinetics produced by the cell soma. The membrane kinetics measured using intrameatal stimulation differ from those recorded with scala tympani stimulation indicating that the mechanisms for scala tympani and intrameatal stimulation differ.

Animals↗
PubMed2000

Imiquimod, a topical immune response modifier, induces migration of Langerhans cells.

Langerhans cells are bone marrow derived dendritic cells that represent the major antigen-presenting cells in the skin. Langerhans cells take up and process antigen within the epidermis and present processed antigen to T lymphocyte in the regional lymph nodes and thus form an integral part of the cutaneous immune response. The cutaneous immune response can be modified by a number of pharmacologic agents, including corticosteroids, cyclosporine, and retinoids as well as physical agents, such as ultraviolet light. For the most part these agents act by suppressing immune function. A topical immune response modifier, imiquimod has been shown to enhance the cutaneous immune response. Imiquimod has anti-viral and anti-tumor effects in animal models and has been approved for the topical treatment of external genital and perianal warts in humans. The biologic activity of imiquimod in part is due to its effect as a cytokine inducer. Preliminary data suggested that imiquimod could have an effect on Langerhans cells. In order to clarify this effect on Langerhans cells, we examined Langerhans cell morphology and migration in imiquimod-treated skin. The density of Ia + cells decreased 2 d after treatment, falling to approximately 43% by day 10. The Ia positive in cells remaining in the skin appeared larger and more dendritic suggesting an activated state. ATPase staining of epidermal sheet confirmed the decreased number of Langerhans cells. To clarify status of Langerhans cells, the activation of B7 was examined. Activation of B7-1 or B7-2 was not detected. Imiquimod, however, did enhance Langerhans cell migration from skin to draining lymph nodes. This enhanced Langerhans cell migration was also associated with an enhanced allergic contact hypersensitivity. These results suggest that the mechanism of modulation of immune response by imiquimod is in part due to effects on Langerhans cells.

Adenosine Triphosphatases↗
PubMed2000

Correlation between pretreatment levels of interferon response genes and clinical responses to an immune response modifier (Imiquimod) in genital warts.

Imiquimod (IQ) has been successfully used in treatment of genital warts. In clinical settings, patients responded well but wart reduction rates varied. Our aim was to find a correlation between clinical responses and pretreatment (constitutive) levels of genes that might be involved in the molecular action of IQ. Since IQ is a cytokine inducer, we analyzed levels of expression of genes of the JAK/STAT signaling pathway and their inhibitors as well as interferon response factors (IRFs) in pretreatment biopsy specimens from complete responders (99 to 100% wart reduction rate) versus incomplete responders (75 to 92% wart reduction rate) by reverse transcription-PCR. We found that mRNA levels of signal transducer and activator of transcription 1 (STAT1) and IRF1 were higher in complete responders than in incomplete responders. Incomplete responders expressed larger amounts of STAT3, IRF2, and protein inhibitor of activated STAT1 (PIAS1) mRNAs compared to complete responders before IQ treatment. We hypothesize that high-level expression of STAT1 and IRF1 is advantageous for a better IQ response. The observed differences in constitutive mRNA levels of these genes may be the consequence of alterations in cellular differentiation and/or variable expression of endogenous interferons. Previous in vitro studies showed that keratinocyte differentiation coordinates the balance between positive and negative signals along the JAK/STAT pathway by regulating the IRF1:IRF2 and STAT1:PIAS1 ratios and thus affecting induction of IQ-inducible genes. Specifically, differentiation supports constitutive expression of STAT1 and IRF1 mRNAs but not expression of IRF2 and PIAS1. Our data are in good agreement with studies that showed the importance of STAT1 in cytokine induction and activation of interferon-responsive genes by IQ.

Aminoquinolines↗
PubMed2000

Odontogenic carcinoma occurring in a dentigerous cyst: case report and clinical management.

This case report describes an unusual odontogenic carcinoma, which was detected during routine periodontal examination. The lesion occurred in a dentigerous cyst associated with an impacted third molar in an otherwise asymptomatic 66-year-old male patient. The impacted tooth and lesion were excised based on evidence of radiographic change and clinical findings. An unusual histopathologic presentation is reported. The treatment provided for this tumor and the management of impacted teeth is reviewed.

Aged↗
PubMed1999

Sulfhydryl reactivity demonstrates different conformational states for arrestin, arrestin activated by a synthetic phosphopeptide, and constitutively active arrestin.

The sulfhydryl groups of the three cysteines in bovine arrestin react with DTNB very slowly (over a period of several hours). In the presence of the synthetic phosphopeptide comprising the fully phosphorylated carboxyl-terminal 19 amino acids of bovine rhodopsin, the reactivity of one of the sulfhydryls was enhanced while that of another was greatly reduced. Since this synthetic peptide was shown to activate arrestin with respect to its binding to unphosphorylated, light-activated rhodopsin, the reactivity of the sulfhydryl groups of a constitutively active R175Q arrestin mutant was examined. All three of the sulfhydryl groups of the mutant arrestin R175Q reacted rapidly with DTNB, but not as rapidly as with SDS-denatured arrestin. The arrestin mutant R175Q bound to light-activated, unphosphorylated rhodopsin in ROS disk membranes. The arrestin mutant R175Q also inhibited the light-activated PDE activity with an IC50 of 1.3 microM under the experimental conditions that were used. These data indicate that each of these forms of arrestin is a different conformation. The activated conformation of arrestin that binds to phosphorylated rhodopsin in vivo may be yet another conformation. We conclude that arrestin is a flexible molecule that is able to attain several different conformations, all of which are able to attain the activated functional state of arrestin.

Animals↗
PubMed1999

Modulation of TH1 and TH2 cytokine production with the immune response modifiers, R-848 and imiquimod.

Cytokines produced by antigen-presenting cells are known to affect the development and cytokine profile of T cells. The immune response modifiers imiquimod and R-848 were previously shown to stimulate human and mouse cultures to secrete interferon-alpha. Results from the present study demonstrate that R-848 and imiquimod are capable of inducing interleukin-12 and interferon-gamma in mouse and human cell cultures. Both CD4(+) and CD8(+) T lymphocytes were responsible for producing IFN-gamma following stimulation with R-848. Macrophages were required for induction of interferon-gamma by R-848 and the cytokines IFN-alpha and IL-12 mediated this response. R-848 and imiquimod were also found to inhibit IL-4 and IL-5 production in mouse and human culture systems. The inhibition of IL-5 in response to R-848 is seen in cultures containing CD4(+) lymphocytes and macrophages and is mediated in part by IFN-alpha. These data suggest that imiquimod and R-848 may have clinical utility in diseases where cell-mediated immune responses are important and in diseases associated with overexpression of IL-4 or IL-5 such as atopic disease.

Adjuvants, Immunologic↗
PubMed1999

Enhancement of the innate and cellular immune response in patients with genital warts treated with topical imiquimod cream 5%.

The mechanism of action of imiquimod 5% cream applied topically to patients with genital warts was evaluated in a double-blind, placebo-controlled study. Imiquimod (16 patients) or placebo (three patients) was applied three times per week for up to 16 weeks. All imiquimod-treated patients had a > or =75% reduction in total wart area while only one of three placebo-treated patients had a similar reduction. Wart biopsies were taken at prestudy, week 6, and end of treatment. Polymerase chain reaction (PCR) for human papillomavirus (HPV) DNA and reverse transcriptase (RT)-PCR for messenger (m)RNAs were used to identify cytokines, cellular markers, viral gene products, and cell cycle markers in these biopsies. Treatment with imiquimod, an immune response modifier, stimulated significant increases in mRNA for interferon (IFN)-alpha, IFN-gamma and 2',5' oligoadenylate synthetase (2',5'-AS) as well as a tendency towards increases in tumor necrosis factor (TNF)-alpha and interleukin-12 p40. Significant increases in mRNA for CD4 and a trend toward increases in CD8 were also observed in imiquimod-treated patients, suggesting activation of a cell mediated immune response. Imiquimod administration was also associated with a significant decrease in viral load as measured by HPV DNA and L1 mRNA. The effects on HPV markers were accompanied by an apparent decrease in mRNA expression for markers of cell proliferation and an increase in mRNA for markers of keratinocyte differentiation and tumor suppressors.

Adolescent↗
PubMed1999

Treatment of primary herpes simplex virus infection in guinea pigs by imiquimod.

Imiquimod (also known as R-837 and S-26308) is an imidazoquinoline immune response modifier and is available in the US and several other countries for the treatment of external genital warts. Imiquimod has no direct antiviral activity but demonstrates efficacy in several animal models of virus infection. The drug is recognized by antigen presenting cells including monocytes, macrophages, B-cells and dendritic cells and induces these cells to produce cytokines including interferon-alpha (IFN-alpha) and others. Imiquimod's ability to inhibit primary lesion development in the guinea pig model of Herpes simplex virus (HSV) intravaginal infection was studied. Imiquimod given intravaginally reduced primary lesions, reduced virus shedding and reduced virus content of spinal cords from HSV infected guinea pigs. A single drug application of 0.5 mg/kg reduced lesion frequency when given between 24 h before inoculation to 16 h after inoculation. A single drug application of 5 mg/kg reduced lesion frequency and severity when administered between 72 h before inoculation to 24 h after inoculation. The antiviral effect resulting from interferon induction in the animal lasts much longer than the drug itself, thus imiquimod is different than drugs having direct antiviral activity. Twice daily drug application for 4 days was effective when initiated up to 72 h after inoculation, however, once lesions began to appear, imiquimod treatment was not able to stop lesion development. Imiquimod treatment inhibited lesion development and/or virus shedding in guinea pigs inoculated with HSV-1, HSV-2 or virus isolates resistant to acyclovir. Imiquimod is currently in clinical trials for treating human HSV infections.

Aminoquinolines↗
PubMed1999

Imiquimod applied topically: a novel immune response modifier and new class of drug.

Imiquimod (S-26308, R-837) (1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4 amine), an immune response modifier, demonstrates potent antiviral and antitumor activity in animal models (see structure in Fig. 1). The drug exhibits no direct antiviral or antiproliferative activity when tested in a number of cell culture systems. Imiquimod's activity was discovered while screening for anti-herpes virus activity. One of the first analogs in the series, S-25059 was tested in the early 1980's and due to slight toxicity, caused slightly reduced herpes cytopathology in Vero cell cultures. Follow-up testing in herpes infected guinea pigs showed complete protection toward lesion development. Activity of these drugs results primarily from interferon alpha (IFN-alpha) induction and other cytokine induction. At least part of the cytokine induction is mediated through NF-kappaB activation. These cytokines stimulate several other aspects of the innate immune response. In addition, imiquimod stimulates acquired immunity, in particular the cellular arm which is important for control of viral infections and various tumors. This effect is mediated by drug induced IFN-alpha and Interleukin-12 (IL-12) and IFN-gamma induced by these cytokines. Imiquimod is expected to be effective where exogenous IFN-alpha has shown utility and where enhancement of cell-mediated immunity is needed. The following is a brief review of the preclinical pharmacology of imiquimod and the clinical results of genital wart trials. The mechanism of action of topically applied imiquimod will likely lead to benefits in several other chronic virus infections and tumors of the skin. Two other reviews on imiquimod that focus mainly on the clinical results have been published (Beutner & Geisse, 1997; Slade, Owens, Tomai & Miller, 1998).

Adjuvants, Immunologic↗
PubMed1999

Malignant tumors of Stensen's duct.

A rare case of squamous cell carcinoma arising in Stensen's duct is reported. The literature concerning malignant neoplasia originating in this site is reviewed, with attention given to the histopathologic diversity of neoplasms occurring in the duct, criteria for determination of origin in the duct, and outcomes of therapy.

Aged↗
PubMed1999

Discriminability of vowel representations in cat auditory-nerve fibers after acoustic trauma.

This paper attempts to connect deficits seen in the neural representation of speech with perceptual deficits. Responses of auditory-nerve fibers were studied in cats exposed to acoustic trauma. Four synthetic steady-state vowels were used as test signals; these stimuli are identical, except that the second format (F2) resonator in the synthesizer was set to 1.4, 1.5, 1.7, or 2 kHz, producing four spectra that differ mainly in the vicinity of the F2 frequency. These stimuli were presented to a large population (523) of auditory-nerve fibers in four cats with sloping high-frequency threshold shifts that reached 50-70 dB at 2-4 kHz. In normal animals, May et al. [Auditory Neurosci 3, 135-162 (1996)] showed previously that the discharge rates of fibers with best frequencies near the F2 frequencies provide enough information to allow discrimination of these stimuli at the performance levels shown by cats in behavioral experiments. Here it is shown that, after acoustic trauma, there is essentially no rate information which would allow the vowels with different F2 frequencies to be discriminated. However, information that could allow discrimination remains in the temporal (phase-locked) aspects of the responses.

Animals↗
PubMed1999

Contrast enhancement improves the representation of /epsilon/-like vowels in the hearing-impaired auditory nerve.

This study examines the neural representation of the vowel /epsilon/ in the auditory nerve of acoustically traumatized cats and asks whether spectral modifications of the vowel can restore a normal neural representation. Four variants of /epsilon/, which differed primarily in the frequency of the second formant (F2), were used as stimuli. Normally, the rate-place code provides a robust representation of F2 for these vowels, in the sense that rate changes encode changes in F2 frequency [Conley and Keilson, J. Acoust. Soc. Am. 98, 3223 (1995)]. This representation is lost after acoustic trauma [Miller et al., J. Acoust. Soc. Am. 105, 311 (1999)]. Here it is shown that an improved representation of the F2 frequency can be gained by a form of high-frequency emphasis that is determined by both the hearing-loss profile and the spectral envelope of the vowel. Essentially, the vowel was high-pass filtered so that the F2 and F3 peaks were amplified without amplifying frequencies in the trough between F1 and F2. This modification improved the quality of the rate and temporal tonotopic representations of the vowel and restored sensitivity to the F2 frequency. Although a completely normal representation was not restored, this method shows promise as an approach to hearing-aid signal processing.

Animals↗
PubMed1999

Disposition of morphine in tissues of the pregnant rat and foetus following single and continuous intraperitoneal administration to the mother.

Foetal exposure to maternally administered opiates such as morphine represent a serious human health problem but disposition studies in man are difficult to perform. Morphine disposition was therefore investigated in pregnant rats and their foetuses near term as a model. Disposition was examined either following intraperitoneal dosing as a single dose or continuous infusion. A high-pressure liquid chromatography assay for morphine in plasma and tissue was developed and validated. Following the single morphine dose, foetal distribution was rapid and concentrations in foetal and placental tissue were from 2.6 (whole foetus) to 27.6 (placenta) times higher compared with maternal plasma. The rank order of the area under the concentration vs time curve (AUC) of morphine in tissues was: placenta > or = foetal liver > foetal brain > whole foetus > maternal brain. The foetal brain to maternal brain AUC ratio for morphine was 9.5, suggesting large differences in their blood-brain barrier permeability. Following continuous administration of morphine there were significant linear relationships between maternal plasma and tissue concentrations with the same rank order as the single dose study. However, following continuous administration the relative amount of morphine in placenta and foetal liver was reduced by half and one-third, respectively, compared with the single dose study. These results document why the rat foetus is particularly susceptible to the pharmacodynamic effects of morphine following maternal administration.

Analgesics, Opioid↗
PubMed1999

Contamination of intact apples after immersion in an aqueous environment containing Escherichia coli O157:H7.

The extent and location of Escherichia coli O157:H7 contamination after intact apples were immersed in cold (2 degrees C) 1% peptone water containing approximately 3x10(7) CFU/ml was assessed using four apple varieties, Golden Delicious, McIntosh, Red Delicious, and Braeburn. Room temperature and refrigerated apples were used to determine the effect of temperature differential on E. coli infiltration. The highest levels of E. coli were associated with the outer core region of the apple, followed by the skin. Apples were subsequently treated by immersing them for 1 min in 2,000 mg/liter sodium hypochlorite, followed by a 1-min tapwater rinse. This treatment reduced pathogen levels by 1- to 3-log cycles but did not eliminate the microorganism, particularly from the outer core region. While E. coli was not detected in the inner core of most apples, warm fruit immersed in cold peptone water occasionally internalized the pathogen. The frequency and extent of internalization of the pathogen was less when cold apples were immersed in cold peptone water. Subsequent dye uptake studies with Golden Delicious apples indicated that approximately 6% of warm apples immersed into a cold dye solution accumulated dye via open channels leading from the blossom end into the core region. However, dye uptake did not occur when the dye solution was warmer than the apple.

Coloring Agents↗
PubMed1998

Interferon induction in turkeys by oral administration of the imidazoquinolinamine S-28828 and modulation of the pathogenesis of Escherichia coli.

A synthetic imidazoquinolinamine, S-28828, has been shown to be an effective antiviral and antitumor agent in mammals. This immune modifier induces a number of cytokines such as interferons, tumor necrosis factor-alpha, interleukins and granulocyte-macrophage colony-stimulating factors in mammals. We showed that when turkeys were given S-28828 orally, high serum titers of IFN were induced in a dose-dependent manner. Turkeys, once stimulated by S-28828, became refractory to IFN production by repeated stimulation. S-28828 induced spleen, bone marrow and peripheral leukocytes to produce IFN in vitro. Splenic adherent cells were the main producers of IFN after in vitro stimulation. S-28828-induced IFN was identified as type I IFN that was pH-resistant but heat-labile. We examined the effect of a high dose (100 mg kg(-1) body weight) of S-28828 on the pathogenesis of E. coli in turkeys. Treatment with S-28828 increased mortality in infected birds and impaired E. coli clearance from the liver. The enhancement of the pathogenicity of E. coli by S-28828 may have been due to the massive release of cytokines inducing a shock-like syndrome in infected turkeys.

Administration, Oral↗