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Biomedical subjects

R L Miller

Publications and source records attributed to R L Miller.

At least 19 recordsLinked to original sources
PubMed2001

Prenatal exposure, maternal sensitization, and sensitization in utero to indoor allergens in an inner-city cohort.

Primary sensitization to antigens may occur prenatally. We hypothesized that high prenatal exposure to indoor antigens increases the risk for sensitization in newborns in New York City populations with increased risk for asthma. We also investigated whether maternal sensitization is required for in utero sensitization to occur. One hundred sixty-seven pregnant African American or Dominican women residing in northern Manhattan were recruited and antigen was measured from home dust. After delivery, newborn cord and maternal blood were assayed for IgE and mononuclear cell proliferation and cytokine production in response to antigen. Cockroach, mouse, but not dust mite antigens, were commonly elevated in the kitchens and pregnant mothers' beds. Increased mononuclear cell proliferation occurred in 54% of newborns in response to cockroach, 25% in response to dust mite Dermatophagoides pteronyssinus, 40% in response to dust mite D. farinae, and 34% in response to mouse protein extracts. Antigen-induced mononuclear cell proliferation occurred in cord blood even in the absence of antigen-induced mononuclear cell proliferation in the mother. Proliferation in response to antigens did not correlate with IgE levels, but proliferation in response to dust mite extracts correlated with interluekin-5 (IL-5) production in cord blood. These results suggest that (1) high prenatal exposures to cockroach and mouse antigens are prevalent; (2) in utero sensitization to multiple indoor antigens is common, occurs to a different degree than maternal sensitization, and may involve IL-5 upregulation.

Adult↗
PubMed2001

Modified lattice Boltzmann method for compressible fluid simulations.

A modified lattice Boltzmann algorithm is shown to have much better stability to growing temperature perturbations, when compared with the standard lattice Boltzmann algorithm. The damping rates of long-wavelength waves, which determine stability, are derived using a collisional equilibrium distribution function which has the property that the Euler equations are obtained exactly in the limit of zero time step. Using this equilibrium distribution function, we show that our algorithm has inherent positive hyperviscosity and hyperdiffusivity, for very small values of viscosity and thermal diffusivity, which are lacking in the standard algorithm. Short-wavelength modes are shown to be stable for temperatures greater than a lower limit. Results from a computer code are used to compare these algorithms, and to confirm the damping rate predictions made analytically. Finite amplitude sound waves in the simulated fluid steepen, as expected from gas dynamic theory.

Journal Article↗
PubMed2001

Daily or weekly therapy with resiquimod (R-848) reduces genital recurrences in herpes simplex virus-infected guinea pigs during and after treatment.

The effect of resiquimod (R-848), an immune-response modifier that is similar to imiquimod, on recurrent herpes simplex virus (HSV) was evaluated using the guinea pig model of genital herpes. Guinea pigs were intravaginally infected with HSV-2 and then were randomized on day 14 to receive nothing or 0.1 mL/kg per dose of subcutaneous resiquimod, given either daily, every other day, or weekly from days 15-35. During a 3-week course of therapy, recurrences in all 3 treated groups were reduced by >80%, compared with the control group. After therapy, recurrences remained significantly (P<.05) decreased in all 3 groups for the next 3 weeks. The group treated weekly developed the fewest recurrences. Significant increases in interleukin-2 levels, produced by incubation of mononuclear cells with HSV-2 antigens, but not in circulating antibody also were detected in the treated groups. Resiquimod treatment may offer significant advantages to present antiviral therapies for the control of recurrent genital herpes.

Animals↗
PubMed2001

Reduction of recurrent HSV disease using imiquimod alone or combined with a glycoprotein vaccine.

The aim of this study is to evaluate the effects of an immune modulator, imiquimod, given alone or in combination with an HSV vaccine on HSV immune responses and as immunotherapy of a genital recurrence model. After recovery from primary genital HSV infection, animals were randomized to placebo, 21 days of imiquimod plus a placebo vaccine, or 21 days of imiquimod plus an HSV-2 glycoprotein vaccine. Placebo or HSV vaccine was given in the footpad on days 16 and 37 after HSV-2 genital inoculation. Daily imiquimod or placebo was given subcutaneously in the shoulder on days 16 through 37. Genital recurrences were monitored and HSV specific NK activity, IL-2 response and ELISA antibody were assayed. For the entire 15 week observation period, imiquimod alone reduced recurrences 62.6%, while addition of HSV vaccine to imiquimod reduced recurrences 80.6% compared to placebo/placebo. The duration of significant recurrence reduction was more notable with the addition of vaccine. Imiquimod alone significantly reduced the weekly HSV recurrent disease in the first 10 weeks (53-94% reduction, mean 75.9%), as did imiquimod plus HSV-vaccine (71-98% reduction, mean 89.5%). In weeks 10-15, imiquimod alone reduced recurrences significantly only in week 10 (20-53% reduction, mean 33%), whereas the addition of vaccine extended the significant recurrence reduction to 14 weeks (44-71% reduction, mean 56.8%). The recurrence reduction is correlated to an increased HSV-induced in vitro IL-2 response and NK activity against HSV targets in treated groups. Both imiquimod and the imiquimod/vaccine combination significantly reduced genital HSV recurrences, but the combination extended the duration and extent of protection for recurrences compared to imiquimod alone. Enhanced HSV specific immune responses correlated to the protection.

Adjuvants, Immunologic↗
PubMed2001

Anaphylaxis in the United States: an investigation into its epidemiology.

BACKGROUND: Anaphylaxis is a severe, life-threatening allergic reaction that affects both children and adults in the United States. However, data regarding the incidence and prevalence of anaphylaxis and the number of deaths caused by it are limited. OBJECTIVE: To provide a better understanding of the magnitude of the problem of anaphylaxis in the United States. METHODS: A thorough review of the current medical literature was conducted to obtain prevalence estimates on each of the 4 major subtypes of anaphylaxis (food, drugs, latex, and insect stings). We calculated an overall estimate of the risk of anaphylaxis by using only estimates that are specifically derived from epidemiologic studies measuring anaphylaxis in the general population. RESULTS: Known rates or cases of anaphylaxis were 0.0004% for food, 0.7% to 10% for penicillin, 0. 22% to 1% for radiocontrast media, and 0.5% to 5% after insect stings. There were 220 cases after latex exposure. Considering the 1999 US population of 272 million, the population at risk for anaphylaxis from food is 1099, from penicillin is 1.9 million to 27. 2 million, from radiocontrast media is 22 000 to 100 000, from latex is 220, and from insect stings is 1.36 million to 13.6 million. These calculations yield a total of 3.29 million to 40.9 million individuals at risk of anaphylaxis. CONCLUSION: The occurrence of anaphylaxis in the US is not as rare as is generally believed. On the basis of our figures, the problem of anaphylaxis may, in fact, affect 1.21% to 15.04% of the US population.

Anaphylaxis↗
PubMed2001

Innovation in HIV prevention: organizational and intervention characteristics affecting program adoption.

A multiple case study design was used to explore the organizational characteristics of community-based organizations that provide HIV prevention programs and the criteria these organizations employ when judging the merits of externally-developed HIV prevention programs. In-depth interviews were conducted with organizational representatives of 38 randomly-selected HIV prevention providers throughout Illinois. Results indicated that there were three main types of adopting organizations: adopters of entire programs, adopters of program components and practices, and adopters of common ideas. These three types of organizations were distinguished by their level of organizational commitment to HIV prevention, organizational resources, and level of organizational maturity. Narrative data from the interviews are used to describe the dimensions that underlie the organizations' program adoption criteria. The criteria of merit used by these organizations to evaluate prevention programs provide partial empirical support for existing theories of technology transfer. Implications for designing and disseminating HIV prevention programs are discussed.

Adolescent↗
PubMed2001

Immunologic approach to herpes simplex virus.

The fundamental biological characteristic of herpes simplex virus (HSV) infection is its ability to establish latency and periodically reactivate, resulting in productive infectious virus. Recurrent HSV infections occur in spite of the presence of host immune responses to the virus. Because genital herpes is currently one of the three most prevalent sexually transmitted diseases worldwide, its potential public health impact has contributed to increased awareness in medical communities. The current state of knowledge on the immunological control of primary and recurrent HSV infections is reviewed, as well as the various immune-based therapeutic approaches to resultant disease. Finally, the potential benefit of immune response modifiers (IRMs), which have shown promise in early clinical studies, is discussed.

Herpes Simplex↗
PubMed2001

Activation of arrestin: requirement of phosphorylation as the negative charge on residues in synthetic peptides from the carboxyl-terminal region of rhodopsin.

PURPOSE: To determine whether substitution of the potential phosphorylation sites of bovine rhodopsin's carboxyl-terminal region with the acidic residues aspartic acid, glutamic acid, or cysteic acid promotes the activation of arrestin. METHODS: Three peptide analogues of the 19-residue carboxyl-terminal region of rhodopsin (330-348) were synthesized: the fully phosphorylated peptide (7P-peptide), the peptide with all potential phosphorylation sites substituted with glutamic acid (7E-peptide), and the peptide with the phosphorylation sites substituted with cysteic acid (7Cya-peptide). The peptides were tested in assays in which the 7P-peptide had previously been shown to have an effect. Rhodopsin with glutamic acid (Etail) or aspartic acid (Dtail) substituted for the phosphorylation sites in rhodopsin were constructed and expressed in COS-7 cells and tested in an in vitro assay. RESULTS: Earlier work has demonstrated that the 7P-peptide activates arrestin, showing induction of arrestin binding to light-activated unphosphorylated rhodopsin, inhibition of the light-induced phosphodiesterase (PDE) activity in rod outer segments (ROS) with excess arrestin, increase in the initial rapid proteolysis of arrestin by trypsin, and enhanced reactivity of one of arrestin's sulfhydryl groups with inhibition of the reactivity of another. None of these effects was observed in the presence of 7E-peptide or 7Cya-peptide. The 7Cya-peptide inhibited the PDE activity in ROS, but the same effect was observed both in the presence and the absence of excess arrestin. Because none of the other effects was observed with the 7Cya-peptide, the authors conclude that the 7Cya-peptide does not activate arrestin, but acts, probably nonspecifically, through some other part of the transduction system. Considerable arrestin-mediated rhodopsin inactivation was observed with both the Etail and the Dtail mutant, although these substitutions did not yield rhodopsins that were equivalent to phosphorylated rhodopsin. CONCLUSIONS: These results, taken together, suggest that the negative charge due to phosphates in the carboxyl-terminal region of rhodopsin are required for the full activation of arrestin and that acidic amino acids (carboxyl and sulfonic) do not mimic the negative charge of phosphorylated residues.

3',5'-Cyclic-GMP Phosphodiesterases↗
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↗