Pepper spray exposure during a carjacking attempt.
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Adult↗
Biomedical subjects
R L Miller
Publications and source records attributed to R L Miller.
In vivo and In vitro interferon induction in chickens by S -28828, an imidazoquinolinamine immunoenhancer.
Imiquimod and its analogs belonging to a class of imidazoquinolinamines, activate immune system via cytokine induction, and have antitumor and antiviral effects in mammals. In this study, we showed that a related analog, designated S-28828, induced interferon (IFN) and macrophage activating cytokine(s) (macrophage activating factor, MAF) in chickens in vivo, ex vivo, and in vitro. IFN and MAF were detectable in the serum of chickens following oral administration. Serum IFN levels were the highest at 2 h after treatment. Although there was no detectable IFN in sera of chickens at 8, 24, and 48 h after treatment, high levels of interferon inducible enzyme, 2'-5' oligoadenylate synthase (2'5'OAS) were present at these time points. In vitro and ex vivo studies showed that spleen cells, bone marrow (BM) cells, and peripheral blood leukocytes (PBL) were capable of producing IFN and MAF, although spleen cells produced the highest levels. Our results suggest that S-28828 administered orally may be a useful immunoenhancing and antiviral agent for chickens.
2',5'-Oligoadenylate Synthetase↗
Effect of a novel topical immunomodulator, S-28463, on keratinocyte cytokine gene expression and production.
A new immunomodulating agent, imiquimod, has been reported to have antiviral and antitumor activities in animal models. S-28463 (4-amino-2-ethoxymethyl-alpha, alpha-dimethyl-1H-imidazo[4, 5-c]quinoline-1-ethanol), an analog of imiquimod, has more potent antiviral activity in animals than imiquimod. It has also been shown to be more potent at inducing cytokines in human blood in vitro. However, its precise role as an immunomodulator in the skin has not been determined. We investigated the effect of S-28463 on human keratinocyte (KC) production of interferon-alpha (IFN-alpha) and other proinflammatory cytokines, including interleukin (IL)-1alpha, IL-8, and tumor necrosis factor-alpha (TNF-alpha). Human KC were incubated with S-28463 at two concentrations (1 microgram/ml and 10 micrograms/ml) for 6 h. Cytokine gene expression was analyzed by reverse-transcriptase PCR. In human KC, S-28463 stimulated significant increases in IFN-alpha mRNA at both concentrations. IL-1alpha mRNA increased 1.4-fold at 10 micrograms/ml. IL-8 mRNA was upregulated 2.5-fold at 10 micrograms/ml. Twenty-four hours after treatment, IL-1 alpha, IL-8, and TNF-alpha protein were increased, but IFN-alpha was below the level of detection. These results suggest that in the skin, S-28463-induced-IL-1 alpha, IL-8, and TNF-alpha production may be involved in the immunomodulating action of S-28463.
Adjuvants, Immunologic↗
Effects of somatosensory and parallel-fiber stimulation on neurons in dorsal cochlear nucleus.
1. Single units and evoked potentials were recorded in the dorsal cochlear nucleus (DCN) of paralyzed decerebrate cats in response to electrical stimulation at two sites: 1) in the somatosensory dorsal column nuclei (together called MSN below for medullary somatosensory nuclei), which activates mossy-fiber inputs to granule cells in superficial DCN, and 2) on the free surface of the DCN, which activates granule cell axons (parallel fibers) directly. The goal was to evaluate hypotheses about synaptic interactions in the cerebellum-like circuitry of the superficial DCN. A four-pulse facilitation paradigm was used (50-ms interpulse interval); this allows identification of three components of the responses of DCN principal cells (type IV units) to these stimuli. The latencies of the response components were compared with the latency of the evoked potential in DCN, which signals the arrival of the parallel fiber volley at the recording site. 2. The first component is a short-latency inhibitory response; this component is seen only with MSN stimulation and is seen almost exclusively in units also showing the second component, the transient excitatory response. The short-latency inhibitory component precedes the evoked potential. No satisfactory explanation for the short-latency component can be given at present; it most likely reflects a fast-conducting inhibitory input that arrives at the type IV unit before the slowly conducting parallel fibers. 3. The second component is a transient excitatory response; this component is seen with both MSN and parallel fiber stimulation; it is weak and appears to be masked easily by the inhibitory response components. The excitatory component occurs at the same latency as the evoked potential and probably reflects direct excitation of principal cells by granule cell axons. The excitatory component is seen in about half the type IV units for both stimulating sites. With MSN stimulation, the lack of excitation in some units suggests a heterogeneity of cochlear granule cells, with some carrying somatosensory information and some not carrying this information; with parallel fiber stimulation, excitation probably requires the stimulating and recording electrodes to be lined up on the same "beam" of parallel fibers. 4. The third component is a long-lasting inhibitory response that is observed in virtually all type IV units with both MSN and parallel-fiber stimulation; its latency is longer than the evoked potential. Evidence suggests that it is produced by inhibitory input from cartwheel cells. The appearance of this inhibitory component in almost all type IV units can be accounted for by the considerable spread of cartwheel-cell axons in the direction perpendicular to the parallel fibers. 5. The evoked potential and all three components of the unit response vary systematically in size over the four pulses of the electrical stimulus. These results can be accounted for by two phenomena: 1) a facilitation of the granule cell synapses on all cell types that produces a steadily growing response through the four pulses, resembles presynaptic facilitation, and is seen with both MSN and parallel-fiber stimulation; and 2) a strong reduction in the granule cell response between the first and second pulse for MSN stimulation only. This reduction probably occurs presynaptically in the glomerulus or in the granule cell itself and could reflect inhibitory inputs. 6. The response components described above are seen in type IV units recorded in both the fusiform-cell and deep layers of the DCN; this suggests that both pyramidal and giant cells are activated similarly. The simplest interpretation is that both principal cell types are activated by the cerebellum-like circuitry in superficial DCN. Alternatively, because giant cells appear to make limited contact with the granule-cell circuits of superficial DCN, this finding may suggest the existence of currently undescribed granule cell circuits in deep DCN that are si
Animals↗
Minimal toxicity and mortality in high-risk breast cancer patients receiving high-dose cyclophosphamide, thiotepa, and carboplatin plus autologous marrow/stem-cell transplantation and comprehensive supportive care.
PURPOSE: To assess the clinical toxicity and outcome associated with a comprehensive supportive care approach in poor-risk breast cancer (BrCA) patients with high-dose chemotherapy (HDC). PATIENTS AND METHODS: One hundred twenty-five consecutive patients with stages II, III or metastatic breast cancer received HDC between February 1992 and June 1994. Recipients received 4 days of continuous infusion of cyclophosphamide 1.5 g/m2/d, thiotepa 125 mg/m2/d, and carboplatin 200 mg/m2/d followed by infusion of bone marrow or peripheral-blood stem cells (PBSC) and recombinant human growth factor (rhu-GF) support. Patients received similar supportive care that included administration of prophylactic antibiotics, management of neutropenic fevers, and transfusion support. RESULTS: There were 38 women with stage II or III (27 patients with > or = 10 lymph nodes), four with stage IIIB, and 83 with metastatic breast cancer. The median age was 44 years (range, 27 to 61). Grade II or greater nonhematologic toxicities included diarrhea (66%), stomatitis (33%), hepatic venoocclusive disease (VOD) (5%), and pulmonary toxicity (4%). Myeloid and platelet engraftment was comparable between bone marrow and PBSC recipients (P > .1). Infectious complications were rare and consisted of gram-negative bacteremia (1.6%), gram-positive bacteremia (1.6%), fungemia (1.6%), and documented or suspected aspergillosis infection (3%). There was one treatment-related death secondary to severe VOD. CONCLUSION: A comprehensive supportive care approach was associated with a low treatment-related mortality rate of less than 1%. With the observed reduction in treatment-related mortality, it is reasonable to evaluate the efficacy of HDC in women with less than 10 positive nodes and stage II disease in well-designed clinical trials.
Actuarial Analysis↗
An N-terminal partial sequence of the 13 kDa Pycnopodia helianthoides sperm chemoattractant 'startrak' possesses sperm-attracting activity.
Freshwater extracts of starfish ovaries were used to purify the sperm-attracting peptide 'startrak' from Pycnopodia helianthoides using hydrophobic interaction chromatography and DEAE-high-pressure liquid chromatography. Partially purified attractant had a molecular mass of 13 kDa, estimated from gel filtration and polyacrylamide gel electrophoresis results. The purified attractant was subjected to amino acid analysis and direct sequencing, and was found to consist largely of a single peptide composed of an estimated 127 residues based on a molecular mass of 13kDa. An N-terminal sequence of amino acids from positions 3 to 34 was obtained and synthesized as: NH2-Ala-Glu-Leu-Gly-Leu-Cys-Ile-Ala-Arg-Val-Arg-Gln-Gln-Asn-Gln-Gly-Gln- Asp-Asp-Val-Ser-Ile-Tyr-Gln-Ala-Ile-Met-Ser-Gln-Cys-Gln-Ser-COOH. The synthetic peptide possessed sperm-attracting activity 130 times greater than the activity of partially purified startrak and showed a pattern of species-specificity of sperm chemotaxis similar to that of startrak. Antibody prepared against synthetic peptide removed the sperm-attracting activity from crude and partially purified preparations of startrak. The partial sequence of startrak was not homologous with that of any of the known echinoid sperm motility-activating peptides.
Amino Acid Sequence↗
Association between reduced cuff leak volume and postextubation stridor.
STUDY OBJECTIVE: Laryngotracheal injury or edema in the setting of intubation may narrow the upper airway and predispose toward postextubation stridor. The presence or absence of an audible airleak when the sealing balloon cuff of the endotracheal tube is deflated has been demonstrated to be a marker of laryngotracheal edema in high-risk patients. We hypothesized that (1) the volume of the cuff leak can be quantified in a general medical ICU population, and (2) the cuff leak volume can be correlated with likelihood of postextubation stridor. METHODS: Within 24 h of both the initiation and termination of mechanical ventilation, the cuff leak volume, defined as the difference between the inspiratory tidal volume and the averaged expiratory tidal volume while the cuff around the endotracheal tube was deflated, was recorded. RESULTS: In 100 consecutive intubations, the preextubation cuff leak volume was 349 +/- 163 mL [mean +/- SD]). Overall, 6% of extubations were accompanied by postextubation stridor. The mean cuff leak volume measured within 24 h of planned extubation was significantly lower in those who subsequently developed stridor in comparison to those who did not (180 +/- 157 mL vs 360 +/- 157 mL; p = 0.012). The positive predictive value for postextubation stridor in the setting of a cuff leak less than 110 mL was 0.80, the predictive value for absence of postextubation stridor with a cuff leak volume greater than 110 mL was 0.98, and the specificity of the test was 0.99. No other demographic factors or indexes related to mechanical ventilation were significantly different between the two groups. CONCLUSIONS: A reduced cuff leak volume prior to extubation identifies a population at increased risk for postextubation stridor.
Aged↗
Cytokine induction by the immunomodulators imiquimod and S-27609.
Imiquimod (R-837, S-26308) and the analogue S-27609 were evaluated for cytokine induction in human blood cells. Both compounds induced interferon-alpha (IFN), tumor necrosis factor-alpha (TNF), interleukin (IL)-1 beta, and IL-6 with S-27609 being 5 to 10 times more potent. Imiquimod and S-27609 also induced IL-1 alpha, IL-1 receptor antagonist, IL-10, granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte CSF (G-CSF), and macrophage inflammatory protein-1 alpha. The profile of cytokines induced by imiquimod and S-27609 was different from those seen with lipopolysaccharide and polyinosinic-polycytidylic acid. Kinetic studies with both imiquimod and S-27609 revealed induction of cytokines as early as 1-4 h after stimulation. Although most of the cytokines produced by S-27609 were secreted, significant concentrations of IL-1 alpha and IL-1 beta remained intracellular. Monocytes were largely responsible for the cytokines produced. Finally, S-27609-induced mRNA expression for TNF, IFN, and IL-8, and this induction did not require protein synthesis. Taken together, these studies extend previous findings by showing induction of additional cytokines and providing insight into the mechanism of cytokine induction by these molecules.
Adjuvants, Immunologic↗
Development and validation of adolescent-perceived microsystem scales: social support, daily hassles, and involvement.
Developed and validated instruments for urban and culturally diverse adolescents to assess their self-reported transactions with family, peer, school, and neighborhood microsystems for the constructs of social support, daily hassles, and involvement. The sample of 998 youth were from schools in three Eastern cities with high percentages of economically disadvantaged youth. Data were collected before and after the transition to junior high school or to senior high school. Blacks constituted 26%, whites 26%, and Latinos 37% of the sample. Factor analyses confirmed and enhanced the hypothesized four-factor microsystem factor structure for support, hassles, and involvement; internal consistency and stability coefficients were consistent with these structures. In general, the microsystem factors were common across gender, ethnicity, and age. However, when group differences did occur on these demographic variables, they tended to validate the salience of microsystem specificity. In contrast to the total scores, the microsystem-specific factors yielded more meaningful and differential information with regard to demographic differences and the mediating processes across a school transition.
Adolescent↗
Immunomodulating and antiviral activities of the imidazoquinoline S-28463.
Recently, a new class of immunomodulating agents, represented by the molecules imiquimod and R-842, has demonstrated potent antiviral and antitumor activities in animal models. In this study, another representative of this class, S-28463 (4-amino-2-ethoxymethyl-alpha,alpha-dimethyl-1H-imidazo[4,5-c]quinoline- 1- ethanol) was evaluated for its immunomodulating and antiviral activities. S-28463 induced IFN and other cytokines in vivo in mice, rats, monkeys and in vitro in human peripheral blood mononuclear cell cultures. S-28463 showed potent antiviral activity against herpes simplex virus-challenged guinea pigs when given subcutaneously, dermally, or intravaginally 24 h before infection. Antiviral activity in guinea pigs correlated with the induction of serum 2',5'-oligoadenylate synthetase activity. Thus, S-28463, like the other imidazoquinolines, demonstrates potent antiviral and immunomodulating effects in a number of models.
2',5'-Oligoadenylate Synthetase↗
Effect of imiquimod as an adjuvant for immunotherapy of genital HSV in guinea-pigs.
Imiquimod, an immunomodulator which upregulates cell-mediated immune responses, was evaluated as an adjuvant for immunotherapy of recurrent genital herpes simplex virus (HSV) infection in guinea-pigs. In two experiments at separate research centres, animals were immunized with HSV glycoprotein and either placebo, 1 or 5 days of imiquimod, or complete Freund's adjuvant, 14 and 35 days after genital HSV-2 infection. Recurrent lesion days were then evaluated from days 15-91. In both experiments, immunization with glycoprotein and imiquimod most effectively reduced recurrence compared with unimmunized controls (53-69%, p < 0.001-0.05). A peak reduction of 70-80% was observed following the second immunization. This reduction was greater than that provided by immunization with glycoprotein and complete Freund's adjuvant in these experiments or those previously reported.
Adjuvants, Immunologic↗
Characteristics of blood-containing aerosols generated by common powered dental instruments.
Powered dental instruments applied to whole-blood in a typodont field of operation generated aerosols of red blood cell and hemoglobin-tinged plasma at rates ranging from 0.003 to 2.2 microL of plasma per minute with particle sizes ranging from 0.06 to 13 microns and half-lives of 35 minutes to 17 hours. Particles 0.06 to 0.38 microns were plasma spheroids that contained no detectable hemoglobin or red blood cell fragments. Particles 0.66 to 13 microns were mostly plasma spheroids, only a small fraction of which contained whole and fragmented red blood cells. All the recovered particles physically could contain the 0.042 microns hepatitis B virus, could be inhaled, and 20 to 100% of them could be retained in the human respiratory system. Of 0.06 to 2.5 microns plasma aerosol particles, 15-83% passed through the filter media of nine makes of surgical masks used by dentists for protection from occupational infection. These findings lend support to the hypothesis of an airborne route for the hepatitis B infections reported for dental professionals.
Aerosols↗
Cellular requirements for cytokine production in response to the immunomodulators imiquimod and S-27609.
Imiquimod (R-837) and its analog, S-27609, belong to a class of imidazoquinolinamines that have potent antitumor and antiviral effects in animals. Much of their biologic activity is a result of the induction of cytokines, including interferon-alpha (IFN-alpha), tumor necrosis factor alpha (TNF), and others. In this study, the cells responsible for S-27609- and imiquimod-induced cytokine production were characterized. E rosette+ T cells were not the major cell population responsible for IFN-alpha and TNF in response to S-27609 or imiquimod. In contrast, E rosette- cells and unseparated PBMC produced similar concentrations of IFN-alpha and TNF in response to S-27609 and imiquimod. Elimination of monocytes by treatment with the lysosomotropic agent L-leucine methyl ester (LME) or depletion using antibody to CD14 and immunomagnetic beads abrogated IFN-alpha and TNF production induced by S-27609, imiquimod, or LPS but not poly(I)/(C). LME treatment also abolished interleukin (IL)-1 alpha, IL-beta, IL-6, and IL-8 production stimulated by S-27609 and imiquimod. Removal of HLA-DR+ or CD36+ monocytes also caused a significant reduction in S-27609- and imiquimod-induced IFN-alpha and TNF. Elimination of B cells, NK cells, and dendritic cells did not significantly reduce cytokine induction in response to S-27609. Thus, the cell population responsible for the majority of cytokine release in human PBMC in response to S-27609 and imiquimod is a E rosette-, CD14+, CD36+, HLA-DR+ monocyte.
Adjuvants, Immunologic↗
Stimulation of interferon and cytokine gene expression by imiquimod and stimulation by Sendai virus utilize similar signal transduction pathways.
The imidazoquinolineamine derivative 1-(2-methyl propyl)-1H-imidazole [4,5-c]quinoline-4-amine (imiquimod) has been shown to induce alpha interferon (IFN-alpha) synthesis both in vivo and in peripheral blood mononuclear cells in vitro. In this study, we show that, in these cells, imiquimod induces expression of several IFNA genes (IFNA1, IFNA2, IFNA5, IFNA6, and IFNA8) as well as the IFNB gene. Imiquimod also induced the expression of interleukin (IL)-6, IL-8, and tumor necrosis factor alpha genes. Expression of all these genes was transient, independent of cellular protein synthesis, and inhibited in the presence of tyrosine kinase and protein kinase C inhibitors. Infection with Sendai virus led to expression of a similar set of cytokine genes and several of the IFNA genes. Imiquimod stimulates binding of several induction-specific nuclear complexes: (i) the NF-kappa B-specific complexes binding to the kappa B enhancer present in the promoters of all cytokine genes, but not in IFNA genes, and (ii) the complex(es) binding to the A4F1 site, 5'-GTAAAGAAAGT-3', conserved in the inducible element of IFNA genes. These results indicate that imiquimod, similar to viral infection, stimulates expression of a large number of cytokine genes, including IFN-alpha/beta, and that the signal transduction pathway induced by both of these stimuli requires tyrosine kinase and protein kinase activity.
Aminoquinolines↗
New age public won't settle for old-fashioned facilities.
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Forecasting↗
Assisting gay men to maintain safer sex: an evaluation of an AIDS service organization's safer sex maintenance program.
As the second decade of the AIDS crisis unfolds, increasing concern has been raised that the widespread adoption of condom use that occurred among gay men in the 1980s is not being maintained. Most interventions to promote condom use among gay men are delivered by community-based organizations via programs that are virtually undocumented; little is known about their effectiveness, or the processes by which they may work. This study describes safer sex practices among self-identified gay men following their participation in an intervention developed and implemented by a community-based organization. The intervention was designed to enhance men's attitudes, beliefs, and self-efficacy expectations to maintain safer sex. Among 150 men with complete data at both assessments, self-reported condom use was low. Men reported using condoms more consistently for anal sexual behavior than oral sexual behavior, but there were men who reported consistent unprotected anal sexual intercourse. The intervention had little impact on patterns of behavior over time, although desired changes in attitudes, beliefs, and self-efficacy expectations were evidenced following the intervention. The results suggest the importance of assisting community-based organizations to document program models. Findings also suggest that community-based organizations can develop interventions to successfully enhance factors that theoretically support maintenance of safer sexual behaviors.
Acquired Immunodeficiency Syndrome↗
Cytokine induction in mice by the immunomodulator imiquimod.
Imiquimod has been identified as a potent antiviral and antitumor agent in animal models. The biological activity associated with imiquimod has been attributed to its induction of interferon (IFN)-alpha. The present studies evaluated imiquimod administered orally for its ability to stimulate production of IFN and other cytokines in mice. The cytokine profile induced by imiquimod was compared with other known immunomodulators. Imiquimod was found to stimulate increased serum IFN in mice. Daily dosing of imiquimod for five consecutive days led to diminished production of IFN in mice as measured after the final dose. Elevated levels of serum tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 but not IL-1 alpha were found in serum from mice treated with imiquimod. Imiquimod produced significantly higher levels of IFN but lower levels of TNF and IL-6 and IL-1 alpha than lipopolysaccharide. Polyinosinic acid:polycytidylic acid induced significantly higher amounts of IFN but lower levels of TNF and IL-6 than imiquimod. Imiquimod stimulated significantly higher levels of IFN when compared with 2-amino-5-bromo-6-phenyl-4(3H)-pyrimidinone (ABPP) and similar levels of IFN when compared with tilorone. Neither ABPP nor tilorone induced TNF or IL-6. Finally, imiquimod stimulated TNF, IFN, and IL-6 production in cultures of mouse spleen and bone marrow cells. These studies demonstrate that imiquimod induces not only IFN but other cytokines as well, all of which may contribute to its biological activity.
Aminoquinolines↗
Identification of trisomy in Macaca fascicularis by fluorescence in situ hybridization with a human chromosome 13 DNA library.
A juvenile macaque monkey with abnormal phenotypic and behavioral features was studied cytogenetically. An additional autosome was found in over 90% of the animal's cultured cells. This chromosome, subsequently identified as number 16 in the macaque karyotype by G-banding, was shown to be mostly homologous with human chromosome 13 using fluorescence in situ hybridization of a human chromosome specific cosmid library. Although the monkey, now deceased, exhibited some abnormal physical and behavioral features, none of the severe clinical characteristics associated with human chromosome 13 trisomy were apparent. We suggest that the incomplete expression of 13-trisomy observed could result if the macaque chromosome were deficient in some of the region(s) of chromosome 13 common to humans affected with the disorder.
Animals↗