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Biomedical subjects

Paul A Moore

Publications and source records attributed to Paul A Moore.

At least 19 recordsLinked to original sources
PubMed2006

Global transcriptional effects of PEG-IFN-alpha and ribavirin on peripheral blood cells obtained from patients with chronic hepatitis C.

The global transcriptional profile during the first 4 weeks of treatment with pegylated interferon alfa (PEG-IFN-alpha) therapy for chronic hepatitis C (CHC) was evaluated. cDNA array technology was used to assess expression of 10,918 human genes in peripheral blood cells obtained from 17 CHC patients at days 0, 7, and 28 following treatment with PEG-IFN-alpha and ribavirin. Hierarchical average linkage clustering identified seven temporal profiles of differential expression comprising 148 genes. Gene expression profiles were comparable between the PEG-IFN-alpha-2a and PEG-IFN-alpha-2b therapy. Genes representing a broad range of molecular functions were differentially regulated with distinct temporal patterns of expression. The initial global response to interferon treatment appears to be a net up-regulation of genes, consistent with gene responses identified previously in vitro, though by 4 weeks an overall down-regulation of genes was observed. Novel transcription factors potentially involved in secondary gene regulation cascades, a potential dsRNA receptor and members of the ubiquitin signaling, including a novel predicted deubiquitinating peptidase were all identified as being up-regulated upon treatment with IFN. The overall findings provide new light on possible physiological effects of IFN-alpha and open new lines of investigations on the mode of action of PEG-IFN-alpha combination therapy.

Journal Article↗
PubMed2006

Granzyme B is critical for T cell receptor-induced cell death of type 2 helper T cells.

Although CD95L is required for T cell receptor (TCR)-induced cell death (TCR-ICD) in T helper 1 cells, the molecular mechanisms mediating TCR-ICD in Th2 cells are unknown. We found that death receptors were not involved in TCR-ICD of Th2 cells because blocking their cognate ligands had no effect on apoptosis of activated Th2 cells. Furthermore, we showed that caspases were not actively involved in TCR-ICD of Th2 cells. However, inhibition of granzyme B (GrB) activity abolished TCR-ICD in Th2 cells but not Th1 cells. Likewise, Th2 cells derived from GrB-deficient mice were resistant to TCR-ICD, and GrB deficiency or inhibition of GrB activity consequently enhanced the production of Th2 cytokines. GrB-deficient mice exhibited increased susceptibility to allergen-induced asthma. Thus, GrB plays a critical role in the TCR-ICD of Th2 cells.

Allergens↗
PubMed2006

Dynamics of interferon-specific gene expression in peripheral blood of interferon alfa-naïve patients with genotype 1 chronic hepatitis C infection treated with albumin-interferon alfa.

Albumin-interferon alfa (alb-IFN) is a novel recombinant protein derived from IFNalpha-2b genetically fused to human albumin, which combines in a single polypeptide the antiviral properties of IFNalpha with the long serum half-life of albumin. Interferon alfa (IFNalpha) mediated biological responses stem from the engagement of IFNalpha with its target receptor and subsequent modulation of interferon-specific gene (ISG) expression. The dynamics of ISG expression were evaluated in a Phase 2a study conducted in IFNalpha naïve patients with genotype 1 chronic hepatitis C (CHC) treated with alb-IFN. Whole blood was obtained pre-dose and on days 7 and 28 from 47 patients enrolled to receive two subcutaneous injections of alb-IFN 14 days apart in five dose cohorts ranging from 200 to1200mug. Gene expression of nine candidate genes including four ISGs was determined by a TaqMan Real-time PCR assay. There was sustained >5-fold median induction on days 7 and 28 of the ISG's- OAS1, IRF7, IFI44 and IFI27. While all subjects showed a molecular response to alb-IFN, individual variability in pre-treatment gene expression levels and fold of modulation during treatment was observed. At days 7 and 28, induction of OAS1, IFI44 and IRF7 showed significant pair-wise correlation in individual patients (r>0.7 and P<0.001). There was no correlation of baseline expression or induction of gene expression with antiviral response. In conclusion, alb-IFN demonstrated robust induction of ISG that was consistent with the molecular response associated with an IFNalpha.

Journal Article↗
PubMed2006

Common medications prescribed for adolescent dental patients.

Common prescription medications taken by adolescent patients include various psychopharmacologic agents (to manage depression,obsessive-compulsive disorders, and attention deficit/hyperactivity disorders), pulmonary drugs (to prevent and treat asthma), and dermatologic agents (to treat acne). Other agents encountered when treating adolescent patients are antidiabetes agents, antibiotics, and birth control medications. This overview identifies prescription medications commonly used by adolescent patients and discusses their possible impact on dental care.

Adolescent↗
PubMed2006

Analysis of IFN-kappa expression in pathologic skin conditions: downregulation in psoriasis and atopic dermatitis.

Interferon-kappa (IFN-kappa) is a type I IFN expressed by keratinocytes, monocytes and dendritic cells (DCs). In human keratinocytes, it is produced in response to double-stranded RNA (dsRNA) and other IFNs and protects from viral infections. In monocytes and DCs, IFN-kappa induces tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) and inhibits lipopolysaccharide (LPS)-induced IL-12. In this study, we evaluated IFN-kappa expression in skin lesions of patients with common immune-mediated inflammatory disorders using immunohistochemical techniques. IFN-kappa was not detectable in healthy skin but was strongly expressed in allergic contact dermatitis and lichen planus-affected skin. IFN-kappa was localized mainly in basal and suprabasal keratinocytes and in some leukocytes infiltrating the dermis. In contrast, IFN-kappa expression in psoriatic or atopic dermatitis (AD) pidermis was weak and detectable in only 2 of 5 patients examined. Consistently, cultured keratinocytes and monocytes obtained from psoriatic and AD patients expressed null or low levels of IFN-kappa in response to IFN-gamma, which strongly upregulates IFN-kappa in normal keratinocytes. IFN-kappa accumulated in keratinocyte cytoplasm and plasma membrane, and only limited amounts were released extracellularly. Soluble IFN-kappa did not influence keratinocyte proliferation or chemokine and membrane molecule expression, and only its membrane-associated form activated IFN-stimulated response element (ISRE) signaling. Given the difference in IFN-kappa expression levels in the skin disorders examined, IFN-kappa presence or deficiency might have different pathogenetic consequences depending also on other disease-specific intrinsic alterations.

Adult↗
PubMed2006

The pharmacokinetics and cardiovascular effects of high-dose articaine with 1:100,000 and 1:200,000 epinephrine.

OBJECTIVES: The authors conducted a randomized, double-blind, two-way crossover clinical trial to compare the pharmacokinetics and cardiovascular effects of 11.9 milliliters of 4 percent articaine hydrochloride (HCl) plus 1:100,000 epinephrine (A100) with those of 11.9 mL of 4 percent articaine HCl plus 1:200,000 epinephrine (A200). METHODS: During two testing sessions, the authors administered injections of A100 and A200 over a seven-minute period (in one-cartridge doses unless otherwise noted): maxillary right first molar infiltration, maxillary left first molar infiltration, maxillary right first premolar infiltration, maxillary left first premolar infiltration, right inferior alveolar injection, left inferior alveolar injection, right long buccal infiltration (one-half cartridge) and left long buccal infiltration (one-half cartridge). They analyzed venous blood samples for articaine levels. They used noninvasive acoustic tonometry to measure a variety of cardiovascular parameters over a two-hour period. RESULTS: Plasma concentration curves of articaine over time were similar for both solutions, with peak concentrations and times to maximum concentration being 2,037 nanograms per milliliter and 22 minutes for A100 and 2,145 ng/mL and 22 minutes for A200. At the 10-minute point, the mean systolic blood pressure and heart rate were significantly elevated (P < .05) with A100 versus A200. CONCLUSIONS: Maximum dose recommendations for the A100 solution also can be applied to the A200 solution. A200 produces less cardiovascular stimulation than does A100. CLINICAL IMPLICATIONS: A200 is as safe as A100, and may be preferable to A100 in patients with cardiovascular disease and in those taking drugs that reportedly enhance the systemic effects of epinephrine.

Adult↗
PubMed2006

The anesthetic efficacy of 4 percent articaine 1:200,000 epinephrine: two controlled clinical trials.

OBJECTIVE: The authors conducted two double-blinded, randomized, multicenter clinical trials to determine the efficacy and clinical anesthetic characteristics of 4 percent articaine hydrochloride (HCl) with 1:200,000 epinephrine (A200) as compared with those of 4 percent articaine HCl with 1:100,000 epinephrine (A100) and 4 percent articaine HCl without epinephrine (Aw/o). METHODS: During separate testing sessions, members of the authors' research team used three articaine study formulations to induce either inferior alveolar nerve block anesthesia (Trial 1) or maxillary infiltration anesthesia (Trial 2). In each trial, subjects received, in a randomized sequence, each of the three formulations to determine efficacy (success rate) and anesthetic characteristics (onset time and duration). The authors evaluated pulpal anesthesia via subjects' response to electric pulp testing (EPT). RESULTS: A total of 126 subjects were enrolled in the two studies (63 subjects in each trial). In both mandibular and maxillary trials, the success rates for inducing profound anesthesia (EPT score > 80), the mean onset times and the mean durations of anesthesia were similar for both epinephrine-containing formulations (A200 and A100). In subjects who received the formulation containing no epinephrine (Aw/o), the success rate for profound anesthesia was significantly less. CONCLUSION: These studies demonstrated that the inclusion of epinephrine in 4 percent articaine anesthetic formulations is essential for achieving profound anesthesia. The authors found that the A200 formulation provided a level of pulpal anesthesia comparable with that of the A100 formulation.

Adult↗
PubMed2006

Balancing efficacy and safety in the use of oral sedation in dental outpatients.

BACKGROUND: Concerns about the safety of pediatric oral sedation and the incremental use of triazolam in adults prompted a workshop cosponsored by several professional organizations. OVERVIEW: There is a strong need and demand for adult and pediatric sedation services. Using oral medication to achieve anxiolysis in adults appears to have a wide margin of safety. Mortality and serious morbidity, however, have been reported with oral conscious sedation, especially in young children. Most serious adverse events are related to potentially avoidable respiratory complications. CONCLUSIONS: Clinical trials are needed to evaluate oral sedative drugs and combinations, as well as to develop discharge criteria with objective quantifiable measures of home readiness. Courses devoted to airway management should be developed for dentists who provide conscious sedation services. State regulation of enteral administration of sedatives to achieve conscious sedation is needed to ensure safety. PRACTICE IMPLICATIONS: Safety in outpatient sedation is of paramount concern, with enteral administration of benzodiazepines appearing safe but poorly documented in the office setting. Conscious sedation by the enteral route, including incremental triazolam, necessitates careful patient evaluation, monitoring, documentation, facilities, equipment and personnel as described in American Dental Association and American Academy of Pediatric Dentistry guidelines.

Adult↗
PubMed2005

Osteostat/tumor necrosis factor superfamily 18 inhibits osteoclastogenesis and is selectively expressed by vascular endothelial cells.

Vascular endothelial cells (EC) participate in the process of bone formation through the production of factors regulating osteoclast differentiation and function. In this study, we report the selective expression in primary human microvascular EC of Osteostat/TNF superfamily 18, a ligand of the TNF superfamily. Osteostat protein is detectable in human microvascular EC and is highly up-regulated by IFN-alpha and IFN-beta. Moreover, an anti-Osteostat antibody strongly binds to the vascular endothelium in human tissues, demonstrating that the protein is present in the EC layers surrounding blood vessels. Functional in vitro assays were used to define Osteostat involvement in osteoclastogenesis. Both recombinant and membrane-bound Osteostat inhibit differentiation of osteoclasts from monocytic precursor cells. Osteostat suppresses the early stage of osteoclastogenesis via inhibition of macrophage colony-stimulating factor-induced receptor activator of NF-kappaB (RANK) expression in the osteoclast precursor cells. This effect appears to be specific for the differentiation pathway of the osteoclast lineage, because Osteostat does not inhibit lipopolysaccharide-induced RANK expression in monocytes and dendritic cells, or activation-induced RANK expression in T cells. These findings demonstrate that Osteostat is a novel regulator of osteoclast generation and substantiate the major role played by the endothelium in bone physiology.

Acid Phosphatase↗
PubMed2005

Preemptive rofecoxib and dexamethasone for prevention of pain and trismus following third molar surgery *.

Objective The goal of this preliminary randomized prospective clinical trial was to compare the analgesic efficacy and the reduction in trismus of preoperative rofecoxib, intraoperative dexamethasone, and both rofecoxib and dexamethasone following third molar extraction surgery. Study design Thirty-five subjects requiring surgical removal of at least 1 partial bony impacted mandibular third molar were invited to participate in this double-blind and double-dummy placebo-controlled clinical trial. Subjects were randomly assigned into 1 of 4 treatment groups: (1) placebo po preoperatively and placebo IV intraoperatively; (2) rofecoxib 50 mg po preoperatively and placebo IV intraoperatively; (3) placebo po preoperatively and dexamethasone10 mg IV intraoperatively; and (4) rofecoxib 50 mg po preoperatively and dexamethasone 10 mg IV intraoperatively. Subjects completed a diary assessing postoperative pain onset and intensity using categorical and visual analogue scales. Interincisal opening was assessed 1, 2, 3, and 7 days postoperatively using a Therabite ruler. Results This randomized controlled clinical trial enrolled 35 subjects. Two subjects did not meet the inclusion criteria and 4 did not return completed diaries. The mean age of the remaining 29 subjects (11 males, 18 females) was 22.8 years (+/- 0.6 year). The active treatments tended to delay the need for initial pain medication. When compared to other active treatments and to placebo, the combination of preoperative rofecoxib and intraoperative dexamethasone significantly reduced initial pain intensity ( P < .05). Baseline interincisal opening was 52.6 mm (+/- 6.2). The greatest decrease in interincisal opening was 43.3% for the placebo group at 24 hours. Preoperative rofecoxib alone showed a decrease in interincisal opening of 42.3% ( P = ns) at 24 hours. Intraoperative dexamethasone alone showed a decrease in the interincisal opening of 24.1% of baseline ( P < .05 vs placebo). The group receiving the combination of rofecoxib and dexamethasone showed a decrease in interincisal opening of 23.7% of baseline ( P < .05 vs placebo). Conclusions The results of this trial indicate that the use of intraoperative dexamethasone is an effective therapeutic strategy for limiting trismus following surgical removal of impacted third molars. The combination of preoperative rofecoxib 50 mg and intraoperative dexamethasone 10 mg was most effective in minimizing pain and trismus following third molar surgery.

Adolescent↗
PubMed2005

Anesthetic management of a patient with celiac disease.

A 22-year-old female with an extensive medical and surgical history that included mental retardation presented for dental treatment under conscious sedation at a special needs clinic. The patient's history revealed a delayed diagnosis of celiac disease (CD) that resulted in growth retardation with poor muscle development. Because of the patient's delayed diagnosis of CD and history of difficult airway management, special considerations were necessary for proper anesthesia administration.

Adult↗
PubMed2005

Update on cyclooxygenase inhibitors: has a third COX isoform entered the fray?

It has been more than 30 years since Sir John Vane first reported that the pharmacological actions of aspirin-like drugs could be explained by their ability to inhibit cyclooxygenase (COX). Since then, a second isoform of COX, named COX-2, has been discovered and highly selective inhibitors of this isoform have been marketed. Most recently, a splice variant of COX-1 mRNA, retaining intron 1, and given the names COX-3, COX-1b or COX-1v, has been described. Non-selective NSAIDs such as ibuprofen and naproxen, which inhibit both COX-1 and COX-2, have proven highly effective and safe in the short-term management of acute pain. Highly selective COX-2 inhibitors including celecoxib, rofecoxib, valdecoxib, lumiracoxib, and etoricoxib were developed with the hope of significantly reducing the serious gastrointestinal toxicities associated with chronic high-dose NSAID use. While long-term studies demonstrated that rofecoxib and lumiracoxib reduced the incidence of GI perforations, ulcerations and bleeds by approximately 60% compared to non-selective NSAIDs, recent reports also demonstrated that the chronic use of rofecoxib and celecoxib in arthritis and colorectal polyp patients, and the short-term use of parecoxib and valdecoxib in patients who had undergone coronary artery bypass surgery, resulted in a significant increase in serious cardiovascular events, including myocardial infarction and stroke compared to naproxen or placebo. COX-3 mRNA has been isolated in many tissues including canine and human cerebral cortex, human aorta, and rodent cerebral endothelium, heart, kidney and neuronal tissues. In transfected insect cells, canine COX-3 protein is expressed and was selectively inhibited by acetaminophen. However, in humans and rodents an acetaminophen sensitive COX-3 protein is not expressed because the retention of intron-1 adds 94 and 98 nucleotides to the COX-3 mRNA structure respectively. Since the genetic code is a triplicate code (3 nucleotides to form one amino acid), the retention of the intron in both species results in a frame shift in the RNA message and the production of a truncated protein with a completely different amino acid sequence than COX-1 or COX-2 lacking acetaminophen sensitivity. Advances made through a combination of basic molecular biological and pharmacological techniques, and well designed randomized controlled clinical trials have demonstrated that the apparent gastrointestinal advantage of selective COX-2 inhibitors appears to be outweighed by their potential for cardiovascular toxicity and that acetaminophen's analgesic and antipyretic effects do not involve the inhibition of the COX-1 splice variant protein, putative COX-3.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2004

Spatial arrangement of odor sources modifies the temporal aspects of crayfish search strategies.

In natural habitats, animals encounter cues from multiple odor sources that may impact foraging decisions. Previous work has focused on orientation behavior to one food odor source, and does not distinguish between mechanosensory and chemosensory guidance of orientation. The present study investigated how the spatial distribution of two food cues affects crayfish orientation behavior. Crayfish, Orconectes virilis, were presented with odor sources that were separated in an artificial stream. Orientation behavior was filmed from above and digitized at a rate of 1 frame per sec. Electrochemical recordings were taken to characterize the odor plume, and an acoustic doppler velocimeter was used to characterize the hydrodynamic structure of the artificial stream. Temporal changes in odor plume structure were seen as a result of the positioning of the odor sources. Changes in the intermittency of the odor pulses as well as concentration, rise time, and slope of the pulse were observed. Time series analysis showed that the lower frequency signals of the dual odor source were higher in energy than the single 1X or single 2X sources. Crayfish altered orientation strategies when presented with different spatial arrangements of food cues. In particular, the temporal aspects of the orientation pattern were most altered by the differences in odor presentations. Crayfish responded with faster walking speeds as a function of distance to the odor source and exhibited more consistent turning angles. This correlates with temporal changes in odor structure, and indicates that the temporal pattern of odor stimulation may be driving the temporal pattern of behavior.

Animals↗
PubMed2004

Selective induction of tumor necrosis receptor factor 6/decoy receptor 3 release by bacterial antigens in human monocytes and myeloid dendritic cells.

Tumor necrosis factor (TNF) receptor 6/decoy receptor 3 (TR6/DcR3) is an antiapoptosis soluble receptor of the TNF family produced by tumor cells. In this study, TR6 expression in human immune cells was investigated. TR6 mRNA and protein were detectable in selected antigen-presenting cells. Monocytes and myeloid-derived dendritic cells (MDC) released the protein exclusively following stimulation of Toll-like receptor 2 (TLR2) and TLR4 by gram-positive and gram-negative bacterial antigens. Plasmacytoid dendritic cells, activated by bacterial antigens via TLR9 or by viral infection, did not produce the protein. Similarly, activated T cells did not release TR6. The release of TR6 by MDC was dependent on the activation of p42/p44 mitogen-activated protein kinases, Src-like protein tyrosine kinases, and phosphatidylinositol 3-kinase, signaling pathways important for MDC maturation and survival. In agreement with the in vitro data, TR6 levels in serum were significantly elevated in patients with bacterial infections. Overall, these data suggest a novel role for TR6 in immune responses to bacteria.

Antigen-Presenting Cells↗
PubMed2004

Drug interactions in dentistry: the importance of knowing your CYPs.

BACKGROUND: The hepatic and intestinal cytochrome, or CY, P450 enzyme system is responsible for the biotransformation of a multitude of drugs. Certain medications used in dentistry can act as substrates, inducers or inhibitors of this system. METHODS: The authors conducted a MEDLINE search of articles appearing between 1976 and the present using the keywords "drug interactions" and "cytochrome P450," and reviewed reports involving dental therapeutic agents using PubMed links from an Indiana University CYP450 drug interaction table on the World Wide Web. RESULTS: The antibiotics erythromycin and clarithromycin are potent inhibitors of CYP3A4 and can increase blood levels and toxicity of CYP3A4 substrates. Likewise, quinolone antibiotics such as ciprofloxacin inhibit the metabolism of CYP1A2 substrates. Other dental therapeutic agents are substrates for CYP2C9 (celecoxib, ibuprofen and naproxen), CYP2D6 (codeine and tramadol), CYP3A4 (methylprednisolone) and CYP2E1 (acetaminophen). Because codeine and tramadol are prodrugs, inhibition of their metabolism can lead to a diminution of their analgesic effects. While inducers of acetaminophen metabolism, including alcohol, theoretically can increase the proportion of it that is biotransformed into a potentially hepatotoxic metabolite, recent research suggests that concomitant alcohol intake does not increase the hepatotoxic potential of therapeutic doses of acetaminophen. CONCLUSIONS: A number of clinically significant drug interactions can arise with dental therapeutic agents that act as substrates or inhibitors of the CYP450 system. Clinical Implications. As polypharmacy continues to increase, the likelihood of adverse drug interactions in dentistry will increase as well. Ensuring that patients' medical histories are up to date and acquiring knowledge of the various substrates, inducers and inhibitors of the CYP450 system will help practitioners avoid potentially serious adverse drug interactions.

Cytochrome P-450 Enzyme Inhibitors↗
PubMed2003

Clinical significance of detecting elevated serum DcR3/TR6/M68 in malignant tumor patients.

TR6/DcR3/M68 is a soluble receptor that belongs to the TNF receptor family. It is expressed in malignant cells of several tumor types and has been postulated to help tumor cells to gain survival advantage by inhibiting apoptosis and by interfering with immune surveillance. In our study, we assessed for the first time serum TR6 in tumor patients to explore its diagnostic and prognostic value. We examined serum TR6 levels with ELISA in 146 tumor patients, 19 patients with acute infection, 5 patients with liver cirrhosis and 29 healthy individuals. TR6 expression in tumor mass was studied with immunohistochemistry. TR6 gene copy number in tumor tissues was evaluated by real time PCR. Ninety-seven point nine percent (47 of 48 cases) of healthy individuals and patients with acute infection were serum TR6-negative. In contrast, 56.2% (82 of 146 cases) of the tumor patients were serum TR6-positive. Almost all serum TR6-positive individuals (98.8%, 82 out of 83 cases) had malignancy, excluding the cases of liver cirrhosis. In gastric carcinomas, serum TR6 levels were closely correlated with tumor differentiation status and TNM classification. Tumor mass was the source of serum TR6 because its levels decreased drastically after curative tumor resection. TR6 gene amplification occurred in about half of liver carcinomas, but not in gastric or pancreatic carcinomas, indicating plural mechanisms of TR6 upregulation. Our study demonstrated that serum TR6 should be considered as a novel parameter for the diagnosis, treatment and prognosis of malignancies.

Adenocarcinoma, Follicular↗