Search PubMed⌕ Search

Biomedical subjects

R L Smith

Publications and source records attributed to R L Smith.

At least 19 recordsLinked to original sources

Effects of a p38 MAP kinase inhibitor on bone ingrowth and tissue differentiation in rabbit chambers.

The effects of an oral p38 mitogen-activated protein kinase (MAPK) inhibitor and polyethylene particles separately and together on tissue differentiation in the bone harvest chamber (BHC) in rabbits over a 3-week treatment period were investigated. The harvested tissue was analyzed histomorphometrically for markers of bone formation (percentage of bone area), osteoblasts (alkaline phosphatase staining), and osteoclasts (CD51, the alpha chain of the vitronectin receptor). Polyethylene particles decreased the percentage of bone ingrowth and staining for alkaline phosphatase. The p38 MAPK inhibitor alone decreased alkaline phosphatase staining. When the oral p38 MAPK inhibitor was given and the chamber contained polyethylene particles, there was a suppression of bone ingrowth and alkaline phosphatase staining. In contrast to oral non-steroidal anti-inflammatory drugs (NSAIDs) and local Interleukin-1 receptor antagonist (IL-1ra) administration, the oral p38 MAPK inhibitor alone did not suppress bone formation when given during the initial phase of tissue differentiation. Particle-induced inflammation and the foreign body reaction were not curtailed when the p38 MAPK inhibitor was given simultaneously with particles. Additional experiments are needed to establish the efficacy of p38 MAPK inhibitor administration on mitigating an established inflammatory and foreign body reaction that parallels the clinical situation more closely.

Administration, Oral↗

Effects of local infusion of OP-1 on particle-induced and NSAID-induced inhibition of bone ingrowth in vivo.

Excessive polyethylene wear particles from joint replacements may lead to periprosthetic osteolysis and loosening. Nonsteroidal anti-inflammatory drugs (NSAIDs) decrease fracture healing and bone ingrowth. We hypothesized that continuous local infusion of OP-1 (BMP-7) would increase local bone formation in the presence of two different adverse stimuli, polyethylene particles, and an oral NSAID. The Drug Test Chamber (DTC) was implanted in the proximal tibia of mature rabbits. The tissue growing into the chamber was exposed to OP-1 solution (110 ng/day), which was infused via an osmotic pump. Infusion of OP-1 alone for 6 weeks enhanced local bone formation in the chamber by 80% (p < 0.05) over infusion of carrier alone. In the presence of polyethylene particles, infusion of OP-1 increased local bone formation by 38% (p < 0.05) over treatment with particles and carrier. Oral administration of NSAID reduced local bone formation by 58% (p < 0.05); this suppressive effect caused by NSAIDS was completely reversed by the infusion of OP-1 (p < 0.05). These findings underline a potential role for local treatment with OP-1 to increase bone formation in the presence of potentially adverse stimuli such as polyethylene wear particles or NSAID use.

Alkaline Phosphatase↗

The FEMA GRAS assessment of aromatic substituted secondary alcohols, ketones, and related esters used as flavor ingredients.

This publication is the 11th in a series of safety evaluations performed by the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA). In 1993, the Panel initiated a comprehensive program to re-evaluate the safety of more than 1700 GRAS flavoring substances under conditions of intended use. The list of GRAS substances has now grown to more than 2100 substances. Elements that are fundamental to the safety evaluation of flavor ingredients include exposure, structural analogy, metabolism, pharmacokinetics and toxicology. Flavor ingredients are evaluated individually and in the context of the available scientific information on the group of structurally related substances. In this monograph, a detailed interpretation is presented on the renal carcinogenic potential of the aromatic secondary alcohol alpha-methylbenzyl alcohol, aromatic ketone benzophenone, and corresponding alcohol benzhydrol. The relevance of these effects to the flavor use of these substances is also discussed. The group of aromatic substituted secondary alcohols, ketones, and related esters was reaffirmed as GRAS (GRASr) based, in part, on their rapid absorption, metabolic detoxication, and excretion in humans and other animals; their low level of flavor use; the wide margins of safety between the conservative estimates of intake and the no-observed-adverse effect levels determined from subchronic and chronic studies and the lack of significant genotoxic and mutagenic potential.

Alcohols↗

The effects of titanium and polymethylmethacrylate particles on osteoblast phenotypic stability.

Wear particles generated following total joint arthroplasty interact with cells at the periprosthetic margin and induce an inflammatory response that contributes to osteolysis, aseptic loosening, and implant failure. This study examined the long-term effects of particles from two commonly implanted materials, titanium (Ti) and polymethylmethacrylate (PMMA), on cell viability and metabolism over a 21-day time course, using the human osteoblast-like cell line MG-63. Addition of particles was not associated with increased cell death or nitric oxide production at the particle concentration chosen. Collagen production was increased with exposure to titanium particles, whereas alkaline phosphatase and osteocalcin expression remained unchanged following exposure to both types of particles. The data show that titanium but not PMMA particles shifts bone cell metabolism to preferentially produce fibrous tissue rather than bone.

Biocompatible Materials↗

Comparison of VEGF-producing cells in periprosthetic osteolysis.

The pro-angiogenic cytokine vascular endothelial growth factor (VEGF) has been implicated in periprosthetic osteolysis and subsequent aseptic loosening of implants following total hip arthroplasty (THA). The goal of this study was to investigate whether increased VEGF at the bone-implant interface is secondary to a greater number of VEGF-producing cells or to increased VEGF production by individual cells. Real time polymerase chain reaction (RT-PCR) techniques were used to assess the expression of VEGF mRNA (isoforms 121, 165, 189) in periprosthetic tissues from revision THAs. Immunofluorescence was used to determine both differences in overall cellularity and in VEGF-producing cell type (macrophages, fibroblasts, endothelial cells) between patients with periprosthetic osteolysis (OL) and a control group undergoing primary THA for osteoarthritis (OA). Quantitative analysis of VEGF release in periprosthetic membranes via RT-PCR demonstrated no significant difference in the per-cell mRNA production of VEGF isoforms 121 165, or 189 between OL and OA patient groups. Immunofluorescence showed both higher cellularity and higher overall VEGF expression in the OL group. Immunofluorescence also showed a significant increase in macrophages in the OL group, but no significant difference in the proportion of fibroblasts or endothelial cells between the OL and OA groups. Co-localization of CD68+ and CD11b+ macrophage fluorescent signals with VEGF signal was greater in the OL group than in the OA group. Our results demonstrate that increased VEGF in OL periprosthetic tissue compared to OA synovium is correlated to increased numbers of VEGF-producing CD68+ and CD11b+ macrophages. Impact statement: Aseptic loosening, caused in large part by OL, remains the major cause of failed THAs leading to revision surgery. At the bone-implant interface, we found increased numbers of macrophages-cellular mediators of OL-and increased VEGF expression. VEGF may be a possible target for therapeutic intervention in mitigating OL.

Aged↗

Denitrification potential in stream sediments impacted by acid mine drainage: effects of pH, various electron donors, and iron.

Acid mine drainage (AMD) contaminates thousands of kilometers of stream in the western United States. At the same time, nitrogen loading to many mountain watersheds is increasing because of atmospheric deposition of nitrate and increased human use. Relatively little is known about nitrogen cycling in acidic, heavy-metal-laden streams; however, it has been reported that one key process, denitrification, is inhibited under low pH conditions. The objective of this research was to investigate the capacity for denitrification in acidified streams. Denitrification potential was assessed in sediments from several Colorado AMD-impacted streams, ranging from pH 2.60 to 4.54, using microcosm incubations with fresh sediment. Added nitrate was immediately reduced to nitrogen gas without a lag period, indicating that denitrification enzymes were expressed and functional in these systems. First-order denitrification potential rate constants varied from 0.046 to 2.964 day(-1). The pH of the microcosm water increased between 0.23 and 1.49 pH units during denitrification. Additional microcosm studies were conducted to examine the effects of initial pH, various electron donors, and iron (added as ferrous and ferric iron). Decreasing initial pH decreased denitrification; however, increasing pH had little effect on denitrification rates. The addition of ferric and ferrous iron decreased observed denitrification potential rate constants. The addition of glucose and natural organic matter stimulated denitrification potential. The addition of hydrogen had little effect, however, and denitrification activity in the microcosms decreased after acetate addition. These results suggest that denitrification can occur in AMD streams, and if stimulated within the environment, denitrification might reduce acidity.

Acids↗

Assessment of nitrification potential in ground water using short term, single-well injection experiments.

Nitrification was measured within a sand and gravel aquifer on Cape Cod, MA, using a series of single-well injection tests. The aquifer contained a wastewater-derived contaminant plume, the core of which was anoxic and contained ammonium. The study was conducted near the downgradient end of the ammonium zone, which was characterized by inversely trending vertical gradients of oxygen (270 to 0 microM) and ammonium (19 to 625 microM) and appeared to be a potentially active zone for nitrification. The tests were conducted by injecting a tracer solution (ambient ground water + added constituents) into selected locations within the gradients using multilevel samplers. After injection, the tracers moved by natural ground water flow and were sampled with time from the injection port. Rates of nitrification were determined from changes in nitrate and nitrite concentration relative to bromide. Initial tests were conducted with (15)N-enriched ammonium; subsequent tests examined the effect of adding ammonium, nitrite, or oxygen above background concentrations and of adding difluoromethane, a nitrification inhibitor. In situ net nitrate production exceeded net nitrite production by 3- to 6- fold and production rates of both decreased in the presence of difluoromethane. Nitrification rates were 0.02-0.28 mumol (L aquifer)(-1) h(-1) with in situ oxygen concentrations and up to 0.81 mumol (L aquifer)(-1) h(-1) with non-limiting substrate concentrations. Geochemical considerations indicate that the rates derived from single-well injection tests yielded overestimates of in situ rates, possibly because the injections promoted small-scale mixing within a transport-limited reaction zone. Nonetheless, these tests were useful for characterizing ground water nitrification in situ and for comparing potential rates of activity when the tracer cloud included non-limiting ammonium and oxygen concentrations.

Bromides↗

Arytenoid mucosal injury in young Thoroughbred horses--investigation of a proposed aetiology and clinical significance.

AIM: To determine whether trauma to the larynx caused by nasotracheal intubation induced mucosal ulceration of the arytenoid cartilages of adult horses, and to determine the incidence of such ulceration in yearling Thoroughbred horses and its effect on athletic performance. METHODS: Laryngeal trauma was induced in a group of 21 adult horses by introduction of a nasogastric tube into the trachea three times within 5 min. Injury to the arytenoid cartilages or vocal cords was subjectively assessed immediately after intubation, and thereafter at weekly intervals for 10 weeks. The outcome and athletic performance of 33 Thoroughbred yearling horses with idiopathic disease of the arytenoid cartilages, diagnosed at the yearling sales, were evaluated and compared to those of control horses of the same gender and age, from the same sale. RESULTS: Mucosal injury was noted immediately after intubation in every horse. Evidence of injury to the vocal or corniculate processes of the arytenoid cartilages or vocal cords was still apparent in 10/21 (48%) horses 1 week after intubation, five of which developed persistent lesions that remained present and unchanged from 28 days following intubation until the end of the 10-week observation period. All persistent lesions were nodules or focal swellings of the vocal cords or arytenoid cartilages, and there was no evidence of mucosal ulceration, infection or discharge. Mucosal ulceration of the vocal processes was the most common abnormality detected in the yearlings, affecting 16/33 (48%) that were diagnosed with idiopathic arytenoid disease at the yearling sales. Five of the 33 (15%) horses were diagnosed with arytenoid chondritis at the time of sale and were excluded from the performance outcome analysis. Of the 28 horses diagnosed with arytenoid abnormalities excluding chondritis, 19 (68%) raced with no history of respiratory-related problems, two (7%) were subsequently diagnosed with laryngeal hemiplegia, and seven (25%) were lost to follow-up. The case animals were 2.7 times more likely to race than control horses, but there was no difference between cases and controls in the likelihood of starting more than three times. CONCLUSIONS: This study showed that nasotracheal intubation in adult horses could result in immediate mucosal trauma, persistent swelling, and focal scarring of the arytenoid cartilages, but this did not mimic mucosal ulceration or chondritis of the arytenoid cartilages observed in yearling Thoroughbred horses. The population studied, however, may not accurately represent the population in which idiopathic disease occurs. In this study, arytenoid mucosal ulceration detected at sale did not commonly progress to arytenoid chondritis. However, a study of a larger population of horses with untreated, naturally occurring disease is required to confirm these findings. CLINICAL RELEVANCE: It is unlikely that trauma from nasogastric intubation caused arytenoid mucosal ulceration, therefore this procedure should not necessarily be discouraged. This study did not find evidence that horses diagnosed with arytenoid mucosal ulceration at yearling sales had a reduced performance history, therefore it is reasonable to continue to pass horses with uncomplicated arytenoid mucosal ulceration during post-sale endoscopic examination. However, monitoring of the lesions and treatment, if required, may be indicated in the post-sale period.

Animals↗

Intercellular junctions in rabbit eye ora serrata.

Summary The aim of this study was to describe and localize the intercellular junctions in the ora serrata region of albino and pigmented rabbit eyes. Eyes of albino and pigmented rabbits were fixed and processed for transmission electron microscopy. Light and electron microscope examination was carried out on semithin and ultrathin sections. The ora serrata region showed adherens, gap and tight junctions in the retinal and ciliary margins of albino and pigmented rabbit eyes. In the retinal margin, zonulae adherens between Müller cells and photoreceptors are associated with tight junctions. In the ciliary margin, epithelial cells are joined by adherens, gap and tight junctions localized between apical and apicolateral cell membranes. Tight junctions appear as zonulae occludens in the non-pigmented apicolateral cell membranes and as tight focal junctions between pigmented and non-pigmented apical cell membranes. Between the ciliary and retinal margins there are adherens and tight focal junctions which attach pigmented apical cell membranes to adjacent cells. There were no differences in the distribution of intercellular junctions between albino and pigmented rabbits.

Animals↗

Evaluation of environmental sampling and culture to determine Mycobacterium avium subspecies paratuberculosis distribution and herd infection status on US dairy operations.

The objectives of this study were to determine the distribution of Mycobacterium avium subspecies paratuberculosis (MAP) in the environment and assess the relationship between the culture status of MAP in the farm environment and herd infection status. The National Animal Health Monitoring System's Dairy 2002 study surveyed dairy operations in 21 states. One component of the study involved collection and culturing of environmental samples for MAP from areas on farms where manure accumulated from a majority of a herd's cows. Operations were selected for inclusion based on perceived risk factors for MAP infection identified in a previously administered questionnaire. Individual animal and environmental samples were collected and used to determine the efficiency of environmental sampling for determination of herd infection status. Individual animal fecal, serum, and milk samples were used to classify herds as infected or not infected based on the presence of at least one test-positive animal in the herd. A total of 483 environmental samples (approximately 5 per farm) were collected, and 218 (45.1%) were culture-positive for MAP. A similar percentage of environmental cultures collected from all designated areas were positive [parlor exits (52.3%), floors of holding pens (49.1%), common alleyways (48.8%), lagoons (47.4%), manure spreaders (42.3%), and manure pits (41.5%)]. Of the 98 operations tested with the environmental sample culture, 97 had individual serum ELISA results, 60 had individual fecal culture results, and 34 had individual milk ELISA results. Sixty-nine of the 98 operations (70.4%) had at least one environmental sample that was culture-positive. Of the 50 herds classified as infected by fecal culture, 38 (76.0%) were identified by environmental culture. Two of the 10 operations classified as not infected based on individual animal fecal culture were environmental culture-positive. Of the 80 operations classified as infected based on serum ELISA-positive results, 61 (76.3%) were identified as environmental-positive, whereas 20 of the 28 (71.4%) operations identified as infected based on milk ELISA were detected by environmental sampling. Environmental sample culturing is less costly than individual animal sampling, does not require animal restraint, and identified more than 70% of infected operations. Environmental sampling is another diagnostic tool that veterinarians and dairy producers can use to determine herd infection status for MAP.

Animals↗

The FEMA GRAS assessment of hydroxy- and alkoxy-substituted benzyl derivatives used as flavor ingredients.

This publication is the ninth in a series of safety evaluations performed by the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA). In 1993, the Panel initiated a comprehensive program to re-evaluate the safety of more than 1700 GRAS flavoring substances under conditions of intended use. Elements that are fundamental to the safety evaluation of flavor ingredients include exposure, structural analogy, metabolism, pharmacokinetics and toxicology. Flavor ingredients are evaluated individually and in the context of the available scientific information on the group of structurally related substances. Scientific data relevant to the safety evaluation of the use of hydroxy- and alkoxy-substituted benzyl derivatives as flavoring ingredients is evaluated. The group of hydroxy- and alkoxy-benzyl derivatives was reaffirmed as GRAS (GRASr) based, in part, on their self-limiting properties as flavoring substances in food; their rapid absorption, metabolic detoxication, and excretion in humans and other animals; their low level of flavor use; the wide margins of safety between the conservative estimates of intake and the no-observed-adverse effect levels determined from subchronic and chronic studies and the lack of significant genotoxic and mutagenic potential. This evidence of safety is supported by the fact that the intake of hydroxy- and alkoxy-substituted benzyl derivatives as natural components of traditional foods is greater than their intake as intentionally added flavoring substances.

Alcohols↗

The FEMA GRAS assessment of phenethyl alcohol, aldehyde, acid, and related acetals and esters used as flavor ingredients.

This publication is the ninth in a series of safety evaluations performed by the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA). In 1993, the Panel initiated a comprehensive program to re-evaluate the safety of more than 1700 GRAS flavoring substances under conditions of intended use. Elements that are fundamental to the safety evaluation of flavor ingredients include exposure, structural analogy, metabolism, pharmacokinetics and toxicology. Flavor ingredients are evaluated individually and in the context of the available scientific information on the group of structurally related substances. Scientific data relevant to the safety evaluation of the use of phenethyl alcohol, aldehyde, acid, and related acetals and esters as flavoring ingredients is evaluated. The group of phenethylalcohol, aldehyde, acid, and related acetals and esters was reaffirmed as GRAS (GRASr) based, in part, on their self-limiting properties as flavoring substances in food, their rapid absorption, metabolic detoxication, and excretion in humans and other animals, their low level of flavor use, the wide margins of safety between the conservative estimates of intake and the no-observed-adverse effect levels determined from subchronic and chronic studies and the lack of significant genotoxic and mutagenic potential. This evidence of safety is supported by the fact that the intake of phenethyl alcohol, aldehyde, acid, and related acetals and esters as natural components of traditional foods is greater than their intake as intentionally added flavoring substances.

Acetaldehyde↗

The FEMA GRAS assessment of benzyl derivatives used as flavor ingredients.

This publication is the eighth in a series of safety evaluations performed by the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA). In 1993, the panel initiated a comprehensive program to re-evaluate the safety of more than 1700 GRAS flavoring substances under conditions of intended use. Elements that are fundamental to the safety evaluation of flavor ingredients include exposure, structural analogy, metabolism, pharmacokinetics and toxicology. Flavor ingredients are evaluated individually and in the context of the available scientific information on the group of structurally related substances. Scientific data relevant to the safety evaluation of the use of benzyl derivatives as flavoring ingredients is evaluated. The group of benzyl derivatives was reaffirmed as GRAS (GRASr) based, in part, on their self-limiting properties as flavoring substances in food; their rapid absorption, metabolic detoxication, and excretion in humans and other animals, their low level of flavor use, the wide margins of safety between the conservative estimates of intake and the no-observed-adverse effect levels determined from subchronic and chronic studies and the lack of significant genotoxic and mutagenic potential. This evidence of safety is supported by the fact that the intake of benzyl derivatives as natural components of traditional foods is greater than their intake as intentionally added flavoring substances.

Animals↗

A procedure for the safety evaluation of natural flavor complexes used as ingredients in food: essential oils.

A scientifically based guide has been developed to evaluate the safety of naturally occurring mixtures, particularly essential oils, for their intended use as flavor ingredients. The approach relies on the complete chemical characterization of the essential oil and the variability of the composition of the oil in the product intended for commerce. Being products of common plant biochemical pathways, the chemically identified constituents are organized according to a limited number of well-established chemical groups called congeneric groups. The safety of the intake of the each congeneric group from consumption of the essential oil is evaluated in the context of data on absorption, metabolism, and toxicology of members of the congeneric group. The intake of the group of unidentified constituents is evaluated in the context of the consumption of the essential oil as a food, a highly conservative toxicologic threshold, and toxicity data on the essential oil or an essential oil of similar chemotaxonomy. The flexibility of the guide is reflected in the fact that high intake of major congeneric groups of low toxicologic concern will be evaluated along with low intake of minor congeneric groups of significant toxicological concern (i.e., higher structural class). The guide also provides a comprehensive evaluation of all congeneric groups and constituents that account for the majority of the composition of the essential oil. The overall objective of the guide is to organize and prioritize the chemical constituents of an essential oil in order that no reasonably possible significant risk associated with the intake of essential oil goes unevaluated. The guide is, however, not intended to be a rigid checklist. The Flavor and Extract Manufacturers Association (FEMA) Expert Panel will continue to evaluate each essential oil on a case by case basis applying their scientific judgment to insure that each natural flavor complex is exhaustively evaluated.

Animals↗

Ocular toxoplasmosis in mice: comparison of two routes of infection.

This paper aims to test the influence of route of infection (intravitreal and instillation) on the course of ocular toxoplasmosis in mice, using the Toxoplasma gondii Me-49 strain. All mice inoculated intravitreally or by instillation presented the same pattern of infection. Using either route, parasites were observed in the retinal vessel with the formation of a glial reaction in the inner plexiforme layer and discontinuity of the pigmented epithelium of the retina 7 days after infection. However, when the intravitreal route was used a more intense inflammatory infiltrate was observed in the retina. The results suggest that inoculation route remarkably influences the inflammatory pattern in ocular toxoplasmosis and that the instillation route should be preferentially used in experimental infections in the murine ocular model of infection by T. gondii, specially with small animals where there is extensive needle damage, which is not observed in the instillation route.

Animals↗

Evidence for PTZ-like cues as a function of time following treatment with chlordiazepoxide: implications for understanding tolerance and withdrawal.

The present study used a two-lever, drug-discrimination procedure to train rats to discriminate between the cues associated with 5 mg/kg of the anxiolytic, chlordiazepoxide (CDP) and 15 mg/kg of the anxiogenic, pentylenetetrazol (PTZ), to investigate the relationship between withdrawal and acute tolerance. Training doses of the two drugs were chosen so that rats responded about equally on both levers when tested on saline (SAL). Following acquisition of the discrimination, rats were injected with 10 mg/kg CDP and tested for lever choice at various intervals from 6 h to 192 h. These tests revealed that cues associated with CDP withdrawal lasted approximately three times longer than the cues associated with the drug's primary effects. At the shortest retest interval (6 h) after treatment with 10 mg/kg CDP, rats responded primarily on the CDP lever, followed by a shift to predominant responding on the PTZ lever at the 16 h and 24 h intervals before returning to predrug, baseline levels at the longer intervals (48-192 h). In order to investigate the relationship between tolerance and withdrawal to the cue properties of CDP, CDP dose-response curves were determined 24 h following treatment with SAL or 10 mg/kg CDP. Acute tolerance, as defined by a rightward, parallel shift in the dose-response function, was observed in the rats pretreated with CDP. Furthermore, it was evident that the baseline shift associated with CDP withdrawal, rather than a weaker drug cue, accounted for acute tolerance. The results from this study are relevant to evaluating the role positive and negative reinforcement play in motivating compulsive drug use.

Animals↗