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Robert L Smith

Publications and source records attributed to Robert L Smith.

31 records · Page 2Linked to original sources
PubMed2004

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

This publication is the seventh 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 cinnamyl derivatives as flavoring ingredients is evaluated.

Acrolein↗
PubMed2004

Chromogenic derivatives of AHTN (6-acetyl-1,1,2,4,4,7-hexamethyltetralin) react with amino acids and protein in vitro. Spectral characteristics of the colour products.

Three chromogenic products of AHTN have been detected after photo-oxidation and shown to react with glycine or albumin, giving rise first to a blue color, followed by pink and, finally, a dark green colour. The absorption spectrum associated with the late green colour showed an increased absorbance in the long wavelength region of the spectrum, similar to the green colour extracted from the liver of AHTN-treated animals. The colour produced by the chromogenic derivatives of AHTN and by o-diacetylbenzene (a model chromogenic compound) were tightly bound to the protein pellet and resistant to acidic pH, unlike the colour from the ninhydrin reaction. The dark green colour produced in the liver by feeding AHTN to rats was also tightly bound to proteins and stable to acidic pH. These results suggest that both the photo-oxidized chromogenic derivatives of AHTN and o-diacetylbenzene, produce coloured derivatives with amino acids and proteins by a mechanism unrelated to ninhydrin. They also suggest that a chromogenic derivative of AHTN, produced in vivo during prolonged treatment with high doses of AHTN, may be responsible for the green colour of the livers and other tissues from treated animals. The data suggest that the AHTN-derived chromogenic material is metabolite-related rather than representative of a toxic process, although further work is necessary to confirm this hypothesis.

Amino Acids↗
PubMed2004

Evaluation of the oral subchronic toxicity of AHTN (7-Acetyl-1,1,3,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthalene) in the rat.

7-Acetyl-1,1,3,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthalene (AHTN) is used as a fragrance material in a wide variety of consumer products. Because of its widespread exposure, a 90-day oral feeding study, with 4-week recovery periods for selected rats, was conducted. AHTN was added to the diet of rats at levels calculated to result in mean daily doses of 1.5, 5, 15 or 50 mg AHTN/kg body weight/day. On completion of the treatment period, 3 males and 3 females from each of the high dose groups and controls were maintained for a treatment free period of 4 weeks. There were no adverse effects revealed upon clinical examination or following extensive histopathological examinations. Histopathological examination of the prostate, seminal vesicles, mammary gland and testes of males and ovaries, mammary gland, uterus and vagina of females, undertaken on all animals in all test groups, revealed no evidence of hormonal effects of AHTN. A statistically significant decrease in body weight gain was observed in both sexes in the high dose group only. Statistically significant effects were observed in hematology and blood chemistry, although these effects were all within the range for historical controls and were not proportional to dose. A green to dark brown coloration in the livers and mesenteric lymph nodes was also seen in high dose animals. At the end of the treatment-free period, the color change was almost completely reversed; one high dose male still had green colored lymph nodes, but the liver appeared normal. A green coloration of the lacrimal glands in females, but not males, was also seen in 8/12, 4/15 and in 1 female given 50, 15 and 5 mg/kg body weight/day, respectively. This green color was still present in 2/3 of the high dose females after the treatment-free period. Microscopic examination of unstained sections of frozen livers under UV illumination did not reveal any fluorescence that might have been consistent with porphyrin accumulation. These findings were clearly related to administration of AHTN, but were not accompanied by any histopathological changes. In discolored livers, all fractions of liver homogenate were abnormally colored; the change was most prominent in the mitochondria. Some dissolved pigment was obtained by extraction of liver homogenates with DMSO/trichloroacetic acid mixtures, but its identity remains to be established. Further work on the mechanism of production of the abnormal color is in progress. Based on these results, the 90-day conservative no-observed-effect level (NOAEL) is 1.5 mg/kg body weight/day.

Administration, Oral↗
PubMed2004

The evolution of ischemic spinal cord injury in function, cytoarchitecture, and inflammation and the effects of adenosine A2A receptor activation.

OBJECTIVE: Spinal cord ischemia/reperfusion injury involves multiple factors that may be modulated by adenosine A 2A receptor activation. This study defines injury progression in terms of function, cytoarchitecture, and inflammation and assesses whether adenosine A 2A receptor activation by ATL-146e limits injury progression. METHODS: Mature swine were divided into 3 groups: sham thoracotomy, IR (30 minutes of ischemia followed by reperfusion), and ATL (ischemia/reperfusion with ATL-146e administration for the first 3 hours of reperfusion). Subgroups were killed at 0, 3, 6, 12, 24, and 48 hours after reperfusion. Function was followed up with Tarlov scores. Spinal cord tissue was evaluated for neuronal viability, microtubule-associated protein-2 immunohistochemistry, and neutrophil sequestration (myeloperoxidase assay). Spinal cord tissue, cerebrospinal fluid, and serum were evaluated for tumor necrosis factor-alpha by enzyme-linked immunosorbent assay. RESULTS: Function was significantly impaired at 24, 36, and 48 hours in the IR group compared with the sham and ATL groups ( P < .05). Neuronal viability and microtubule-associated protein-2 staining were significantly preserved in the sham and ATL groups compared with the IR group at 24 and 48 hours ( P < .05). Spinal cord myeloperoxidase levels were significantly higher in the IR group than in the sham and ATL groups at 24 and 48 hours. Although negligible in serum and cerebrospinal fluid, tumor necrosis factor-alpha levels in the spinal cord peaked significantly higher in the IR group compared with the sham and ATL groups at 6 and 24 hours ( P < .05). CONCLUSIONS: Spinal cord ischemia/reperfusion induced changes in neutrophil sequestration, microtubule-associated protein-2 expression, and neuronal viability within 24 hours of reperfusion. Spinal cord tumor necrosis factor-alpha increased significantly by 6 to 12 hours after reperfusion. Adenosine A 2A receptor activation attenuates spinal cord inflammation, which may be critical for the preservation of neuronal function and cytoarchitecture after ischemia/reperfusion.

Animals↗
PubMed2004

Impact of immunomodulatory oligodeoxynucleotides on cytokine production in the lipopolysaccharide-stimulated human whole blood model.

BACKGROUND: In studying potential immunotherapeutics for sepsis, we used a lipopolysaccharide (LPS)-stimulated whole blood model to test the immunomodulating capacity of cytosine-phospho-guanine oligodeoxynucleotides (CpG ODNs). We hypothesized that CpG ODNs would have considerable counterinflammatory effects on LPS-induced cytokine production. METHODS: We administered 4 micromol/L of CpG ODNs (2216, D19, 2006, K3, or 1668) or guanine-phospho-cytosine (GpC) ODNs (control D or control K) immediately after LPS (10 ng/mL) stimulation of heparinized human whole blood. Samples were incubated for 1, 3, 6, 12, and 24 hours. Media and LPS were used as negative and positive controls. Cell-free supernatants were obtained and evaluated for interferon gamma (IFN-gamma), interleukin (IL)-12(p40), tumor necrosis factor alpha, IL-6, IL-10, IFN-alpha, IL-8, and IL-1beta by ELISA. RESULTS: Compared to LPS alone, significantly reduced levels of IFN-gamma, IL-12(p40), tumor necrosis factor alpha, and IL-6 were associated with both CpG and GpC ODNs administration to LPS-stimulated whole blood. IL-10 levels were concomitantly increased. However, IFN-alpha generation was CpG specific as was increased IL-8 levels. Lastly, only 2216 was associated with decreased IL-1beta levels. CONCLUSIONS: CpG ODNs and GpC ODNs in the LPS-stimulated whole blood model demonstrate differential counterinflammatory effects, but only CpG ODNs were associated with proinflammatory cytokine production. With further examination, we may find that these observed immunomodulatory differences could potentially be exploited for therapeutic benefit.

Adjuvants, Immunologic↗
PubMed2004

Effect of an intensive care unit rotating empiric antibiotic schedule on the development of hospital-acquired infections on the non-intensive care unit ward.

OBJECTIVE: We have previously shown that a rotating empirical antibiotic schedule could reduce infectious mortality in an intensive care unit (ICU). We hypothesized that this intervention would decrease infectious complications in the non-ICU ward to which these patients were transferred. DESIGN: Prospective cohort study. SETTING: An ICU and the ward to which the ICU patients were transferred at a university medical center. PATIENTS: All patients treated on the general, transplant, or trauma surgery services who developed hospital-acquired infection while on the non-ICU wards. INTERVENTIONS: A 2-yr study consisting of 1-yr non-protocol-driven antibiotic use and 1-yr quarterly rotating empirical antibiotic assignment for patients treated in the ICU from which a portion of the patients were transferred. MEASUREMENTS AND MAIN RESULTS: There were 2,088 admissions to the non-ICU wards during the nonrotation year and 2,183 during the ICU rotation year. Of these patients, 407 hospital-acquired infections were treated during the nonrotation year and 213 were treated during the ICU rotation (19.7 vs. 9.8 infections/100 admissions, p <.0001). During the ICU rotation year a decrease in the rate of resistant Gram-positive and resistant Gram-negative infections on the non-ICU wards occurred (2.5 vs. 1.6 infections/100 admissions, p =.04; 1.0 vs. 0.4 infections/100 admissions, p =.03). Subgroup analysis revealed that the decrease in resistant infections on the wards was due to a reduction in resistant Gram-positive and resistant Gram-negative infections among non-ICU ward patients admitted initially from areas other than the ICU implementing the antibiotic rotation (e.g., home, other ward, or a different ICU) (1.8 vs. 0.5 infections/100 admissions, p =.0001; 0.7 vs. 0.2 infections/100 admissions, p =.02), not due to differences for those transferred to the ward from the rotation ICU (10.4 vs. 9.7 infections/100 admissions, p = 1.0; 4.3 vs. 1.9 infections/100 admissions, p =.3). No differences in infection-related mortality were detected. CONCLUSIONS: An effective rotating empirical antibiotic schedule in an ICU is associated with a reduction in infectious morbidity (hospital-acquired and resistant hospital-acquired infection rates) on the non-ICU wards to which patients are transferred.

Anti-Bacterial Agents↗
PubMed2004

Wound infection after elective colorectal resection.

INTRODUCTION: Surgical site infection (SSI) is a potentially morbid and costly complication following major colorectal resection. In recent years, there has been growing attention placed on the accurate identification and monitoring of such surgical complications and their costs, measured in terms of increased morbidity to patients and increased financial costs to society. We hypothesize that incisional SSIs following elective colorectal resection are more frequent than is generally reported in the literature, that they can be predicated by measurable perioperative factors, and that they carry substantial morbidity and cost. METHODS: Over a 2-year period at a university hospital, data on all elective colorectal resections performed by a single surgeon were retrospectively collected. The outcome of interest was a diagnosis of incisional SSI as defined by the Center of Disease Control and Prevention. Variables associated with infection, as identified in the literature or by experts, were collected and analyzed for their association with incisional SSI development in this patient cohort. Multivariate analysis by stepwise logistic regression was then performed on those variables associated with incisional SSI by univariate analysis to determine their prognostic significance. The incidence of SSI in this study was compared with the rates of incisional SSI in this patient population reported in the literature, predicted by a nationally based system monitoring nosocomial infection, and described in a prospectively acquired intradepartmental surgical infection data base at our institution. RESULTS: One hundred seventy-six patients undergoing elective colorectal resection were identified for evaluation. The mean patient age was 62 +/- 1.2 years, and 54% were men. Preoperative diagnoses included colorectal cancer (57%), inflammatory bowel disease (20%), diverticulitis (10%), and benign polyp disease (5%). SSIs were identified in 45 patients (26%). Twenty-two (49%) SSIs were detected in the outpatient setting following discharge. Of all preoperative and perioperative variables measured, increasing patient body mass index and intraoperative hypotension independently predicted incisional SSI. Although we could not measure statistically increased length of hospital stay associated with SSI, a representative population of patients with SSI accumulated a mean of $6200/patient of home health expenses related to wound care. Our rates of SSI were substantially higher than that reported generally in the literature, predicted by the National Nosocomial Infection System, or described by our own institutional surgical infection data base. CONCLUSIONS: The incidence of incisional SSI in patients undergoing elective colorectal resection in our cohort was substantially higher than generally reported in the literature, the NNIS or predicted by an institutional surgical infection complication registry. Although some of these differences may be attributable to patient population differences, we believe these discrepancies highlight the potential limitations of systematic outcomes measurement tools which are independent of the primary clinical care team. Accurate surgical complication documentation by the primary clinical team is critical to identify the true frequency and etiology of surgical complications such as incisional SSI, to rationally approach their reduction and decrease their associated costs to patients and the health care system.

Aged↗
PubMed2003

The safety assessment of fragrance materials.

Safety evaluation of the large number of diverse chemicals used as fragrance ingredients follows a systematic prioritization of data generation and analysis, consideration of exposure and critical analysis of the quality of the available information. In prior publications the research priorities used by the Research Institute for Fragrance Materials (RIFM), and the methods of exposure estimation used by industry have been summarized. This paper provides details of the approach used by the RIFM Expert Panel (REXPAN), to examine the dermal effects, systemic toxicity and environmental consequences of the use of and exposure to fragrance materials, which allow a reliable determination of safe use under intended conditions. The key to the usefulness of this analysis is the grouping of more than 2600 discrete ingredients into classes, based on chemical structures. Research sponsored by RIFM, data supplied by member companies, and relevant published reports from many sources are all considered during hazard characterization. A discussion is provided of REXPAN's decision tree approach to assessing the dermal, systemic and environmental endpoints and the types and quality of data included. This overall process results in well-documented conclusions which are provided to the International Fragrance Association (IFRA) as the basis for consideration of a new or existing Fragrance Material Standard and to industry for appropriate product risk management actions.

Consumer Product Safety↗
PubMed2003

Contact isolation in surgical patients: a barrier to care?

BACKGROUND: Contact isolation is commonly used to prevent transmission of resistant organisms. We hypothesized that contact isolation negatively impacts the amount of direct patient care. METHODS: For 2 hours per day over a 5-week period, a single observer recorded provider/patient contact in adjacent isolated and nonisolated patient rooms on both the surgical intensive care unit (ICU) and surgical wards of a university hospital. Number of visits, contact time, and compliance with isolation were recorded, as was illness severity as assessed by APACHE II score. RESULTS: Isolated patients were visited fewer times than nonisolated patients (5.3 vs 10.9 visits/h, P <.0001) and had less contact time overall (29 +/- 5 vs 37 +/- 3 min/h, P =.008), in the ICU (41 +/- 10 vs 47 +/- 5 min/h, P =.03), and on the floor (17 +/- 3 vs 28 +/- 4 min/h, P =.039), in spite of higher mean APACHE II scores in the isolated (10.1 +/- 1.0 vs 7.6 +/- 0.8, P =.05). Among floor patients with APACHE II scores greater than 10, patients in the isolated group had nearly 40% less contact time per hour than patients in the nonisolated group (19 +/- 4 vs 34 +/- 7 min/h, P =.05). CONCLUSIONS: Because of the significantly lower contact time observed, particularly among the most severely ill of floor patients, we propose a reexamination of the risk-benefit ratio of this infection control method.

Adult↗
PubMed2003

Does prior transfusion worsen outcomes from infection in surgical patients?

BACKGROUND: Controversy continues to exist regarding the immunomodulatory effects of cellular blood transfusions in the fields of oncology, transplantation, and infectious diseases. Numerous studies have correlated transfusion with hospital-acquired infection, but the impact of transfusion on infection-related mortality has not been addressed. The objective of this study was to determine the effect of transfusion on outcomes among infected surgical patients. METHODS: Data on all hospital-acquired infectious episodes among surgical intensive care unit and ward patients were collected prospectively over 39 months at a single university hospital. The relationships between prior transfusion (defined as the receipt of allogeneic red blood cells or platelets during the index hospitalization but prior to the development of infection) and over 100 variables were examined using univariate and multiple logistic regression analysis, with inclusion of a propensity score for prior transfusion to attempt to account for treatment selection bias. RESULTS: During the study period, 1,228 infectious episodes occurred; 641 were associated with the transfusion of packed red blood cells or platelets. Univariate analysis revealed that patients with those infectious episodes following transfusion had higher Acute Physiology and Chronic Health Evaluation II (APACHE II) scores (18.3 +/- 0.3 vs. 10.9 +/- 0.3, p < 0.0001) and higher mortality (26.0% vs. 8.9%, p < 0.0001). Those patients who died received a greater number of transfusions prior to infection than those who lived (7.7 +/- 0.8 vs. 4.5 +/- 0.3, p = 0.0002). Multiple logistic regression analysis revealed that the propensity score for prior transfusion independently predicted mortality (odds ratio 9.45, 95% confidence interval 3.71-24.09, p < 0.001), but that neither the presence or absence of transfusion (OR 0.89, 95% CI 0.54-1.46, p = 0.6) nor the absolute number of units of red blood cells or platelets transfused (OR for red blood cells 1.00, 95% CI 0.98-1.02, p = 0.7; OR for platelets 0.97, 95% CI 0.90-1.05, p = 0.5) independently predicted mortality. CONCLUSIONS: The transfusion of packed red blood cells or platelets prior to infection is associated with more severe disease among surgical patients, but once corrected for treatment selection bias does not appear to worsen outcomes from infection.

Anti-Bacterial Agents↗
PubMed2003

Biochemical and clinical aspects of the human flavin-containing monooxygenase form 3 (FMO3) related to trimethylaminuria.

Trimethylaminuria is a rare metabolic disorder that is associated with abnormal amounts of the dietary-derived trimethylamine. Excess unmetabolized trimethylamine in the urine, sweat and other body secretions confers a strong, foul body odor that can affect the individual's ability to work or engage in social activities. This review summarizes the biochemical aspects of the condition and the classification of the disorder into: 1) primary genetic form, 2) acquired form, 3) childhood forms, 4) transient form associated with menstruation, 5) precursor overload and 6) disease states. The genetic variability of the flavin-containing monooxygenase (form 3) that is responsible for detoxication and deodoration of trimethylamine is discussed and put in context with other variant forms of the flavin-containing monooxygenase (forms 1-5). The temporal-selective expression of flavin-containing monooxygenase forms 1 and 3 is discussed in terms of an explanation for childhood trimethylaminuria. Information as to whether variants of the flavin-containing monooxygenase form 3 contributes to hypertension and/or other diseases are presented. Discussion is provided outlining recent bioanalytical approaches to quantify urinary trimethylamine and trimethylamine N-oxide and plasma choline as well as data on self-reporting individuals tested for trimethylaminuria. Finally, trimethylaminuria treatment strategies and nutritional support are described including dietary sources of trimethylamine, vitamin supplementation and drug treatment and issues related to trimethylaminuria in pregnancy and lactation are discussed. The remarkable progress in the biochemical, genetic, clinical basis for understanding the trimethylaminuria condition is summarized and points to needs in the treatment of individuals suffering from trimethylaminuria.

Animals↗
PubMedDate not supplied

Candida albicans and Saccharomyces cerevisiae expressing ALA1/ALS5 adhere to accessible threonine, serine, or alanine patches.

Saccharomyces cerevisiae transformed with Candida albicans ALA1/ALS5 exhibits adherence properties similar to C. albicans. Adherence of the fungi to immobilized proteins involves hydrogen bonds, is stable to shear forces, and is resistant to competition from various biological molecules. The specificity determinants of target recognition in Ala1/Als5p-mediated adherence are not known. To determine features of target recognition, proteins and small peptides were covalently coupled at the N-terminus to the surface of carboxylate-modified magnetic beads. C. albicans yeast cells, germ tubes and pseudohyphae and S. cerevisiae expressing the adhesin, Ala1/Als5p, adhered to beads coated with fibronectin, laminin, type IV collagen, bovine serum albumin, and casein. No adherence to beads was observed if a single amino acid was coupled to the beads. However, 10-mer homopolymers of threonine, serine, and alanine served as ligands for adherence. The presence of a minimum of four contiguous threonine residues in a peptide was required for maximal adherence. Coupling of 10-mer peptides from fibronectin and Ala1/Als5p each possessing 5-7 threonine or serine residues also initiated adherence. On the other hand, a collagen and a fibronectin 10-mer peptide with few threonine and serine residues and lysine at the C-terminus did not serve as adherence ligands. Both of them are converted to adherence ligands by adding threonine or serine residues at the C-terminus or removing the lysine residue and adding threonine residues anywhere in the peptide. The presence of lysine at the C-terminus may have resulted in coupling of the peptides at both the N- and C-termini, thus making the threonine residues inaccessible for adherence. Thus, Ala1/Als5p recognizes patches of certain amino acids, which must be accessible before adherence will occur.

Alanine↗