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Biomedical subjects

S E Hill

Publications and source records attributed to S E Hill.

At least 19 recordsLinked to original sources
PubMed2001

Effect of tracheotomy tube occlusion on upper esophageal sphincter and pharyngeal pressures in aspirating and nonaspirating patients.

The biomechanics of the pharyngeal swallow in patients with a tracheotomy tube were investigated with manometry. Upper esophageal sphincter (UES) and pharyngeal pressure recordings were made with and without occlusion of the tracheotomy tube. Criteria for selection were ability to tolerate tracheotomy tube occlusion for both 5 minutes prior to and during the first manometric analysis, absence of surgery to the upper aerodigestive tract other than tracheotomy, and no history of oropharyngeal cancer or stroke. Aspiration was determined objectively by fiberoptic endoscopic evaluation of swallowing (FEES) immediately prior to manometric recording. Eleven adult individuals with tracheotomy participated; 7 swallowed successfully and 4 exhibited aspiration on FEES. The results indicated no significant effect of tracheotomy tube occlusion on UES or pharngeal pressures in either aspirating or nonaspirating patients. It was concluded that the biomechanics of the swallow as determined by UES and pharyngeal manometric pressure measurements were not changed significantly by tracheotomy tube occlusion in aspirating or nonaspirating patients. These results support previous observations that subjects either aspirated or swallowed successfully regardless of tracheotomy tube occlusion status.

Adult↗
PubMed2001

Oxygen therapeutics--current concepts.

PURPOSE: In an effort to develop agents that enhance the oxygen-delivery capability of blood without the risks associated with allogeneic blood transfusions, several products are undergoing development and clinical trials. These oxygen transport agents can be divided into two main groups, perfluorocarbon (PFC) emulsions and modified hemoglobin solutions. SOURCE: Articles from the literature on the development and clinical trials of oxygen therapeutic agents were reviewed. PRINCIPAL FINDING: PFCs are synthetic fluorinated hydrocarbons that increase dissolved oxygen in the fluid phase of the blood without binding the oxygen molecule. They enhance oxygen delivery significantly and may be used to augment the technique of intraoperative autologous donation. Two PFC products have been tested in Phase III clinical trials. Hemoglobin-based oxygen carriers (HBOCs) are either cross-linked or microencapsulated hemoglobin molecules. Modification of the human hemoglobin molecule with intra- and inter-molecular cross-linking eliminates renal toxicity and improves the oxygen dissociation characteristics of the molecule. These modifications are necessary because stroma-free hemoglobin (Hb) does not release oxygen in the physiologic range and dissociates into dimers which can be rapidly filtered by the kidney, leading to renal toxicity. In addition to human Hb, bovine hemoglobin is another source of raw material for HBOC products. Recombinant human Hb has also been produced, using an E. coli expression system, for HBOC manufacturing. Four cross-linked hemoglobin products have been tested in Phase III clinical trials. CONCLUSION: While no product has yet been approved for clinical use, preliminary studies with oxygen therapeutics show promising results, with effective oxygen carrying capacity and acceptable side effect profiles. In the future, the formation of a hybrid product which combines the best features from several of the products currently undergoing development may yield the ideal oxygen therapeutic agent.

Aspirin↗
PubMed2000

Maillard reaction causes suppression of virulence gene expression in Listeria monocytogenes.

Many environmental signals affect the expression of virulence genes of the food borne pathogen Listeria monocytogenes. In addition media composition has been shown to suppress levels of haemolytic activity. Using a Pr(plcA)::luxAB reporter gene fusion it was observed that the heat processing of media also reduces the level of virulence gene expression in L. monocytogenes without affecting its growth. Physicochemical factors that are considered to enhance the Maillard reaction were also found to increase the levels of suppression. The results indicate that heat treatment of a multicomponent matrix gives rise to specific inhibitors of the Listeria virulence gene operon.

Food Microbiology↗
PubMed2000

Intraoperative physiologic variables and outcome in cardiac surgery: Part I. In-hospital mortality.

BACKGROUND: Risk stratification schemes have been developed to predict outcome of coronary artery bypass grafting (CABG) procedures, which are predominately based upon unalterable preoperative patient characteristics. The purpose of this study was to determine if minimum intraoperative hematocrit, maximum glucose concentration, mean arterial pressure on cardiopulmonary bypass, or duration of bypass influence risk-adjusted in-hospital mortality after CABG. METHODS: Outcome data from 2,862 CABG patients were merged with intraoperative physiologic data. A preoperative mortality risk index was calculated for each patient. Variables found significant (p<0.05) by univariate logistic regression were tested in a multiple variable model to determine risk-adjusted association with mortality. RESULTS: Overall mortality rate was 1.85%. The preoperative risk index was significantly associated with mortality (p = 0.0001). No significant association was present between mortality and intraoperative variables. Preexisting hypertension was an independent predictor of mortality after controlling for risk index and bypass duration. CONCLUSIONS: Preexisting hypertension proved to be an independent predictor of mortality in our patient population. This study found no evidence to support the hypothesis that mean arterial pressure less than 50 mm Hg, lower hematocrit, or elevated glucose while on bypass increases in-hospital mortality.

Aged↗
PubMed2000

Intraoperative physiologic variables and outcome in cardiac surgery: Part II. Neurologic outcome.

BACKGROUND: The impact of alterable physiologic variables on neurologic outcome after coronary artery bypass grafting procedures is unknown. The purpose of this study was to determine whether minimum intraoperative hematocrit, maximum glucose concentration, or mean arterial pressure during cardiopulmonary bypass influences risk-adjusted neurologic outcome after coronary artery bypass grafting. METHODS: Outcome data from 2,862 patients undergoing coronary artery bypass grafting were merged with intraoperative physiologic data. A preoperative stroke risk index was calculated for each patient. Variables found significant by univariate logistic regression were tested in a multivariable model to determine association with outcome. RESULTS: The incidence of stroke or coma in the study population was 1.3%. After controlling for stroke risk and bypass time, only an index of low mean arterial pressure during bypass retained a significant inverse association with outcome (p = 0.0304). CONCLUSIONS: This study found no evidence that glucose concentration or minimum hematocrit are associated with major adverse neurologic outcome. The association between lower pressure during bypass and decreased incidence of stroke or coma persisted in all risk groups. This points to mechanisms other than hypoperfusion as the primary cause of neurologic injury associated with cardiac surgery.

Aged↗
PubMed1999

Molecular flexibility profiling using NMR spectroscopy.

Molecular flexibility is a factor that is not extensively studied in most pharmaceutical research efforts. When it is, the level of effort is high involving the preparation of detailed models supported by either molecular dynamics simulations and/or Nuclear Magnetic Resonance data. While these studies are both powerful and illuminating, they cannot be routinely applied in a drug discovery setting as they are time and expertise intensive. Yet there seems to be little doubt that at least in some cases, molecular flexibility plays a key role in complex formation. A simple, rapid and generally applicable flexibility profiling protocol was applied to two model systems and data describing the internal mobility of carbon atoms were obtained. The protocol utilizes the Model Free approach and NMR data to characterize the internal molecular dynamics of these compounds. The first model system consisted of fluorene and diphenylmethane where the anticipated flexibility trends were observed in the data providing a link between chemical intuition and the experimental results. Data on a second model system, which consisted of two Paclitaxel analogs, showed predictable patterns including dynamical phenyl and methyl groups and a relatively immobile taxane core. Subtle differences in the internal dynamics within the taxane core suggest that it cannot be considered as a rigid structure. Key advantages of using this approach are that no prior knowledge or supposition of dynamical features is required, the protocol can be carried out in most medicinal chemistry laboratories and the data obtained provide a common, empirically derived reference point to discuss the effects of molecular flexibility on activity.

Benzhydryl Compounds↗
PubMed1998

Cellular uptake profile of paclitaxel using liquid chromatography tandem mass spectrometry.

A new method for studying cellular uptake has been developed. This method is based on selected reaction monitoring liquid chromatography tandem mass spectrometry analysis of preparations from cell culture. The limit of detection for paclitaxel was approximately 0.1 microM intracellular concentration. This method has been utilized to study the uptake of paclitaxel and an analog (BMS-190616) in normal and multidrug resistant (MDR) cell lines. Paclitaxel and the analog, that had been noted to overcome MDR in animal models, were incubated with normal cells (HCT116) and MDR cells (HCT116(VM)46) at therapeutic concentrations. Intracellular drug concentrations were assayed at intervals from 0 to 1.0 h. Results show that paclitaxel accumulates to a level 12 times greater and BMS-190616 to a level 5 times greater in the normal cells as compared to MDR cells suggesting that paclitaxel is more sensitive to MDR than the analog. Furthermore, the steady state level of BMS-190616 was 4 fold greater than paclitaxel in the MDR cell line suggesting that at least part of this compound's increased therapeutic effect can be attributed to processes of uptake and efflux at the cellular level. These data show that the method is rapid, sensitive and presents a unique advantage over traditional radioisotopic methods in that it can readily be employed on a range of analogs without any additional synthetic effort.

Antineoplastic Agents, Phytogenic↗
PubMed1997

Profiling degradants of paclitaxel using liquid chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry substructural techniques.

A rapid and systematic strategy based on liquid chromatography-mass spectrometry (LC-MS) profiling and liquid chromatography-tandem mass spectrometry (LC-MS-MS) substructural techniques was utilized to elucidate the degradation products of paclitaxel, the active ingredient in Taxol. This strategy integrates, in a single instrumental approach, analytical HPLC, UV detection, full-scan electrospray MS, and MS-MS to rapidly and accurately elucidate structures of impurities and degradants. In these studies, degradants induced by acid, base, peroxide, and light were profiled using LC-MS and LC-MS-MS methodologies resulting in an LC-MS degradant database which includes information on molecular structures, chromatographic behavior, molecular mass, and MS-MS substructural information. The stressing conditions which may cause drug degradation are utilized to validate the analytical monitoring methods and serve as predictive tools for future formulation and packaging studies. Degradation products formed upon exposure to basic conditions included baccatin III, paclitaxel sidechain methyl ester, 10-deacetylpaclitaxel, and 7-epipaclitaxel. Degradation products formed upon exposure to acidic conditions included 10-deacetylpaclitaxel and the oxetane ring opened product. Treatment with hydrogen peroxide produced only 10-deacetylpaclitaxel. Exposure to high intensity ligh produced a number of degradants. The most abundant photodegradant of paclitaxel corresponded to an isomer which contains a C3-C11 bridge. These methodologies are applicable at any stage of the drug product cycle from discovery through development. This library of paclitaxel degradants provides a foundation for future development work regarding product monitoring, as well as use as a diagnostic tool for new degradation products.

Antineoplastic Agents, Phytogenic↗
PubMed1996

Maillard induced complexes of bovine serum albumin--a dilute solution study.

Association of bovine serum albumin (BSA) on heating in the presence and absence of 2% xylose has been studied using dynamic light scattering and sedimentation velocity. When 3% solutions of the protein alone are heated at 95 degrees C association products are formed with molar masses of approximately 2 x 10(6) g/mol, a value which is independent of the time of heating. These aggregates can be dissociated in solvents that disrupt non-covalent bonds. When the reducing sugar xylose is present there is a continuous change in the hydrodynamic properties with time. After 80 min a molar mass in excess of 7 x 10(6) g/mol is obtained. This increase in molar mass is attributed to additional non-disulphide linkages resulting from the Maillard reaction. Information about the gross conformation of the Maillard induced association products has been obtained from MHKS (Mark-Houwink-Kuhn-Sakarada) double logarithmic plots of D20,w and S20,w against molar mass. The values of the MHKS coefficients obtained are most consistent with a linear rod: i.e. the association is of an end-to-end type.

Animals↗
PubMed1996

Himastatin, a new antitumor antibiotic from Streptomyces hygroscopicus. III. Structural elucidation.

The structure of the antitumor antibiotic himastatin was determined using a combination of spectroscopic and chemical degradation techniques. Himastatin is a unique dimeric cyclohexadepsipeptide joined through a biphenyl linkage between two oxidized tryptophan units. The gross structure of the dimer was established through degradative ozonolysis. Himastatin consists of D-valine, D-threonine, L-leucine, L-alpha-hydroxyisovaleric acid, (3R,5R)-5-hydroxypiperazic acid, and (2R,3aR,8aR)-3a-hydroxyhexahydropyrrolo[2,3b]indole 2-carboxylic acid subunits.

Amino Acid Sequence↗
PubMed1995

Differential scanning calorimetry of lupin and soy proteins.

Differential scanning calorimetry (DSC) was used to study the 7S and 11S globulin fractions extracted from lupin seed (Lupinus luteus) flour. In agreement with previous work on other lupin species, the isolate showed three denaturation peaks compared to the two observed with soy. By comparison with the isolated globulin fractions, the denaturation peaks at the two higher temperatures in the lupin isolate were assigned to the 11S and 7S globulins. The denaturation temperature of the lupin 7S globulin was about 10 K higher than that for the corresponding soy globulin, whereas the values for the 11S globulin were similar. All globulins displayed increasing thermal stability with decreasing moisture contents. Possible reasons for the differences in behaviour of soy and lupin protein isolates are discussed.

Calorimetry, Differential Scanning↗
PubMed1994

Profiling taxanes in Taxus extracts using lc/ms and lc/ms/ms techniques.

Analytical methodology developed for the trace analysis of natural products in crude extracts was utilized for the rapid and systematic structure elucidation of taxanes in Taxus extracts and process intermediates. This method integrates analytical hplc, uv detection, uv spectroscopy, full-scan ionspray mass spectrometry and tandem mass spectrometry on-line. The identification of structure of a taxane is based on comparing the mass spectrometric characteristics of the taxane with the paclitaxel substructural "template." Analytical data for taxanes in preparations from Taxus brevifolia and Taxus baccata were observed, including chromatographic characteristics using a standard hplc system, molecular weight, and collision induced dissociation (cid) tandem mass spectrometry (ms/ms) product ion spectra. The data obtained for 18 taxanes from natural sources using this method provided a taxane profile database useful for the rapid identification of taxanes in mixtures and samples of limited quantity.

Bridged Bicyclo Compounds↗
PubMed1992

Signal transduction in murine B16 melanoma cells.

The relationship between lung colonization and signal transduction was investigated for six B16 melanoma variants. A range of experimental metastatic potential (as determined by lung colonization), forskolin-stimulated cyclic AMP accumulation and FCS-stimulated protein kinase C activity was found. The major findings were that: (1) cells with the highest agonist-stimulated cyclic AMP production were those with the highest level of membrane-associated protein kinase C activity; (2) clones which differed in protein kinase C levels and distribution did so in the presence but not in the absence of foetal calf serum; and (3) no simple relationship was seen between either signal transduction system and lung colonization for all six variants. Altered ras expression was also excluded as an explanation for the differences in signal transduction and lung colonization potential which were observed. We conclude that differences in signal transduction in vitro between these cells do not relate simply to lung colonization potential in vivo.

Animals↗
PubMed1991

Evidence for a calcium/calmodulin involvement in density-dependent melanogenesis in murine B16 melanoma cells.

Previous work from our laboratory has shown that both cyclic AMP and calcium/calmodulin appear to be involved in the regulation of melanogenesis in murine B16 melanoma cells. In these cells as in murine Cloudman S91 cells, melanogenic responsiveness to melanocyte-stimulating hormone (MSH) varies with cell density in culture. Our objective in this study was to learn more about the intracellular systems involved in the control of melanogenesis, particularly the role played by calcium. The melanogenic response to alpha MSH was compared to the response to drugs affecting intracellular free calcium and calmodulin over a range of cell densities in B16F1 cells. alpha MSH-stimulated melanin production was extremely density-dependent but alpha MSH-stimulated cyclic AMP production was independent of cell density. The melanogenic response to agents that increased intracellular calcium (A23187) or inhibited intracellular calmodulin varied with cell density. A drug (TMB8) that lowered intracellular free calcium, however, increased melanogenesis independently of cell density. At high cell density it was found that an elevation in calcium decreased melanogenesis, whereas agents that reduced calcium or inhibited calmodulin activity increased melanogenesis. At low cell density, however, the inhibitory response to A23187 was lost and in some experiments even stimulated melanogenesis. These data suggest that the calcium/calmodulin signalling system has an inhibitory influence on melanogenesis, and its expression, which depends upon cell density, may also modulate the response to stimulatory agents such as alpha MSH.

Animals↗
PubMed1989

I alpha-25-dihydroxyvitamin D3 increases intracellular free calcium in murine B16 melanoma.

Vitamin D3 and its active metabolite I alpha-25-dihydroxyvitamin D3 (I alpha-25-(OH)2D3) have been reported to play a role in melanogenesis. Physiological concentrations of I alpha-25-(OH)2D3 were found to acutely elevate intracellular free calcium (using Fura 2) in B16 primary (Io) cells. Membrane phosphoinositide turnover was unaffected by I alpha-25-(OH)2D3. The rise in intracellular free calcium was entirely dependent on extracellular calcium and was not mimicked by vitamin D3. However, in neither B16-Io nor B16-F1 melanoma cells did vitamin D3 or I alpha-25-(OH)2D3 increase melanin production.

Animals↗