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Biomedical subjects

K M Smith

Publications and source records attributed to K M Smith.

At least 73 records · Page 4Linked to original sources
PubMed1997

Lower respiratory rates without decreases in oxygen consumption during neonatal synchronized intermittent mandatory ventilation.

OBJECTIVE: We tested the hypothesis that synchronization to patient effort during intermittent mandatory ventilation (SIMV), when compared to conventional unsynchronized intermittent mandatory ventilation (IMV), will decrease energy expenditure, as reflected by decreased oxygen consumption (VO2). DESIGN: We used a four-period crossover design. Each patient was studied over four 30-min continuous time intervals. Patients were randomized to receive initially IMV or SIMV, then crossed over such that each patient was treated twice with each modality. Data were analyzed using an analysis of variance technique. SETTING: Patients were receiving treatment in the newborn intensive care unit of Children's Hospital, St. Paul. PATIENTS: We studied 17 patients, who ranged from 23 to 37 weeks gestation, were < or = 14 days old, and had study weights from 623 to 3015 g. All were mechanically ventilated for hyaline membrane disease. MEASUREMENTS AND RESULTS: We measured and compared VO2, carbon dioxide consumption (VCO2), minute ventilation (VE), total respiratory rate, heart rate, arterial blood pressure, and arterial oxygen saturation (SaO2) values during IMV and SIMV. Total respiratory rate fell significantly during SIMV (73 +/- 26 during IMV, 57 +/- 17 during SIMV, p < 0.01) in spite of no significant change in VO2 (0.6 +/- 0.16% fall in VO2 during SIMV) or VCO2 (4.2 +/- 0.19% increase in VCO2 during SIMV) values. Moreover, there were no significant differences in heart rate, blood pressure, VE, or SaO2 values with either form of therapy. CONCLUSIONS: Though total respiratory rate fell, these data do not support the hypothesis that SIMV significantly reduces respiratory rate by decreasing oxygen consumption and carbon dioxide production during infant mechanical ventilation. Rather, the marked fall in respiratory rate may be due to a more efficient respiratory pattern.

Analysis of Variance↗
PubMed1997

Biological variation of prostate specific antigen levels in serum: an evaluation of day-to-day physiological fluctuations in a well-defined cohort of 24 patients.

PURPOSE: We evaluated the daily biological variation of serum prostate specific antigen (PSA) concentrations to determine the critical difference required between 2 consecutive PSA measurements that would indicate a significant elevation. MATERIALS AND METHODS: A total of 24 men, grouped according to clinical diagnosis and PSA, underwent phlebotomy for 10 consecutive weekdays. Duplicate serum samples were measured using 3 separate lots of Tandem-E and IMx PSA assays. The biological variation was calculated and the 2 PSA assay systems were compared. The critical difference was examined to determine the percent elevation necessary to indicate (with 95% confidence) that PSA had increased beyond what would be expected from biological and analytical variation. RESULTS: The biological variation, defined in terms of percent coefficient of variation, had a log-normal distribution with a geometric mean of 7.3% coefficient of variation and a 95th percentile value of 19.2% coefficient of variation using the Tandem-E PSA assay. Assuming an analytical variation of 5% coefficient of variation, the median critical difference was 20.5% and the 95th percentile critical difference was 45.8%. There was no significant difference between the 2 PSA assay systems in biological variation. However, PSA concentrations measured by the IMx assay were consistently lower compared to values measured by the Tandem-E assay. CONCLUSIONS: Characterizing the biological variation of serum PSA assists in evaluating the significance of changes in serial PSA measurements. The degree of biological variation differs among patients, such that an increase between 2 consecutive PSA levels that is less than 20 to 46% may be due to biological and analytical variation. These data influence interpretation of repeated measurements of serum PSA with time.

Aged↗
PubMed1997

Effect of central metal substitution on linear dichroism of porphyrins: evidence of out-of-plane transition moments.

Absorption anisotropy and emission anisotropy measurements in poly(vinyl) alcohol (PVA) films of different porphyrin derivatives are reported. Wavelength dependent absorption anisotropy in oriented PVA films, and wavelength dependent excitation spectrum of emission anisotropy of fluorescent porphyrin derivatives in isotropic PVA films indicate the presence of multiple transition moments with different well-defined orientation. Comparison of linear dichroism and orientation behavior in stretched PVA films of deuteroporphyrin III (C2V symmetry) and its iron derivative reveals significant out-of-plane transition moment components. A considerable participation of out-of-plane polarized absorption components is also observed for metal derivatives of non-symmetrical protoporphyrin IX. It appears that central metal substitutions in porphyrin rings do not produce 'circular' degeneration of electronic transition moments. Instead, the presence of metal induces absorption components orthogonal to the porphyrin plane.

Anisotropy↗
PubMed1997

Investigation of alpha1-adrenoceptor subtypes mediating vasoconstriction in rabbit cutaneous resistance arteries.

1. Cutaneous resistance arteries (c.r.a.) (internal diameter=240.94+/-5.42 microm, n=67/25 (number arteries/number animals)) from New Zealand white rabbits were mounted in wire myographs and a normalization procedure followed. 2. Cumulative concentration-response curves (CCRCs) were constructed for the alpha-adrenoceptor agonists noradrenaline (NA), (R)A61603 and phenylephrine (PE) in the presence of cocaine (3 microM), propranolol (1 microM) and corticosterone (10 microM). The effects of competitive alpha1-adrenoceptor antagonists, prazosin, WB4101, 5-methyl-urapidil, HV723, BMY7378 and the irreversible alpha1B selective compound chloroethylclonidine (CEC) were examined versus the potency and maximum response of the c.r.a.s to noradrenaline. 3. The high potency of A-61603 relative to PE has been shown to differentiate both functional and binding site alpha1A- or alpha1B-adrenoceptors from alpha1D-adrenoceptors: A-61603 was 944 times more potent than phenylephrine (at EC50) suggesting the presence of a functional alpha1A or alpha1B as opposed to an alpha1D-subtype. 4. Exposure to chloroethylclonidine (CEC; 100 microM) decreased the maximum response to noradrenaline but did not significantly change noradrenaline sensitivity indicating that a substantial part of noradrenaline-induced vasoconstriction in rabbit cutaneous arteries is CEC-insensitive. 5. The potencies of prazosin (pA2=9.14) and WB4101 (pA2=9.30) indicate the involvement of prazosin-sensitive functional alpha1-adrenoceptors. The slopes of corresponding Schild plots for prazosin and WB4101 did not include negative unity which implies the possible involvement of more than one functional alpha1-adrenoceptor subtype in noradrenaline-induced vasoconstriction in rabbit cutaneous resistance arteries. In contrast to this, in the case of 5-methyl-urapidil and HV723, the Schild plot slope parameters were not significantly different from negative unity over the range of concentrations used; the low pA2 value for 5-methylurapidil (7.27) suggests the non-involvement of an alpha1A- or an alpha1D-adrenoceptor; the low pA2 value for HV723 (8.47) was similar to that against responses postulated as alpha1L. 6. We conclude that rabbit cutaneous resistance arteries express a prazosin-sensitive functional alpha1-adrenoceptor resembling the alpha1B and another low affinity site for prazosin which on the basis of the functional antagonism produced by HV723 most closely resembles the alpha1L-adrenoceptor; the low pA2 value for HV723 (8.47) is similar to that against responses postulated as alpha1L.

Acetonitriles↗
PubMed1997

Day to day changes in free and total PSA: significance of biological variation.

In this study we evaluated the physiological variation of free and total prostate-specific antigen (PSA) levels to determine how the percent free/total PSA was affected. Twenty four patients had blood drawn for ten consecutive weekdays. The percent coefficient of variation (%CV) of biological variation was calculated. The results were log-normally distributed with geometric means of 12.0% CV, 7.3% CV, and 8.8% CV for free, total, and percent free/total PSA, respectively. When applied, the percent free/total, PSA would need to fluctuate by 31% to indicate that a significant change (critical difference, P<0.05) between two measurements had occurred. Biological variation of PSA measurements is substantial.

Journal Article↗
PubMed1997

Pancreatic gene expression in rare cells of thymic medulla: evidence for functional contribution to T cell tolerance.

We report the initial characterization of rare cells within the thymus that express 'peripheral' self-antigens and are capable of inducing partial tolerance to a model protein. Mice from two transgenic families that express SV40 T antigen (Tag) in pancreatic islet beta cells under control of a rat insulin promoter (RIP) develop T cell tolerance toward this neo-self antigen. These mice express low levels of Tag mRNA in the thymus. Transplantation of thymus from tolerant RIP-Tag mice into athymic hosts is sufficient to confer tolerance by CD4+ Th cells and elicits variable tolerance by CD8+ cytotoxic T cells. Thymic medulla is shown to contain rare cells that express the endogenous insulin and somatostatin genes, and in the transgenic animals, Tag. These cells are referred to as 'peripheral antigen-expressing' (PAE) cells. Thymic cell fractionation reveals the PAE cells expressing insulin and Tag to be present in a fraction enriched for non-lymphoid, MHC class II+ cells. Notably, absence of thymic expression of the RIP-Tag gene in another transgenic family correlates with failure to establish self-tolerance and susceptibility to autoimmunity. Thus, expression of tissue-restricted genes such as insulin in PAE cells of thymic medulla may serve to limit development of potentially autoimmune T cells.

Animals↗
PubMed1997

Partial liquid ventilation: a comparison using conventional and high-frequency techniques in an animal model of acute respiratory failure.

OBJECTIVE: To test the hypothesis that high-frequency ventilation (HFV), when compared with conventional techniques, enhances respiratory gas exchange during partial liquid ventilation (PLV). DESIGN: A four-period crossover design. SETTING: Animal research laboratory of Children's Health Care-St. Paul. SUBJECTS: Thirty-two newborn piglets, weighing 1.40 +/- 0.39 kg. INTERVENTIONS: Animals were divided into four groups of eight animals: a) PLV with high-frequency jet ventilation; b) PLV with jet ventilation using a background intermittent mandatory ventilation (IMV) rate; c) PLV with high-frequency oscillation; or d) PLV with high-frequency flow interruption using a background IMV rate. After anesthesia, paralysis, and tracheotomy, a normal saline wash procedure produced lung injury. Perfluorocarbon was then instilled via the endotracheal tube in an amount estimated to represent functional residual capacity. Animals received randomly either PLV using conventional techniques or PLV using the selected HFV technique as initial treatment. Then, animals were crossed over to the alternative treatment at equal mean airway pressure, as measured at the endotracheal tube tip. This sequence was repeated for a total of four crossover periods, such that all animals were treated twice with PLV using conventional techniques and twice with PLV using HFV. MEASUREMENTS AND MAIN RESULTS: We measured airway pressures at the endotracheal tube tip, aortic and central venous blood pressures, arterial blood gases, and respiratory system mechanics at baseline, after induction of lung injury, and at specified intervals throughout the experiment. Measurements were made before and 15 mins after crossovers, then ventilators were adjusted to normalize gas exchange. Measurements were again made 30 mins later, at the end of the treatment period. All types of PLV provided adequate gas exchange. Only PLV using jet ventilation with IMV produced gas exchange equal to that seen during PLV using conventional techniques at equivalent mean airway pressure. By the end of the treatment periods, only PLV using high-frequency oscillation continued to require higher airway pressure than PLV using conventional techniques for equivalent gas exchange. CONCLUSIONS: Gas exchange was not enhanced during PLV-HFV. Application of HFV with PLV provides no clear acute physiologic advantages to PLV using more conventional techniques.

Animals↗
PubMed1997

Prolonged partial liquid ventilation using conventional and high-frequency ventilatory techniques: gas exchange and lung pathology in an animal model of respiratory distress syndrome.

OBJECTIVE: To evaluate the effect of prolonged partial liquid ventilation with perflubron (partial liquid ventilation), using conventional and high-frequency ventilatory techniques, on gas exchange, hemodynamics, and lung pathology in an animal model of lung injury. DESIGN: Prospective, randomized, controlled study. SETTING: Animal laboratory of the Infant Pulmonary Research Center, Children's Health Care-St. Paul. SUBJECTS: Thirty-six newborn piglets. INTERVENTIONS: We studied newborn piglets with lung injury induced by saline lavage. Animals were randomized into one of five treatment groups: a) conventional gas ventilation (n = 8); b) partial liquid ventilation with conventional ventilation (n = 7); c) partial liquid ventilation with high-frequency jet ventilation (n = 7); d) partial liquid ventilation with high-frequency oscillation (n = 7); and e) partial liquid ventilation with high-frequency flow interruption (n = 7). After induction of lung injury, all partial liquid ventilation animals received intratracheal perflubron to approximate functional residual capacity. After 30 mins of stabilization, animals randomized to high-frequency ventilation were changed to their respective high-frequency modes. Hemodynamics and blood gases were measured before and after lung injury, after perflubron administration, and then every 4 hrs for 20 hrs. Histopathologic evaluation was carried out using semiquantitative scoring and computer-assisted morphometric analysis on pulmonary tissue from animals surviving at least 16 hrs. MEASUREMENTS AND MAIN RESULTS: All animals developed acidosis and hypoxemia after lung injury. Oxygenation significantly (p < .001) improved after perflubron administration in all partial liquid ventilation groups. After 4 hrs, oxygenation was similar in all ventilator groups. The partial liquid ventilation-jet ventilation group had the highest pH; intergroup differences were seen at 16 and 20 hrs (p < .05). The partial liquid ventilation-oscillation group required higher mean airway pressure; intergroup differences were significant at 4 and 8 hrs (p < .05). Aortic pressures, central venous pressures, and heart rates were not different at any time point. Survival rate was significantly lower in the partial liquid ventilation-flow interruption group (p < .05). All partial liquid ventilation-treated animals had less lung injury compared with gas-ventilated animals by both histologic and morphometric analysis (p < .05). The lower lobes of all partial liquid ventilation-treated animals demonstrated less damage than the upper lobes, although scores reached significance (p < .05) only in the partial liquid ventilation-conventional ventilation animals. CONCLUSIONS: In this animal model, partial liquid ventilation using conventional or high-frequency ventilation provided rapid and sustained improvements in oxygenation without adverse hemodynamic consequences. Animals treated with partial liquid ventilation-flow interruption had a significantly decreased survival rate vs. animals treated with the other studied techniques. Histopathologic and morphometric analysis showed significantly less injury in the lower lobes of lungs from animals treated with partial liquid ventilation. High-frequency ventilation techniques did not further improve pathologic outcome.

Animals↗
PubMed1997

Exogenous surfactant and partial liquid ventilation: physiologic and pathologic effects.

We compared the effects of surfactant and partial liquid ventilation (PLV), and the impact of administration order, on oxygenation, respiratory system compliance (Crs), hemodynamics, and lung pathology in an animal lung injury model. We studied four groups: surfactant alone (S; n = 8); partial liquid ventilation alone (PLV-only; n = 8); surfactant followed by partial liquid ventilation (S-PLV; n = 8); and partial liquid ventilation-followed by surfactant (PLV-S; n = 8). Following treatments, all animals had improved oxygenation index (OI) and Crs. Animals in PLV groups showed continued improvement over 2 h (% change OI: PLV-S -83% versus S -47%, p < 0.05; % change Crs: S-PLV 73% versus S 13%, p < 0.05). We also saw administration-order effects: surfactant before PLV improved Crs (0.92 ml/cm H2O after surfactant versus 1.13 ml/cm H2O after PLV, p < 0.02) without changing OI, whereas surfactant after PLV did not change Crs and OI increased (5.01 after PLV versus 8.92 after surfactant, p < 0.03). Hemodynamics were not different between groups. Pathologic analysis demonstrated decreased lung injury in dependent lobes of all PLV-treated animals, and in all lobes of S-PLV animals, when compared with the lobes of the S animals (p < 0.05). We conclude that surfactant therapy in combination with PLV improved oxygenation, respiratory system mechanics, and lung pathology to a greater degree than surfactant therapy alone. Administration order affected initial physiologic response and ultimate pathology: surfactant given before PLV produced the greatest improvements in pathologic outcomes.

Animals↗
PubMed1997

Profiling primary care physicians for a new managed care network.

We developed methods for comparing physicians who would be selected to participate in a major employer's self-insurance program. These methods used insurance claims data to identify and profile physicians according to deviations from prevailing practice and outcome patterns, after considering differences in case-mix and severity of illness among the patients treated by those providers. The discussion notes the usefulness and limitations of claims data for this and other purposes. We also comment on policy implications and the relationships between our methods and health care reform strategies designed to influence overall health care costs.

Ambulatory Care↗
PubMed1996

Structural and electronic properties of the heme cofactors in a multi-heme synthetic cytochrome.

Resonance Raman, absorption, and electron paramagnetic resonance spectra are reported for a water soluble, synthetic cytochrome. The protein is a variant of the cytochrome beta maquette described by Robertson et al. [Robertson, D. E., et al. (1995) Nature 368, 425-432] and is composed of 62 amino acid residues arranged in a di-alpha-helical unit which dimerizes in solution to form a four-helix bundle. Each di-alpha-helical unit contains histidine residues at the 10,10' positions which serve as ligands to the hemes. When protoheme IX is incorporated, both hemes in the dimer are bis-ligated and low spin. The two hemes are inequivalent with respect to both binding affinity and redox properties. To investigate the properties of the heme cofactors, spectroscopic studies were conducted on peptides reconstituted with protoheme IX (PHa) and several related variants. These hemes include 2-vinyldeuteroheme (2-VDH), 4-vinyldeuteroheme (4-VDH), protoheme III (PHs), and 1-methyl-2-oxomesoheme XIII (2-OMH). Collectively, the spectroscopic studies reveal the following: (1) 2-VDH, 4-VDH, and 2-OMH bind to the protein and form bis-ligated low-spin complexes similar to PHa. The structures of the two hemes in the dimers are identical as are the immediate protein environments around the bound cofactors. These results indicate that the redox inequivalence of the two hemes is due to heme-heme electronic interactions rather than structural and/or environmental differences between the two cofactors. (2) The two hemes in the dimer are arranged in a edge-to-edge arrangement wherein the oxo group (2-OMH) or the vinyl group(s) are in the hydrophobic interface between the two units which comprise the dimer. The propionic acid tails point outward toward the hydrophilic region and extend into the solvent. (3) The PHs protein differs from the other synthetic proteins in that it contains one pentacoordinate, high-spin and one hexacoordinate, low-spin heme rather than two hexacoordinate low-spin cofactors. The open coordination site on the high-spin heme is inaccessible to exogenous imidazole but readily bind cyanide, suggesting that the alpha-helix containing the unbound histidine is nearby and partially shields the coordination site. The high-spin heme converts to low-spin at low-temperature, presumably via binding of the histidine residue on this nearby alpha-helix. It is suggested that the different behavior observed for the PHs protein is due to the fact that this heme is symmetric with respect to rotation about the alpha,gamma-axis of the macrocycle which bisects the meso-carbons between the vinyl groups and propionic acid residues. This symmetry precludes rotational isomerism about the alpha,gamma-axis to establish an unhindered fit. In contrast, all the other hemes examined contain at least one substituent smaller than a vinyl group which together with the fact that two different alpha,gamma-rotational isomers are possible for each heme in the dimer could allow these hemes to avoid the like-substituent--like-substituent heme--heme interactions of PHs. The propensity to avoid such interactions could explain the inequivalent binding properties of the two hemes in the dimer. For the PHs protein wherein these these interactions cannot be mitigated by rotation of the heme, other rearrangements of the protein must occur. These rearrangements could force the second-bound heme to assume a high-spin configuration.

Cytochromes↗
PubMed1996

Factors affecting neuronal birth and death in the mammalian olfactory epithelium.

To identify factors regulating neurogenesis and neuronal death in mammals and to determine the mechanisms by which these factors act, we have studied mouse olfactory epithelium using two different experimental paradigms: tissue culture of olfactory epithelium purified from mouse embryos; and ablation of the olfactory bulb in adult mice, a procedure that induces olfactory receptor neuron (ORN) death and neurogenesis in vivo. Studies of olfactory epithelium cultures have allowed us to characterize the cellular stages in olfactory neurogenesis and to identify factors regulating proliferation and differentiation of precursor cells in the ORN lineage. Studies of adult olfactory epithelium have enabled us to determine that all cell types in this lineage-proliferating neuronal precursors, immature ORNs and mature ORNs-undergo cell death following olfactory bulb ablation and that this death has characteristics of programmed cell death or apoptosis. In vitro studies have confirmed that neuronal cells of the olfactory epithelium undergo apoptotic death and have permitted identification of several polypeptide growth factors that promote survival of a fraction of ORNs. Using this information, we have begun to explore whether these factors, as well as genes known to play crucial roles in cell death in other systems, function to regulate apoptosis and neuronal regeneration in the adult olfactory epithelium following lesion-induced ORN death.

Animals↗
PubMed1996

Drug retention following intravesical delivery of fluorouracil therapeutic adhesive in C3H mouse bladder.

We have developed a fibrinogen-based, sustained-retention drug delivery system, therapeutic adhesive (TA), for application to resected tumor beds to reduce local tumor recurrences. In this study we evaluated the feasibility, safety and retention of the TA formulated with 5-fluorouracil (5-FU TA) after intravesical administration in a mouse bladder model. Radiolabeled [14C]5-FU TA or [14C]5-FU solution was delivered intravesically to C3H/He female mice. After drug administration, retention of 14C in the bladder was quantified by storage-phosphor autoradiography. A 2.6-fold increase in retention was observed with 5-FU TA when compared with 5-FU solution. The AUC(2 min-5 h) for 5-FU TA was 685 nmol h/mm2 compared with 260 nmol h/mm3 for 5-FU solution. No signs of toxicity in the bladder tissue or treatment-associated adverse effects were observed in the mice.

Administration, Intravesical↗
PubMed1996

Alkyl ether analogs of chlorophyll-a derivatives: Part 1. Synthesis, photophysical properties and photodynamic efficacy.

The synthesis, preliminary in vivo biological activity, singlet oxygen and fluorescence yields of a series of alkyl ether derivatives of chlorophyll-alpha analogs are described. For short-chain carbon ethers (1-7 carbon units), it was observed that the biological activity increased by increasing the length of the carbon chain, being maximum in compounds with n-hexyl and n-heptyl chains. Related sensitizers prepared by reacting 2-(1-bromoethyl)-2-devinylpyropheophorbide-alpha with (sec)alcohols were found to be less effective. Under similar treatment conditions, photosensitizers containing cis- and trans- 3-hexenyl side chains were ineffective. Thus, both stereochemical and steric factors caused differences in sensitizing activity. In general, pyropheophorbide-alpha analogs were found to be more active than related chlorin e6 derivatives, in which the isocyclic ring (ring "E") was cleaved. Related photosensitizers in the 9-deoxy- series were found to be as effective as the corresponding pyropheophorbide-alpha analogs. The photosensitizers prepared from pyropheophorbide-alpha methyl ester and chlorin e6 trimethyl ester have long wavelength absorption at 660 nm (epsilon 45 000 to 50 000). Reduction of the carbonyl group in the pyropheophorbide-alpha to methylene (ring E) resulted in a blue shift to 648 nm (epsilon 38 000).

Animals↗
PubMed1996

Regulatory hurdles in bringing an in vitro diagnostic device to market.

We discuss the hurdles that developers and manufacturers of in vitro diagnostic devices face in obtaining regulatory approval to market their products in the US. A thorough understanding of medical device regulation and the early planning of a clinical and regulatory strategy are imperative in assuring successful and timely launches of new products. Finally, it is critical for manufacturers to establish a working partnership with the Food and Drug Administration to expedite their new product applications.

Consumer Product Safety↗