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Biomedical subjects

R E Smith

Publications and source records attributed to R E Smith.

At least 55 records · Page 3Linked to original sources
PubMed2000

Effects of 3 analgesic regimens on the perception of pain after removal of femoral artery sheaths.

BACKGROUND: Effective pain management after removal of femoral artery sheaths after percutaneous transluminal coronary angioplasty is highly individualized and requires frequent, accurate assessment and administration of analgesics as needed. OBJECTIVE: To determine which of 3 analgesic regimens is most effective in decreasing patients' perception of pain with the fewest side effects after removal of a femoral artery sheath. SAMPLE: 130 adult who had undergone percutaneous transluminal coronary angioplasty and were in an 8-bed cardiac short-stay unit in a 1400-bed acute care hospital. METHOD: Patients were randomized to receive either intravenous morphine, intravenous fentanyl, subcutaneous lidocaine around the sheath site, or an intravenous placebo before sheath removal. Rescue analgesia (intravenous fentanyl) was made available to all groups. Patients used a visual analog scale to assess pain within 10 minutes before, 1 minute after, and 20 minutes after sheath removal. Pain levels, frequency of side effects, and use of rescue analgesia were compared among groups. RESULTS: Age, sex, number of stents, and frequency of hematomas did not differ significantly among groups. Pain ratings, use of rescue analgesia, and side effects (nausea, vomiting, or vasovagal symptoms) were not significantly different among treatment groups. Ratings of pain were slightly higher immediately after sheath removal in all groups. CONCLUSION: For most patients, removal of femoral artery sheaths and manual compression for hemostasis are relatively pain-free. Pain scores among patients given analgesia with subcutaneous lidocaine, intravenous morphine, or intravenous fentanyl were not significantly different from pain scores among control patients.

Adult↗
PubMed2000

UFT/leucovorin vs 5-FU/leucovorin in colon cancer.

Adjuvant chemotherapy has been shown to alter the natural history of resected colon cancer. Two regimens (fluorouracil [5-FU] plus leucovorin and 5-FU plus levamisole) have been found to prolong disease-free survival and overall survival in affected patients. Previous comparisons of these two regimens indicate that 5-FU plus leucovorin may offer a small disease-free survival and overall survival advantage. Evidence that UFT (uracil and tegafur) plus oral leucovorin is associated with significant antitumor activity and has an acceptable toxicity profile makes this a logical formulation for the adjuvant treatment of colon cancer. The National Surgical Adjuvant Breast and Bowel Project Protocol C-06 is a randomized comparison of the relative efficacies of 5-FU plus leucovorin vs UFT plus leucovorin. Preliminary analysis of the toxicity findings among 1,530 evaluable patients indicates that both regimens are well tolerated and have similar toxicity profiles.

Aged↗
PubMed1999

Expression of 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD-2) in the developing human adrenal gland and human adrenal cortical carcinoma and adenoma.

The aim of this study was to investigate the ontogeny of localization of 11betaHSD-2 protein in the human adrenal gland. In addition, we have investigated the effects of abnormal adrenal function on 11betaHSD-2 by determining the pattern of localization of 11betaHSD-2 protein, and the amount and level of expression of 11betaHSD-2 mRNA and protein in human adrenal cortical carcinoma and adenoma. In the human foetal adrenal gland 11betaHSD-2 immunoreactivity (11betaHSD-2-ir) was detected in the foetal zone, whereas in normal adult adrenal glands 11betaHSD-2-ir was not detected by immunocytochemistry. In adrenal cortical carcinoma and adenoma, 11betaHSD-2-ir was detectable in specific regions, which have been identified as steroid synthesizing cells using 3betaHSD-ir as a marker. In adrenal cortical carcinoma and adenoma, 11betaHSD-2 mRNA and 11betaHSD-2 protein were detected by nuclease protection analysis and by western blot analysis, respectively. In summary, 11betaHSD-2-ir was detected in the foetal zone of the mid-gestation human foetal adrenal, whereas, 11betaHSD-2-ir was not detectable in the postnatal or normal adult adrenal gland. 11BetaHSD-2 protein and mRNA was induced in adult human adrenal cortical carcinoma and adenoma. The induction of expression of 11betaHSD-2 in the adrenal cortex suggests a possible role in regulating abnormal adrenal steroidogenic function in these patients.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1999

Effects of C-4 stereochemistry and C-4' hydroxylation on the iron clearing efficiency and toxicity of desferrithiocin analogues.

Additional structure-activity studies of desferrithiocin analogues are carried out. The effects of stereochemistry at C-4 on the ligands' iron clearing efficiency are reviewed and assessed using the enantiomers 4,5-dihydro-2-(2, 4-dihydroxyphenyl)thiazole-4(R)-carboxylic acid and 4,5-dihydro-2-(2, 4-dihydroxyphenyl)thiazole-4(S)-carboxylic acid. The utility of 4'-hydroxylation as a method of reducing the toxicity of desazadesferrithiocin analogues is also examined further with the synthesis and in vivo comparison of 4, 5-dihydro-2-(2-hydroxyphenyl)-4-methylthiazole-4(S)-carboxylic acid, which is the natural product 4-methylaeruginoic acid, and 4, 5-dihydro-2-(2,4-dihydroxyphenyl)-4-methylthiazole-4(S)-carboxylic acid. The stereochemistry at C-4 is shown to have a substantial effect on the iron clearing efficiency of desferrithiocin analogues, as does C-4'-hydroxylation on the toxicity profile. All of the compounds are evaluated in a bile-duct-cannulated rodent model to determine iron clearance efficiency and are carried forward to the iron-overloaded primate for iron clearing measurements. On the basis of the results of the present work, although 4,5-dihydro-2-(2, 4-dihydroxyphenyl)thiazole-4(S)-carboxylic acid is still the most promising candidate for clinical evaluation, 4,5-dihydro-2-(2, 4-dihydroxyphenyl)-4-methylthiazole-4(S)-carboxylic acid (4'-hydroxydesazadesferrithiocin) also merits further preclinical assessment.

Animals↗
PubMed1999

Neutralization of the CXC chemokine, macrophage inflammatory protein-2, attenuates bleomycin-induced pulmonary fibrosis.

Few studies have addressed the importance of vascular remodeling in the lung during the development of bleomycin-induced pulmonary fibrosis. For fibroplasia and deposition of extracellular matrix to occur, there must be a geometric increase in neovascularization. We hypothesized that net angiogenesis during the pathogenesis of fibroplasia and deposition of extracellular matrix during bleomycin-induced pulmonary fibrosis are dependent in part upon an overexpression of the angiogenic CXC chemokine, macrophage inflammatory protein-2 (MIP-2). To test this hypothesis, we measured MIP-2 by specific ELISA in whole lung homogenates in either bleomycin-treated or control CBA/J mice and correlated these levels with lung hydroxyproline. We found that lung tissue from mice treated with bleomycin, compared with that from saline-treated controls, demonstrated a significant increase in the presence of MIP-2 that was correlated to a greater angiogenic response and total lung hydroxyproline content. Neutralizing anti-MIP-2 Abs inhibited the angiogenic activity of day 16 bleomycin-treated lung specimens using an in vivo angiogenesis bioassay. Furthermore, when MIP-2 was depleted in vivo by passive immunization, bleomycin-induced pulmonary fibrosis was significantly reduced without a change in the presence of pulmonary neutrophils, fibroblast proliferation, or collagen gene expression. This was also paralleled by a reduction in angiogenesis. These results demonstrate that the angiogenic CXC chemokine, MIP-2, is an important factor that regulates angiogenesis/fibrosis in pulmonary fibrosis.

Animals↗
PubMed1999

Immune-stimulating complexes induce an IL-12-dependent cascade of innate immune responses.

The development of subunit vaccines requires the use of adjuvants that act by stimulating components of the innate immune response. Immune-stimulating complexes (ISCOMS) containing the saponin adjuvant Quil A are potential vaccine vectors that induce a wide range of Ag-specific responses in vivo encompassing both humoral and CD4 and CD8 cell-mediated immune responses. ISCOMS are active by both parenteral and mucosal routes, but the basis for their adjuvant properties is unknown. Here we have investigated the ability of ISCOMS to recruit and activate innate immune responses as measured in peritoneal exudate cells. The i.p. injection of ISCOMS induced intense local inflammation, with early recruitment of neutrophils and mast cells followed by macrophages, dendritic cells, and lymphocytes. Many of the recruited cells had phenotypic evidence of activation and secreted a number of inflammatory mediators, including nitric oxide, reactive oxygen intermediates, IL-1, IL-6, IL-12, and IFN-gamma. Of the factors that we investigated further only IL-12 appeared to be essential for the immunogenicity of ISCOMS, as IL-6- and inducible nitric oxide synthase knockout (KO) mice developed normal immune responses to OVA in ISCOMS, whereas these responses were markedly reduced in IL-12KO mice. The recruitment of peritoneal exudate cells following an injection of ISCOMS was impaired in IL-12KO mice, indicating a role for IL-12 in establishing the proinflammatory cascade. Thus, ISCOMS prime Ag-specific immune responses at least in part by activating IL-12-dependent aspects of the innate immune system.

Adjuvants, Immunologic↗
PubMed1999

Intact and photomodified polycyclic aromatic hydrocarbons inhibit photosynthesis in natural assemblages of Lake Erie phytoplankton exposed to solar radiation.

Recently, there has been a trend toward less turbid water and greater light penetration in parts of western Lake Erie. This could lead to greater phototoxicity from sediment-bound polycyclic aromatic hydrocarbons. To test photosynthesis as a bioindicator of contaminant impacts on algae, water samples containing natural assemblages of phytoplankton were collected from the western and central basins of Lake Erie. These samples were incubated with 0.2 to 2 mg L(-1) anthracene or its photomodified product 1, 2-dihydroxyanthraquinone for 60 min in darkness or in 50% sunlight, to mimic exposure of phytoplankton in the photic zone of a mixed water column. Photosynthetic efficiency was determined from filtered phytoplankton immediately after exposure using a pulse-amplitude modulated chlorophyll fluorometer. Phytoplankton incubated with chemicals in the dark demonstrated chlorophyll fluorescence values similar to those of controls. However, exposure to anthracene or 1, 2-dihydroxyanthraquinone in sunlight diminished photosystem II photosynthetic efficiency and photosynthetic quantum yield in a concentration-dependent manner. Anthracene inhibited photosynthesis at lower concentrations than 1,2-dihydroxyanthraquinone, which is consistent with the different modes of action and toxic strengths of these two contaminants. These results demonstrate that phytoplankton in Lake Erie can be subject to phototoxicity from intact and photomodified polycyclic aromatic hydrocarbons after very short exposures. Further, chlorophyll fluorescence was found to be an effective bioindicator in the field for this form of chemical stress.

Biomarkers↗
PubMed1999

Oral vaccination with immune stimulating complexes.

There is a need for non-living adjuvant vectors which will induce a full range of local and systemic immune responses to orally administered purified antigens. Here we describe our experience with lipophilic immune stimulating complexes (ISCOMS) containing the saponin adjuvant Quil A. When given orally, ISCOMS containing the model protein antigen ovalbumin (OVA) induce a wide range of systemic immune responses, including Th1 and Th2 CD4 dependent activity, class I MHC restricted cytotoxic T-cell responses and local production of secretory IgA antibodies. More recent results indicate that ISCOMS may act partly by enhancing the uptake of protein from the gut. In addition, intraperitoneal injection of ISCOMS recruits and activates many components of the innate immune system. including neutrophils, macrophages, and dendritic cells. In parallel, there is increased production of nitric oxide (NO), reactive oxygen intermediates (ROI), interleukins (IL) 1, 6, 12, and gamma interferon (gammaIFN). Of these factors, only IL12 is essential for the immunogenicity of ISCOMS in vivo, as mucosal and systemic responses to ISCOMS are reduced in IL12KO mice, but not in IL4KO, IL6KO, inducible NO synthase (iNOS) KO, or gammaIFN receptor KO mice. We propose that ISCOMS act by targetting antigen and adjuvant to macrophages and/or dendritic cells. This pathway may be amenable to exploitation for vaccine development, especially if combined with another vector with a different mucosal adjuvant profile, such as cholera toxin.

Adjuvants, Immunologic↗
PubMed1999

Time-averaged mean velocity for volumetric blood flow measurements: an in vitro model validation study using physiological femoral artery flow waveforms.

This study assesses the accuracy of the volume flow measurement of the ATL HDI 3000 duplex ultrasound scanner using a model of the femoral arterial circulation. The beam profile of the transducer was measured, and used to identify regions of the beam where there may be poor insonation characteristics. The flow measurement accuracy was not found to be influenced by the vessel depth between 1.0 cm and 8.0 cm in a 0.7 cm diameter vessel. Overall accuracy was 3%+/-9%. Vessels in excess of 0.9 cm produced larger errors. In the model system, pulse rates between 60 bpm and 120 bpm had no significant effect on the measurement accuracy (p > 0.01). The results of this study suggest that accurate measurements of femoral arterial blood flow are possible. Further work will be required to assess the accuracy of the technique in vivo.

Blood Flow Velocity↗
PubMed1999

Black iris-diaphragm intraocular lens for aniridia and aphakia.

We present the first reported use in the United States of a black iris-diaphragm intraocular lens (IOL) for the treatment of traumatic aniridia and aphakic bullous keratopathy. The patient presented to a university-based practice with contact-lens-intolerant aniridia and aphakia with painful bullous keratopathy from a failed corneal graft. He was treated with combined penetrating keratoplasty and transscleral fixation of an aniridia IOL. The patient's preoperative symptoms of debilitating glare and photophobia resolved substantially after surgery, despite mild postoperative inflammation that resolved. The symptoms associated with aniridia can be successfully treated with a black iris-diaphragm IOL; however, chronic low-grade inflammation has been reported with its use in some cases.

Adult↗
PubMed1999

Endogenous mediators and thrombophilia.

Platelets are one of the most important components of primary haemostasis. Since they lack a nucleus, their functional characteristics are determined at the time of production. The role of platelets in thrombosis is further modified by the interaction with vascular mediators that are endogenously produced in response to a variety of stimuli. This chapter discusses the factors that influence platelet production, the interaction with endogenous mediators, and the potential therapeutic benefits achieved by modifying this interaction in the clinical setting.

Animals↗
PubMed1999

Immunohistochemical identification of androgen receptors in human lacrimal glands.

PURPOSE: Androgens are thought to play a role in the regulation of the human lacrimal gland. Androgen receptor mRNA has been isolated from human lacrimal tissue; however, it is not known which cell(s) in human lacrimal tissue may contain androgen receptors. This study is an immunohistochemical investigation of the location and distribution of androgen receptors in human lacrimal tissue. METHODS: Formalin-fixed, paraffin-embedded human lacrimal gland tissues were subjected to established antigen retrieval techniques. This was followed by routine immunohistochemical staining, employing one of two anti-human androgen receptor monoclonal antibodies, each specific for a different antigenic epitope within the receptor molecule. RESULTS: The two anti-human androgen receptor monoclonal antibodies demonstrated similar staining patterns in adjacent tissue sections from the same human lacrimal gland specimens. Specific staining for androgen receptors was observed in the nucleus and cytoplasm of lacrimal acinar cells, as well as in lacrimal duct cells. Both the intensity of staining and the number of cells demonstrating staining varied among specimens. We also observed staining for androgen receptors in interstitial and inflammatory cells distributed between lacrimal acinar units in some specimens. CONCLUSIONS: Androgen receptors are located in human lacrimal gland acinar cell nuclei as observed in other animals. However, the detection of androgen receptors in lacrimal interacinar interstitial and inflammatory cells suggests that androgens may play a role in modulating the activities of cells other than lacrimal cells within the human lacrimal gland.

Adolescent↗
PubMed1999

Latex vessels with customized compliance for use in arterial flow models.

The physical characteristics of the arterial wall exert a major influence over blood flow patterns and the pulse wave velocity is strongly affected by the elasticity of the vessel. We have developed a technique for manufacturing latex tubing which has physical characteristics similar to those of human arteries. Tubes were produced by painting a plastic rod of diameter 7 x 10(-3) m (the internal diameter of the superficial femoral artery) with liquid latex. The number of coats applied controlled the thickness, and hence the elasticity of the resulting tube. Values of compliance and pulse wave velocity were similar to those observed in vivo. The tubing was tested in a model of the femoral arterial circulation and the typical triphasic arterial now was seen. The mean flow in the vessels was also analysed, and found to be higher for the more elastic vessels, supporting existing mathematical theories and qualitative physiological data. These vessels provide a reliable method of producing physiologically accurate test segments for use in a range of arterial flow models.

Artificial Organs↗
PubMed1999

Superficial punctate keratitis of thygeson: the longest course on record?

PURPOSE: To report the extended clinical course of a case of superficial punctate keratitis of Thygeson. METHODS: A 59-year-old woman with a 40-year history of superficial punctate keratitis of Thygeson is presented, providing a forum to discuss the chronicity of the disease, its treatment, and the potential complications. RESULTS: Our patient has been treated over the years with mild topical corticosteroids, usually with favorable results. Given the chronicity of superficial punctate keratitis of Thygeson, long-term treatment with topical corticosteroids carries the possible side effects of iatrogenic cataract formation and steroid-induced glaucoma, neither of which was seen in our patient. CONCLUSIONS: Superficial punctate keratitis of Thygeson is usually a benign, self-limited disease with exacerbations and remissions. Ophthalmologists must exercise care when using long-term corticosteroid treatment in this condition.

Administration, Topical↗
PubMed1999

Randomized trial of 3-hour versus 24-hour infusion of high-dose paclitaxel in patients with metastatic or locally advanced breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-26.

PURPOSE: Paclitaxel is an active drug for the treatment of breast cancer; however, the appropriate duration of administration is unknown. We assessed and compared the response rate, event-free survival, survival, and toxicity of paclitaxel 250 mg/m(2) delivered every 3 weeks as a 3-hour or 24-hour infusion. PATIENTS AND METHODS: A total of 563 women with stage IV or IIIB breast cancer were randomized into one of two groups: 279 received 3-hour paclitaxel and 284 received 24-hour paclitaxel. Patients were stratified by age, stage of disease, and prior therapy. RESULTS: A significantly higher rate of tumor response occurred in the first four cycles of therapy in patients who received the 24-hour infusion of paclitaxel (51% v 41%, respectively; P =.025). Tumor response over all cycles was also significantly higher in the group that received 24-hour infusion (54% v 44%, respectively; P =.023). There were no significant differences in event-free survival or survival between the two arms of the study (P =.9 and.8, respectively). No treatment by stage or by age interactions were observed. During the first four cycles of therapy, at least one episode of >/= grade 3 toxicity (excluding nadir hematologic values, alopecia, and weight change) occurred in 45% of patients who received the 3-hour paclitaxel infusion and in 50% of those who received the 24-hour paclitaxel infusion. Febrile neutropenia, >/= grade 3 infection, and >/= grade 3 stomatitis were less frequent, and severe neurosensory toxicity was more frequent in those who received the 3-hour paclitaxel infusion. Ten treatment-related deaths occurred in the first four cycles. Age, stage, and prior chemotherapy did not influence the effect of treatment. CONCLUSION: When administered as a continuous 24-hour infusion, high-dose paclitaxel results in a higher tumor response rate than when administered as a 3-hour infusion but does not significantly improve event-free survival or survival. Paclitaxel as a 24-hour infusion results in increased hematologic toxicity and decreased neurosensory toxicity.

Antineoplastic Agents, Phytogenic↗
PubMed1998

Synthesis of reagents for the construction of hypusine and deoxyhypusine peptides and their application as peptidic antigens.

Two new synthetic methods which allow access to (2S)-deoxyhypusine, natural (2S,9R)-hypusine, (2S,9S)-hypusine, and deoxyhypusine- and hypusine-containing peptides are described. The methods involve both the construction of a deoxyhypusine reagent in which the alpha-nitrogen protecting group is orthogonal to the N-7 and N-12 protecting groups and an alternate synthesis of our previous hypusine reagent, a synthesis which provides for better stereochemical control at C-9. Synthetic hypusine and deoxyhypusine can be generated from these reagents. The hypusine-containing hexapeptide (Cys-Thr-Gly-Hpu-His-Gly) is conjugated to ovalbumin (OVA), keyhole limpet hemocyanin (KLH), and a bis-maleimide; KLH conjugates are also made with the deoxyhypusine- and lysine-containing hexapeptides. Monoclonal antibodies are generated to the hypusine-containing hexapeptide-OVA conjugate in mice. These are isolated and screened against the hypusine-containing hexapeptide-KLH and hypusine-containing hexapeptide-bis-maleimide conjugates, as well as against the deoxyhypusine-containing and lysine-containing hexapeptide-KLH conjugates. These antibodies may be useful in localizing intracellular hypusine-containing peptides as well as peptides containing hypusine analogues.

Animals↗