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Biomedical subjects

R E Smith

Publications and source records attributed to R E Smith.

At least 109 records · Page 6Linked to original sources
PubMed1996

Blood flow in the lower limb after balloon angioplasty of the superficial femoral artery.

Using duplex ultrasonography lower-limb blood flow measurements were obtained in 20 patients with intermittent claudication. Assessments of flow were made in the common femoral artery, profunda femoris artery (PFA) and superficial femoral artery (SFA) before and after angioplasty for stenoses of short segments of the SFA. Blood flow was measured at rest and after exercise on a cycle ergometer. Collateral flow was calculated using an established mathematical model. Results were compared with the ankle:brachial systolic pressure index (ABPI) after exercise. Although there was no overall increase in resting limb blood flow, an increase in mean(s.d.) SFA flow from 148(79) to 312(94) ml min-1, with a concomitant decrease in PFA flow from 224(84) to 98(43) ml min-1 was noted 1 week after angioplasty (P < 0.05). At rest there was an increase in mean(s.d.) ABPI from 0.62(0.12) to 0.89(0.23) (P < 0.05). Collateral flow was estimated to have decreased from 186(34) to 18(8) ml min-1; the pattern of change in flow was similar after exercise. Angioplasty of the SFA remains controversial because of the risk of restenosis. The above methodology allows assessment of whether patients can re-establish collateral flow or whether limb blood flow will be significantly compromised if restenosis occurs.

Aged↗
PubMed1996

Evaluation of topotecan in patients with recurrent for metastatic squamous cell carcinoma of the head and neck. A phase II Southwest Oncology Group study.

Twenty-nine patients with persistent, recurrent and/or metastatic squamous cell carcinoma of the head and neck were treated daily for five days at three-week intervals with topotecan 1.5 mg/m2. Four patients received prior chemotherapy, 23 prior surgery and 29 prior radiation therapy. Of the 29 eligible patients, 8 patients were not evaluable for response and were assumed to be non-responders. Of the remaining 21 evaluable patients, there were zero responses (0%, 95% confidence interval [0,.12]). The most common toxicities were myelosuppression, dyspnea and malaise/fatigue/lethargy. Topotecan has limited activity in advanced head and neck cancer with this dose and schedule.

Adult↗
PubMed1996

Observer variability in volumetric blood flow measurements in leg arteries using duplex ultrasound.

Duplex ultrasound volumetric flow measurements have not found a major clinical use because of variability caused by errors in estimating cross-sectional area (CSA) and in measuring time averaged mean velocity (TAMeV). We determined inter- and intraobserver variation in volumetric blood flow measured at rest in the common femoral artery (CFA) and its main branches, the superficial femoral (SFA) and profunda femoris (PFA) arteries, in 20 normal subjects. The product of TAMeV and CSA was taken as volumetric flow. The coefficient of variation of TAMeV was consistently greater than that of CSA. Interobserver variation for blood flow (16.2%, 20.2% and 40.3% for CFA, SFA and PFA, respectively) was larger than intraobserver variation (13.0%, 15.1%, 21.2%). In conclusion, these data define the minimum changes in VQ that can be realistically detected and indicate that, with modern duplex Doppler equipment, volumetric flow can be used as a reliable haemodynamic measure for monitoring patients before and after surgical or radiological intervention.

Adult↗
PubMed1996

Zonal distribution of 11 beta-hydroxysteroid dehydrogenase types 1 and 2 messenger ribonucleic acid expression in the rat placenta and decidua during late pregnancy.

Glucocorticoid action in several target tissues is dependent on expression of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD), and in the placenta 11 beta-HSD is thought to regulate transfer of active glucocorticoid to the fetus. This study compared expression of the two recognized 11 beta-HSD enzymes, types 1 and 2, in the rat placenta and decidua on Days 16 and 22 of gestation (term = Day 23). According to S1 nuclease protection analysis, although mRNA for 11 beta-HSD-1 was only just detectable in the labyrinth zone on Day 16, by Day 22 this expression had increased almost 20-fold. There was also an increase (approximately 2-fold) in 11 beta-HSD-1 mRNA in the basal zone between Days 16 and 22. In Day 16 decidua, 11 beta-HSD-1 mRNA was also highly expressed, but insufficient tissue was available for analysis on Day 22. Western blot analysis showed that immunoreactive 11 beta-HSD-1 (molecular mass 34 kDa) was present in those tissues with the highest 11 beta-HSD-1 mRNA expression (Day 16 decidua and Day 22 labyrinth zone). With respect to mRNA for 11 beta-HSD-2, high expression was observed in the decidua and labyrinth zone at Day 16, but in the latter this expression then declined 90% by Day 22. In contrast, expression of mRNA for 11 beta-HSD-2 increased more than 3-fold in the basal zone over the same period. Consistent with coexpression of the two 11 beta-HSD enzymes, both 11-oxoreductase and 11 beta-dehydrogenase bioactivity were clearly evident in all tissues, and each varied with stage of gestation. Specifically, 11 beta-dehydrogenase activity in the basal zone increased from 38 +/- 2% (mean +/- SEM) on Day 16 to 56 +/- 2% on Day 22, while 11-oxoreductase activity fell from 55 +/- 3% to 43 +/- 2% over the same period. In contrast, 11 beta-dehydrogenase activity in the labyrinth zone fell with advancing pregnancy (Day 16: 63 +/- 2%; Day 22: 48 +/- 2%). Both 11-oxoreductase (58 +/- 3%) and 11 beta-dehydrogenase (38 +/- 4%) activities were also evident in decidua at Day 16. In conclusion, this study shows that expression of 11 beta-HSD-1 and -2 is zone-specific in the placenta and maternal decidua. Moreover, opposite changes in the expression of the two enzymes occur in the basal and labyrinth zones of the placenta over the last days of pregnancy, indicative of distinct regulatory mechanisms and functional significance for the enzymes in the two placental zones.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1996

Anterior segment prosthesis development: evaluation of expanded polytetrafluoroethylene as a sclera-attached prosthetic material.

To further the development of a sclera-attached anterior segment prosthesis we investigated the biocompatibility of expanded polytetrafluoroethylene following its surgical implantation into the rabbit sclera. Thin sheets (250 microns) of expanded polytetrafluoroethylene were cut into pieces measuring either 2 x 2, 2 x 4, 2 x 8, or 4 x 8 mm. The pieces were sterilized and placed individually within surgically prepared pockets in the sclera of rabbit eyes. Animals were sacrificed for routine histopathologic evaluation and transmission electron microscopic study of the eyes at 7 days, 14 days, 1 month, and 4 months following surgical implantation. The implants demonstrated excellent compatibility with the sclera and, by 14 days following implantation surgery, exhibited histiocytes, fibroblasts, and blood vessels infiltrating the internodal spaces of the highly porous material. The number of cells and the amount of extracellular matrix material deposited in the implants appeared to increase with time. Transmission electron microscopic studies revealed deposition of collagen within the implants. Our results suggest that expanded polytetrafluoroethylene has potential for use in the development of a sclera-attached prosthetic device.

Animals↗
PubMed1996

11 beta-Hydroxysteroid dehydrogenase type I enzyme in the hearts of normotensive and spontaneously hypertensive rats.

1. The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta HSD) converts glucocorticoids to their inactive 11-keto metabolites. The ubiquitous expression of the NADP-dependent isoform (11 beta HSD1) suggest an important role in modulating glucocorticoid action, but little is known about 11 beta HSD1 gene expression and enzymatic activity in the rat heart. 2. In the present study rat cardiac 11 beta HSD1 activity and ontogeny of gene expression have been characterized. The addition of NADP, but not NAD, to heart homogenates resulted in significant increases in the metabolism of both corticosterone and cortisol, with the former substrate displaying far greater metabolism. Both 11 beta HSD1 gene expression and enzyme activity increased in parallel from low levels at 1 week of age to maximal levels at 8 weeks, with no further change by 16 weeks of age. 3. We also compared the activity of 11 beta HSD1 in the hearts of male and female spontaneously hypertensive rats (SHR) with normotensive Wistar-Kyoto (WKY) controls. Enzyme activity in the pooled atria of female SHR was significantly higher than in male SHR atria (7.6 +/- 0.6% conversion of corticosterone vs 4.5 +/- 0.5%; P < 0.05). The left ventricles of female WKY rats contained significantly less 11 beta HSD activity than either male WKY rats or female SHR (8.6 +/- 0.8% conversion vs 17 +/- 1.4 and 13.6 +/- 0.5%, respectively; P < 0.05). In the right ventricle, female WKY rats also had significantly less enzyme activity than either female SHR or male WKY rats (4.9 +/- 0.7 vs 10.0 +/- 1.7 and 10.2 +/- 1.4%; P < 0.05). 4. These results clearly show that the rat heart contains significant amounts of the 11 beta HSD1 enzyme and that this activity is sexually dimorphic. Furthermore, significant differences were observed between a normotensive and hypertensive strain of rat. The relevance of these observations to the aetiology and maintenance of hypertension remains to be explored.

Analysis of Variance↗
PubMed1996

Haemodynamic and metabolic responses of the lower limb after high intensity exercise in humans.

This study assessed blood flow in the common femoral, superficial femoral and profunda femoris arteries, the effects of vasodilator metabolites and changes in blood pressure and pulse during recovery after high intensity exercise (Wingate test). Mean common femoral artery flow increased sevenfold in response to the exercise. The subsequent decline in mean common femoral artery flow was mono-exponential with a mean time constant of 19 min. The post-exercise increase in profunda femoris artery flow (ninefold) was significantly greater than the superficial femoral artery flow (fourfold, P < 0.05). Systolic blood pressure and heart rate decreased monotonically throughout recovery. In contrast, diastolic blood pressure showed a significant fall below baseline at 3 min (P < 0.05) with a return to baseline at 60 min. The greatest drop below baseline (approximately 20 mmHg) occurred around 7 min. Lactate reached a maximum of 13.6 +/- 2.3 mmol -1 at 8 min (P < 0.05) and was still significantly above baseline at 60 min. pH remained below 7.2 until 20 min of recovery. The results demonstrate that following high intensity exercise, blood flow to the limbs appears to be controlled by complex interactions of various vaso-active metabolites, each contributing proportionally more at different times during recovery.

Adult↗
PubMed1996

Substrate and inhibitor specificity of the cloned human 11 beta-hydroxysteroid dehydrogenase type 2 isoform.

The 11 beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) enzyme is thought to confer specificity on the mineralocorticoid receptor by inactivating glucocorticoids in mineralocorticoid target organs. The cloned 11 beta HSD2 displayed Michaelis constant values for corticosterone and cortisol of 5.1 and 61 nM, respectively. Linearity in the dose-response curve ranged between 1 and 200 nM for corticosterone and 25 and 2,000 nM for cortisol, with no evidence for complex kinetics. Inhibition of cortisol oxidation by other steroids was purely competitive in nature. Inhibition of 11 beta HSD2 activity by the end product or aldosterone occurred only at supraphysiological levels, whereas corticosterone and deoxycorticosterone displayed significant inhibition at physiological concentrations and progesterone at concentrations that occur during pregnancy. In intact transfected CHOP cells, dexamethasone was converted to 11-dehydrodexamethasone by 11 beta HSD2 but not type 1 11 beta-hydroxysteroid dehydrogenase, an aspect that may be useful in evaluating 11 beta HSD activity in intact cells.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1996

Enoxaparin for unstable angina and ancrod for cardiac surgery following heparin allergy.

OBJECTIVE: To describe a patient who presented with heparin allergy and required alternate anticoagulation for unstable angina and coronary artery bypass surgery. To review therapeutic alternatives to porcine heparin for patients with hypersensitivity or intolerance to standard heparin anticoagulation. CASE SUMMARY: A 74-year-old man with a 15-year-old coronary artery bypass graft presented to the emergency room with unstable angina and was scheduled for urgent coronary artery revascularization. A bolus dose of porcine heparin was administered followed by a continuous infusion. Shortly afterward the patient developed a type I allergic reaction to the porcine heparin that was confirmed by rechallenge. Three alternatives to porcine heparin were tried, including bovine lung heparin, low-molecular-weight heparin (enoxaparin), and ancrod. The patient was found to be cross-sensitive to bovine lung heparin, but tolerated enoxaparin for unstable angina without cross-sensitivity. Anticoagulation for cardiopulmonary bypass was achieved with an infusion of ancrod that was later reversed with cryoprecipitate. The patient was discharged postoperatively on day 5 without the complication of excessive bleeding. DISCUSSION: Type I allergic reaction to unfractionated heparin is a rare occurrence and could be the result of a variety of factors. Possible causes for the reaction include a porcine protein, a preservative contained in the heparin solution, or a hapten formed between heparin and a plasma protein. We considered four alternatives to heparin anticoagulation: rush desensitization, bovine lung heparin, low-molecular-weight heparin, and ancrod. The patient was cross-sensitive to bovine lung heparin, but was able to tolerate low-molecular-weight heparin (enoxaparin). This was unexpected because enoxaparin is derived from unfractionated porcine heparin. Testing for cross-sensitivity had no value in this case, as two negative subcutaneous test doses were followed by dramatic reactions when the drugs were given intravenously. Although enoxaparin has been used for anticoagulation during bypass surgery, there is more experience with ancrod as an alternative to heparin. Repeat bypass surgery, which normally results in above-average blood loss, was successfully performed with a very low fibrinogen concentration (< 0.15 g/L) during ancrod anticoagulation. CONCLUSIONS: We conclude that ancrod was a safe and effective alternative to heparin for coronary artery bypass surgery in this patient in whom a heparin product had caused a hypersensitivity reaction. We discovered on two occasions that a negative subcutaneous test dose for heparin allergy did not predict a severe type I allergic reaction when the heparin was later administered intravenously. Furthermore, we found that a low-molecular-weight heparin administered subcutaneously for a short period of time did not cause cross-sensitivity in a patient with a type I allergy to unfractionated heparin.

Aged↗
PubMed1996

Localization of 11 beta-hydroxysteroid dehydrogenase type II in human epithelial tissues.

The enzyme 11 beta-hydroxysteroid dehydrogenase type II (11 beta HSD2) confers specificity on the renal mineralocorticoid receptor by inactivating glucocorticoids. Mutations in this gene give rise to the syndrome of apparent mineralocorticoid excess, a congenital condition characterized by sodium retention, severe hypertension, and often by growth retardation. It is not known whether 11 beta HSD2 or another enzyme confers specificity in nonrenal sodium transporting epithelia, such as those in the sweat gland, salivary gland, and gastrointestinal tract. We previously have used the HUH23 antibody to localize 11 beta HSD2 in the human kidney, vascular smooth muscle cells, and placenta. In the present study, we have examined a range of human epithelia for the presence of 11 beta HSD2. In the skin, staining was seen in eccrine sweat glands and arterioles, whereas weak HUH23 immunostaining was observed in the epidermis. Staining was absent from sebaceous glands and hair follicles. In the parotid gland, the 11 beta HSD2 enzyme was present in striated and excretory ducts, whereas in the submandibular gland, it was found in striated and interlobular ducts. Acini, adipocytes, and associated tumor tissue did not stain with the HUH23 antibody. In the gastrointestinal tract, HUH23 stained ileal enterocytes, colonic absorptive cells, and epithelial goblet cells, whereas the rectum contained areas of staining and nonstaining absorptive cells. Gastrointestinal structures, such as the lamina propria, Peyer's patch, and goblet cells within the crypts of Lieberkuhn did not stain with the antibody. This study demonstrates the presence of 11 beta HSD2 in nonrenal sodium-transporting epithelia and describes a range of tissues affected in the syndrome of apparent mineralocorticoid excess.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1996

Accessing the particular from the general: the power of distinctiveness in the context of organization.

Recall is inversely related to the number of items sharing a cue. The limiting case of unique cue-target relationships supports extremely high levels of recall, particularly when the cue is self-generated. This fact is incongruous with the importance assigned to the construct of organization in memory theory. Further, self-generated unique cue-target relationships tend to be idiosyncratic, implying that the power of unique cues should be limited to cases of self-cued memory. The experiments presented here suggest a role for organization that reconciles the fact of unique cue effectiveness with the importance of organization to memory. Two new findings are reported: Unique cue production enhances target encoding; and general cues can access particular encodings. The data are further tribute to the importance of simultaneous organizational and distinctive processing and recommend a new perspective on the function of organization in memory.

Adult↗
PubMed1995

Evaluation of 96-hour infusion fluorouracil plus cisplatin in combination with alpha interferon for patients with advanced squamous cell carcinoma of the head and neck: a Southwest Oncology Group study.

BACKGROUND: Recurrent cancer of the head and neck after primary therapy is almost always fatal. The combination of 5-fluorouracil (5-FU) and cisplatin is considered the best available therapy but complete response rates remain too low to affect survival. This study was designed to evaluate the complete response rate and toxicity of 5-FU, cisplatin, and alpha-interferon (alpha-IFN) in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). METHODS: Fifty eligible patients with recurrent or metastatic SCCHN and no prior chemotherapy (40 men, 10 women; age range, 26-77 years; median, 59 years; 82% white; 88% had prior surgery and 92% had prior radiation therapy) were treated every 21 days with 96-hour infusion of 5-FU 1000 mg/m2/day; cisplatin 100 mg/m2, day 1; and alpha-IFN 5 x 10(6) units/day, days 1-4. RESULTS: One hundred fifty-seven courses of chemotherapy were administered, with a median of three courses. Thirty-seven patients experienced Grade 3 or 4 toxicity. Of the 17 patients with Grade 4 toxicity; 12 had hematologic toxicity, 3 stomatitis, and 2 vomiting. Two additional patients died of myelosuppression-related sepsis. Of the 50 patients, 3 (6%) achieved a complete response, five (10%) had a partial response, 3 (6%) had unconfirmed response (1 complete and 2 partial), 10 (20%) had stable disease, 17 (34%) progressed, and 12 (24%) were considered nonresponders owing to early death (6) or inadequate assessment (6). The median survival was 5 months. CONCLUSION: The complete response rate of patients with recurrent or metastatic SCCHN treated with 5-FU, cisplatin, and alpha-IFN does not appear to be superior to that observed for 5-FU and cisplatin. Alpha-interferon appears to augment hematologic and gastrointestinal toxicities associated with this combination.

Adult↗
PubMed1995

Sex- and tissue- specific regulation of 11 beta-hydroxysteroid dehydrogenase mRNA.

In the present study we have investigated the effect of hypophysectomy on 11 beta HSD1 gene expression in a variety of tissues from male and female rats. Of the tissues analysed significant changes were observed only in the male and female livers, and in the female kidney. Hypophysectomy (hypox) increased hepatic message levels in the female 20-fold, and male levels rose 2-fold. Male renal 11 beta HSD1 message levels remained constant following hypophysectomy, whereas female renal 11 beta HSD1 mRNA levels increased approximately 2-fold. In intact animals hepatic 11 beta HSD1 mRNA levels are 18-fold lower in the female than the male, while renal levels are 1.4-fold higher in the male than the female. Hepatic 11 beta HSD1 levels in the female rat appear critically responsive to the pattern of growth hormone (GH) administration. Twice daily injections of GH had no significant effect on hepatic message levels in the hypox female rat, whereas constant infusions of GH, via an osmotic mini-pump produced a marked decrease. Renal 11 beta HSD1 mRNA levels were demonstrated to be under the regulation of estrogen, and 11 beta HSD1 enzyme activity in both liver and kidney correlated with the observed changes in mRNA levels. 11 beta HSD1 gene expression is thus regulated in a tissue-specific and sexually dimorphic manner.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1995

Comparison of responses to adrenomedullin and adrenomedullin analogs in the mesenteric vascular bed of the cat.

Responses to adrenomedullin, a newly discovered hypotensive peptide isolated from human pheochromocytoma cells, and the carboxy terminal 15-52 (adrenomedullin-(15-52)) and 22-52 (adrenomedullin-(22-52)) amino acid fragments of adrenomedullin were investigated in the mesenteric vascular bed of the cat. Under constant flow conditions, injections of adrenomedullin, adrenomedullin-(15-52), and calcitonin gene-related peptide (CGRP) in doses of 0.003-1 nmol into the perfused superior mesenteric artery caused significant dose-related decreases in mesenteric arterial perfusion pressure. Mesenteric vasodilator responses to adrenomedullin and adrenomedullin-(15-52) were similar in magnitude and duration, while vasodilator responses to CGRP were greater in magnitude and longer in duration than those produced by adrenomedullin or adrenomedullin-(15-52) when these agents were injected in doses of 0.1-1 nmol. Adrenomedullin-(22-52) caused no significant change in mesenteric arterial perfusion pressure when injected in doses up to 10 nmol. These results suggest that amino acids 15-52 and the six-membered ring structure of adrenomedullin are important for the expression of vasodilator activity in the mesenteric vascular bed of the cat.

Adrenomedullin↗
PubMed1995

A role for C-C chemokines in fibrotic lung disease.

Pulmonary fibrosis is the end point of a chronic inflammatory process characterized by leukocyte recruitment and activation, fibroblast proliferation, and increased extracellular matrix production. Previous studies of models of pulmonary fibrosis have investigated the role of cytokines in the evolution of the fibrotic response. The involvement of tumor necrosis factor and interleukin-1 in bleomycin-induced lung injury, a model of idiopathic pulmonary fibrosis, has been well established, suggesting that cytokines mediate the initiation and maintenance of chronic inflammatory lesions. However, the aforementioned cytokines alone cannot account for the recruitment and activation of specific leukocyte populations found in the bleomycin model. Recently, a family of novel proinflammatory cytokines (chemokines) was cloned and characterized, yielding many putative mediators of leukocyte functions. Macrophage inflammatory protein-1 alpha (MIP-1 alpha) and monocyte chemoattractant protein-1 (MCP-1) belong to the C-C chemotactic cytokine family, a group of low-molecular-weight peptides. These molecules modulate chemotaxis, proliferation, and cytokine expression in leukocyte subsets. Our group has investigated the roles of MCP-1 and MIP-1 alpha in the bleomycin model. Both MCP-1 and MIP-1 alpha are expressed in a time-dependent manner after bleomycin challenge, and passive immunization of these animals with either anti-MIP-1 alpha or anti-MCP-1 antibodies attenuated leukocyte accumulation. In addition, we have identified specific cell types expressing MCP-1 or MIP-1 alpha by in situ hybridization and immunohistochemical localization, respectively. Furthermore, our results indicate that MIP-1 alpha expression is mediated by alveolar macrophage-derived tumor necrosis factor, identifying an important cytokine pathway in the initiation of pulmonary fibrosis. Finally, anti-MIP-1 alpha therapy attenuated fibrosis, providing direct evidence for its involvement in fibrotic pathology. Our work has clearly established that the C-C chemokines MCP-1 and MIP-1 alpha are expressed and contribute to the initiation and maintenance of the bleomycin-induced pulmonary lesion.

Bleomycin↗
PubMed1995

Changes in the levels of 11 beta-hydroxysteroid dehydrogenase mRNA over the oestrous cycle in the rat.

The NADP dependent enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta HSD) metabolizes glucocorticoids to their inactive 11-keto-metabolites in a wide range of tissues. To date very little is known about the regulation of this enzyme at the level of gene transcription. In this study we show significant changes in the uterine, renal, ovarian and hepatic levels of 11 beta HSD1 mRNA over the oestrous cycle. Uterine and renal message levels followed the same pattern, with the highest levels observed at dioestrus and the lowest levels at oestrus, a pattern that correlates with plasma oestrogen levels during the cycle. In both the uterus and kidney 11 beta HSD1 message levels more than halved from dioestrus to oestrus, while renal levels than doubled at metoestrus. In contrast, hepatic 11 beta HSD1 message levels at prooestrus were twice those observed at metoestrus. Ovarian levels remain constant until metoestrus when a marked decrease in message levels was seen. 11 beta HSD1 mRNA levels are thus differentially regulated in a tissue specific manner throughout the oestrous cycle.

11-beta-Hydroxysteroid Dehydrogenases↗