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Biomedical subjects

M J Stuart

Publications and source records attributed to M J Stuart.

At least 19 recordsLinked to original sources
PubMed1992

15-Hydroxyeicosatetraenoic acid-mediated potentiation of thrombin-induced platelet functions occurs via enhanced production of phosphoinositide-derived second messengers--sn-1,2-diacylglycerol and inositol-1,4,5-trisphosphate.

We investigated whether biologically relevant concentrations of the mono-hydroxyeicosatetraenoic acids (mono-HETEs) modulate platelet functions. We report that 15-HETE, an eicosanoid produced by endothelial cells, granulocytes, and lymphocytes, potentiated platelet aggregation, nucleotide release, and elevation in intracellular calcium levels induced by a threshold concentration of thrombin (0.025 U/mL). Significant potentiation effects on these responses were observed at concentrations between 1 and 100 nmol/L. 15-HETE at these concentrations enhanced thrombin-induced platelet aggregation by 32% to 57%, nucleotide release by 40% to 65%, and elevation of intracellular calcium by 31% to 52% (P < .05 to .01). Both 12-HETE and 5-HETE, the structural isomers of 15-HETE, also potentiated thrombin-induced platelet aggregation and nucleotide release. While 12-HETE showed a small but significant effect at 100 pmol/L, 5-HETE had effects similar to those of 15-HETE at micromolar concentrations. To understand the mechanism of the HETE modulation of platelet functions, we studied the effect of 10 and 100 nmol/L 15-HETE on the production of sn-1,2-diacylglycerol (DAG) and inositol-1,4,5-trisphosphate (1,4,5-IP3). 15-HETE enhanced thrombin-induced production of DAG and 1,4,5-IP3 in a time- and concentration-dependent manner. 15-HETE also potentiated agonist-induced phosphorylation of the 47-Kd platelet protein. These studies demonstrate an important modulatory role for 15-HETE on platelet functions. Since this eicosanoid is elevated in pathologic states associated with platelet hyperfunction, including diabetes mellitus and atherosclerosis, an elucidation of its mechanism(s) of action appears relevant to our understanding of the genesis of atherothrombotic vascular disease.

Adenosine Triphosphate↗
PubMed1992

1-Deamino-8 D-arginine vasopressin decreases the production of 13-hydroxyoctadecadienoic acid by endothelial cells.

1-Deamino-8 D-arginine vasopressin (DDAVP) has been used effectively to normalize the bleeding time in various hemostatic disorders. In von Willebrand disease the reduction in bleeding time is due to the preferential release of large multimers of von Willebrand factor from endothelial cells. However, since the bleeding time correction in patients with uremia and liver disease is independent of the release of von Willebrand antigen and activity, other mechanisms of action of DDAVP need to be considered. Endothelial cells generate several thromborepellant factors including 13-hydroxyoctadecadienoic acid (13-HODE), an inhibitor of platelet adhesion to subendothelium. Using cultured fetal bovine aortic endothelial cells (FBAECs), we have investigated whether DDAVP modulates the production of 13-HODE. We have demonstrated that 14C-linoleic acid labeled FBAECs release several oxygenated derivatives of linoleic acid following a 120 min incubation in the presence of serum. One of these products was identified by chromatographic procedures as 13-HODE. The production of 13-HODE was decreased significantly by DDAVP (1-100 ng/ml) with maximal reduction (approx. 25%) seen at 1 ng/ml of DDAVP. While vehicle treated control FBAECs generated 6780 +/- 690 cpm of 13-HODE per 10(6) cells (mean +/- SE, n = 8), DDAVP treated FBAECs produced 4950 +/- 310 (P < 0.01), 5390 +/- 390 (P < 0.01), and 5720 +/- 410 cpm (P < 0.05) of 13-HODE at 1, 10, and 100 ng/ml DDAVP respectively. Our findings of a decrease in 13-HODE would explain the previously observed morphologic changes of increased platelet adhesion to subendothelium following DDAVP infusion and contributes to our understanding of the mode of action of this therapeutic agent in hemostatic disorders.

Animals↗
PubMed1992

Traumatic disruption of the anterior tibial tendon while cross-country skiing. A case report.

Closed spontaneous rupture of the anterior tibial tendon is an uncommon injury that occurs after relatively minor trauma in middle-aged and elderly men. A 72-year-old retired physician sustained a complete anterior tibial tendon rupture while he was skiing cross-country. Direct primary repair of the tendon resulted in satisfactory restoration of muscle strength and return to an active life-style.

Aged↗
PubMed1991

Identification of prostaglandins and hydroxyeicosatetraenoic acids in kitten retina: comparison with other species.

Conversion of arachidonic acid to eicosanoids by kitten retinae was investigated to evaluate whether the pattern of kitten retinal eicosanoids simulates that found in the human and other animal species. Freshly isolated kitten retinae were incubated with 20 microM radiolabeled arachidonic acid, and the metabolites were analysed by reverse phase-high pressure liquid chromatography, thin-layer chromatography and gas chromatography-mass spectroscopy. Kitten retinal tissues converted arachidonic acid into prostaglandins (PGs), thromboxane (Tx) and hydroxyeicosatetraenoic acids (HETEs). The major eicosanoid identified was 6kPGF1 alpha--the stable non-enzymatic hydrolysis product of prostacyclin. Other eicosanoids identified included TxB2, PGE2, PGF2 alpha, 12-hydroxy-heptadecatrienoic acid, 12-HETE, and 15-HETE. The spectrum of kitten retinal cyclooxygenase metabolites is similar to those obtained from bovine retina and human retinal vascular endothelium with prostacyclin being the major cyclooxygenase metabolite produced.

6-Ketoprostaglandin F1 alpha↗
PubMed1991

A prostacyclin analogue crosses the in vitro perfused human placenta and improves transfer in some pathologic states.

Placental blood flow is reduced in pregnancies complicated by hypertension, intrauterine growth retardation, maternal smoking, or diabetes. Umbilical-placental production of the potent vasodilator prostacyclin is also reduced in these pathologic states and this deficiency may contribute to an associated increase in the incidence of low infant birthweight by affecting a reduction in placental nutrient transfer. We have studied the effects of the prostacyclin analogue carbacyclin on diffusional transfer in the human placenta perfused in vitro. We have found that carbacyclin crosses the human placenta and can significantly increase diffusional transfer in placenta from pregnancies complicated by hypertension or maternal smoking and in the normal term placenta in which prostacyclin production has first been reduced through the administration of ibuprofen. Carbacyclin had no effect, however, in untreated placenta from normal pregnancies or in placenta from diabetic pregnancies. These results suggest that the prostacyclin-deficient perfused placenta may serve as a model for several placental insufficiency syndromes and that the possibility that prostacyclin analogues may improve deficient nutrient transfer in some pathologic pregnancies warrants further investigation.

Antipyrine↗
PubMed1991

Traumatic trabecular lesions observed on MR imaging of the knee.

Examinations carried out on 302 consecutive patients with MR of the knee between January 1988 and March 1989 were reviewed for detection of trabecular lesion. Twenty-seven patients found presenting trabecular lesion were further reviewed with specific reference to their activity level and need for specific therapy to determine the clinical significance of the trabecular lesion. Twenty-one of the trabecular lesions were in the femur, 5 were in the tibia, and one was in the fibula. Three of them were associated with a direct trauma, 12 with a valgus type injury, 3 with pure rotation mechanism, and 5 with a combination of valgus and rotation. In 17 cases trabecular lesion was a single finding, in 10 cases it was associated with some ligamentous tear. At the follow-up visit, 26 of the 27 patients with trabecular lesion had no symptoms, and the patient with moderate knee symptoms had had similar knee symptoms prior to the accident due to an osteochondral defect. We conclude that a trabecular lesion in an MR image is a benign bone change associated with knee trauma which heals without sequelae.

Adolescent↗
PubMed1990

15-Hydroxyeicosatetraenoic acid stimulates migration of human retinal microvessel endothelium in vitro and neovascularization in vivo.

We evaluated 15-hydroxyeicosatetraenoic acid (15-HETE), a major arachidonic acid product of vascular endothelium and leukocytes, for its effect on neovascularization. In a modified Boyden chamber assay, 15-HETE (10-7 M) stimulated human retinal microvessel endothelial cell migration by 42 +/- 10% (mean +/- S.E.M., p less than 0.01). 12-HETE, a major arachidonic acid metabolite of platelets, had no such effect. Further studies in the rabbit corneal pocket assay revealed that 15-HETE stimulated neovascularization in vivo. Concentrations at which the in vivo effects were observed are within the range generated by several cell types and are achievable in human serum. 15-HETE stimulation of human endothelial cell migration in vitro and neovascularization in vivo suggests that it may play a role in vasoproliferative disorders.

Animals↗
PubMed1990

Rehabilitative techniques for athletes after reconstruction of the anterior cruciate ligament.

A wide spectrum of protocols is available for rehabilitation after anterior cruciate ligament reconstruction, and little agreement exists on the specifics of strengthening exercises or the sequence of activities. In this article, we discuss the current rehabilitative techniques used at the Mayo Clinic for athletes who have undergone anterior cruciate ligament reconstruction. These techniques are based on established principles of rehabilitation, clinical experience, and new information about the related biomechanics of the knee. An illustrative case reflects the benefits of this rehabilitation program, which lasts up to 1 year and is divided into five stages. The early stages focus on protected mobilization and a strengthening program that emphasizes closed rather than open kinetic chain exercises. Later, neuromuscular-proprioceptive training and sport-specific agility training redevelop the reaction time and the "coordination engrams" necessary for athletic competition. High-quality surgical care and a closely supervised rehabilitation program, based on kinesiologic and biomechanical factors as they pertain to the anterior cruciate ligament, are necessary for a successful outcome.

Adolescent↗
PubMed1990

Effects of changes in oxygen tension on lipoxygenase metabolites. Serum 15-HETE is increased in kittens exposed to hyperoxia.

The chronic phase of O2-induced retinopathy is characterized by retinal neovascularization. We have previously demonstrated that 15-hydroxy-5,8,11,13-eicosatetraenoic acid (15-HETE), a product of white cells, is proangiogenic. In this study, kittens exposed to in vivo hyperoxia produced increased amounts of 15-HETE. Nine litters of 30 kittens (aged 6-8 days) were used. Control kittens were left in room air; hyperoxic kittens were placed in 80% oxygen for 48 h; recovery kittens were returned to room air for 24 h following hyperoxic exposure. Following treatments, the animals were sacrified, and blood was evaluated for 15-HETE. Stimulated serum 15-HETE levels were assayed by high-performance liquid chromatography and GC-selected ion monitoring. While controls produced 0.48 +/- 0.16 (SE) nmol/ml of 15-HETE, values in the hyperoxic and recovery animals were increased at 0.7 +/0 0.2 and 0.68 +/- 0.15 nmol/ml (p less than 0.05 and p = 0.05, respectively). Increased production of this proangiogenic metabolite by WBCs (which can migrate out of blood vessels to set up extravascular angiogenic foci) may play a role in the genesis of the neovascularization process that occurs in response to oxygen-induced injury.

Animals↗
PubMed1990

Alterations in transfer and lipid distribution of arachidonic acid in placentas of diabetic pregnancies.

Placental tissue from nondiabetic term pregnancies and pregnancies complicated by maternal insulin-dependent diabetes mellitus (IDDM) was perfused in vitro to compare the transfer and lipid distribution of arachidonic acid (AA). Radiolabeled albumin-bound AA was administered into the maternal afferent circulation, and samples of fetal and maternal effluent were collected at 10-min intervals. Perfused placental tissue was collected at the end of each experiment. The effluent was analyzed for total radioactivity, and extracts were subjected to thin-layer chromatography for the assessment of radioactivity associated with various lipid fractions. Placental AA uptake was significantly increased in perfused tissue from diabetic pregnancies (0.88 vs. 1.72 nM.min-1.g-1 in nondiabetic and IDDM, respectively; P less than 0.01), as was AA transfer (0.22 vs. 0.42 ml/min in nondiabetic and IDDM, respectively; P less than 0.01). However, transfer of the highly diffusible marker substance antipyrine was significantly reduced in IDDM placentas (1.79 vs. 2.49 ml/min in IDDM and nondiabetic, respectively; P less than 0.01). Compared with nondiabetic placentas, incorporation of AA into triglyceride was significantly increased in both maternal and fetal effluents and in placental tissue from IDDM pregnancies, whereas the percentage of AA remaining unesterified was reduced in both placental tissue and fetal effluent. Incorporation of AA into phosphoglycerides was significantly reduced in placental tissue but increased in fetal effluent in placentas from IDDM pregnancies. The results of these studies suggest that transfer and lipid distribution of AA are significantly altered in placentas from IDDM pregnancies. These findings may be relevant to the increased incidence of abnormal fetal growth and development associated with IDDM pregnancies.

Arachidonic Acids↗
PubMed1990

Anterior acromioplasty for treatment of the shoulder impingement syndrome.

Between 1975 and 1979, anterior acromioplasty was performed in 65 patients with 66 involved shoulders. The procedure appears to be safe and reasonably effective. Of the 65 patients in this study, 50 had chronic tendon inflammation with fibrosis, and 16 also had a small supraspinatus tendon tear. These 16 had rotator cuff repairs. Twenty-six patients were also treated with distal clavicle excision, and seven had tenodesis of the long head of the biceps brachii. The average age of the patients was 50 years (range, 23-75 years). All patients were followed for an average of eight years (range, three to 13 years). At final evaluation, no or slight pain was present in 77% of the shoulders: 39 of 50 without tendon tearing and 12 of 16 with tendon tearing and repair. Active shoulder abduction averaged 167 degrees. Ninety-two percent returned to employment, including 18% with some job modification. Eighty-six percent returned to recreational athletics, 20% with some modification of activities. Seven patients had additional surgical treatment. The progression of rotator cuff disease is not always prevented, but the need for subsequent shoulder treatment generally decreases.

Acromion↗
PubMed1990

Late recurrence of varus deformity after proximal tibial osteotomy.

One hundred thirteen knees with medial gonarthrosis in 95 patients were treated by valgus-producing proximal tibial osteotomy and followed clinically and roentgenographically for a minimum of five years (mean, 6.3 years). Sixty-four knees (57%) were pain free or had only mild discomfort when walking. The standing femorotibial angle decreased from a postoperative average of 9.3 degrees valgus to 7.8 degrees valgus at the final follow-up examination. The tendency for varus recurrence greater than 5 degrees and for medial- or lateral-compartment arthritic progression was evaluated using the Kaplan-Meier survival method. Varus recurred in 18%, lateral-compartment arthritic progression in 60%, and medial-compartment arthritic progression in 83% by nine years after surgery. The probability of arthritic progression is much higher than the probability of significant varus recurrence in long-term roentgenographic follow-up studies of patients with valgus-producing proximal tibial osteotomies.

Adult↗
PubMed1990

Arthrodesis of the diabetic neuropathic ankle joint.

At the authors' institution from 1964 to 1984, ankle arthrodesis was performed in 13 patients with insulin-dependent diabetes mellitus who had a history of ankle sprain or fracture. Nine patients were diagnosed by clinical exam as having a peripheral neuropathy; nine patients had roentgenographic evidence of neuropathic arthropathy prior to surgery. Follow-up study with examination and roentgenograms averaged 42 months. Clinical and roentgenographic union was achieved in seven ankles at an average of 16 weeks. Two patients developed a nonunion, three had an amputation, and one died at two months postoperatively. Thirteen complications occurred in eight of the 13 patients (62%). Twenty reoperations, excluding pin removal, were performed in eight patients (62%). A satisfactory result was achieved in only 50% overall and in only 38% of patients with roentgenographic changes of neuropathic arthropathy. Neuropathic arthropathy contributes to the inordinate complication and failure rates. Ankle arthrodesis should be considered with caution in the diabetic patient.

Adult↗
PubMed1989

Trans-placental transport and metabolism of carbacyclin by perfused human placental in vitro.

When carbacyclin (5E-6a-carba-prostaglandin I2) was added to the maternal afferent circulation of in vitro perfused placentae from normal term pregnancies, relatively little carbacyclin was found in either the maternal or fetal efferent circulations. When carbacyclin was added to the perfusate at 1.0 microM, the peak level in the maternal effluent was only 0.06 microM and in the fetal effluent, 0.026 microM. When infused at 10 microM, 0.77 microM carbacyclin was measured in the maternal effluent and 0.13 in the fetal effluent. These findings demonstrate that carbacyclin is transferred across the placenta from the maternal side to the fetal, but that the net transfer is small. The assay procedure employed HPLC resolution, followed by capillary gas chromatography and selected ion monitoring using PGB as an internal standard. The low levels of carbacyclin detected in the effluents did not result from poor recovery in the analyses. When carbacyclin was added to maternal or fetal effluents at 1 microM, the recovery averaged 85.4 +/- 14.1% (SD); at 10 microM recovery averaged 97.3 +/- 4.2%. Much of the loss of carbacyclin on passage through placental circulation resulted from metabolism. Extracts of both fetal and maternal effluents from placenta perfused with carbacyclin contained a component which on reverse phase HPLC appeared less polar than carbacyclin. When analyzed by GC/MS as the methyl ester-trimethylsilyl ether, this component had a mass spectrum expected for 15-dehydro-carbacyclin. When the presumed metabolite was further converted to the methoxime, the mass spectrum was identical to published spectra for that derivative of 15-dehydro-carbacyclin. When extracts of fetal effluents were analyzed for 15-dehydro-carbacyclin metabolite as well as carbacyclin, it appeared that the metabolite accounted for the majority of the carbacyclin recovered. Most of the metabolite was apparently not formed in the fetal circulation, since when carbacyclin was added to the fetal afferent circulation, little 15-dehydro-carbacyclin was observed in either efferent fluid, and most of the perfused carbacyclin was recovered unaltered in the fetal effluent.

Biological Transport↗
PubMed1987

The mitogenic effect of 15- and 12-hydroxyeicosatetraenoic acid on endothelial cells may be mediated via diacylglycerol kinase inhibition.

15-Hydroxyeicosatetraenoic acid (15-HETE), a major lipoxygenase metabolite of arachidonic acid in fetal bovine aortic endothelial cells, was a mitogen for these cells, stimulating both cell proliferation and DNA synthesis in the presence of serum and serum-deprived cells. In [14C]arachidonic acid-labeled confluent endothelial cell monolayers, 15-HETE (30 microM) caused an elevation of [14C]diacylglycerol (DAG) with a concomitant decrease in cellular [14C]phosphatidylinositol (PI) in both unstimulated and stimulated cells. 1-Oleoyl-2-acetylglycerol, a synthetic DAG analog, stimulated endothelial cell DNA synthesis in a concentration-dependent manner. In [3H]inositol-labeled cells, 15-HETE also caused a decrease in cellular PI content under both basal and stimulated conditions. 15-HETE, however, had no effect on either isolated phospholipase C activity or phosphoinositide turnover in lithium chloride-treated cells. In intact cells, 15-HETE (30 microM) inhibited the synthesis of [3H]PI from [3H]inositol (80% inhibition, p less than 0.001). In human red cell membranes, the production of phosphatidic acid from endogenous DAG was inhibited by 15-HETE in a concentration-dependent manner with an IC50 of 41 microM. Although 12-HETE had effects similar to those of 15-HETE, the parent compound arachidonic acid did not affect DNA synthesis or DAG kinase activity. Our study thus demonstrates that the mitogenic activity of 15- and 12-HETE on endothelial cells may be mediated via DAG kinase inhibition with the concomitant accumulation of cellular DAG.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1987

Endothelial cell proliferation may be mediated via the production of endogenous lipoxygenase metabolites.

Endogenous regulators of endothelial cell proliferation have not been clearly defined. We investigated whether the cyclooxygenase and/or lipoxygenase metabolites are involved in this process, and report that lipoxygenase products can modulate endothelial cell growth. Nordihydroguaiaretic acid--a lipoxygenase inhibitor, inhibited endothelial cell proliferation as well as DNA synthesis. 5,8,11,14-Eicosatetraynoic acid--an inhibitor of both lipoxygenase and cyclooxygenase also inhibited endothelial cell DNA synthesis, while indomethacin--a selective cyclooxygenase inhibitor did not affect cell proliferation or DNA synthesis. While arachidonic acid stimulated DNA synthesis, this effect was completely abolished by nordihydroguaiaretic acid. These results demonstrate that products of the lipoxygenase pathway can affect endothelial cell proliferation.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1987

Cyclooxygenase inhibition reduces placental transfer: reversal by carbacyclin.

The effect of the cyclooxygenase inhibitors, indomethacin and ibuprofen, on diffusional transfer in the human placenta was assessed with the dual-perfused isolated placental lobe. Antipyrine, a freely diffusible substance, was used as an indicator of placental transfer efficiency. Each inhibitor (100 mumol/L) was perfused for 30 minutes after a baseline period, resulting in a significant reduction in antipyrine clearance. During a subsequent washout period, ibuprofen-inhibited antipyrine clearance returned to baseline values, whereas indomethacin-inhibited clearance remained reduced. An additional 30 minutes perfusion of 500 mumol/L of ibuprofen resulted in a further reduction in antipyrine clearance compared with 100 mumol/L of ibuprofen, suggesting a dosage-related effect. The perfusion of each inhibitor caused a reduced production of 6-keto-prostaglandin F1 alpha (the stable metabolite of prostacyclin) in the fetal circulation. The simultaneous perfusion of carbacyclin, a prostacyclin analogue, at 100 nmol/L and 1 mumol/L resulted in a dosage-dependent reversal of the effects of ibuprofen (500 mumol/L) on antipyrine clearance. The results indicate that the inhibition of cyclooxygenase activity reduces placental transfer and that the effects of these inhibitors are reversed by carbacyclin. This study suggests that the use of cyclooxygenase inhibitors during pregnancy could compromise the developing fetus by reducing placental transfer.

Antipyrine↗