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Biomedical subjects

I Fleming

Publications and source records attributed to I Fleming.

At least 91 records · Page 5Linked to original sources
PubMed1991

The effect of inhibitors of the L-arginine/nitric oxide pathway on endotoxin-induced loss of vascular responsiveness in anaesthetized rats.

1. The effects on blood pressure and on pressor responses to noradrenaline (NA), of NG-monomethyl-L-arginine (L-NMMA) and NG-nitro-L-arginine methyl ester (L-NAME), inhibitors of the L-arginine/nitric oxide pathway, were investigated in anaesthetized rats receiving an infusion of bacterial endotoxin (E. coli lipopolysaccharide, LPS). 2. Infusion of LPS (10 mg kg-1 h-1) for 50 min had no effect on mean arterial blood pressure (MABP) but induced a reduction in responsiveness to noradrenaline (100 ng-1 micrograms kg-1). L-NMMA (30 mg kg-1), but not D-NMMA, caused an increase in MABP of approximately 30 mmHg and restored responses to NA. This effect was reversed by L- but not D-arginine (100 mg kg-1). 3. In LPS-treated rats, blood pressure responses to NA were only marginally increased by the cyclooxygenase inhibitor, indomethacin (5 mg kg-1). L-NAME (1 mg kg-1) caused a similar increase in MABP and restored pressor responses to NA both in the presence and absence of indomethacin. 4. Co-infusion of vasopressin (100 ng kg-1, for 10 min) with LPS (10 mg kg-1 h-1) in order to reproduce the hypertensive effect of L-NMMA and L-NAME increased pressor responsiveness to 100 and 300 ng kg-1 NA but not to 1 microgram kg-1 NA. 5. Infusion of sodium nitroprusside (30 micrograms kg-1 min-1) decreased responsiveness to NA even when the hypotension was corrected by co-infusion of vasopressin (50 ng kg-1 min-1). 6. These results demonstrate that the restoration of vascular responsiveness to NA in LPS-treated anaesthetized rats by inhibitors of the L-arginine/nitric oxide pathway is stereospecific and reversible. Furthermore, the experiments involving indomethacin suggest that although cyclo-oxygenase products of arachidonic acid may contribute to the development of LPS-induced hyporeactivity, the effect of L-NAME is unlikely to involve inhibition of the cyclo-oxygenase pathway. Comparison of NA responsiveness during vasopressin and L-NMMA/L-NAME-induced hypertension shows that increasing the blood pressure may modify LPS-induced hyporeactivity, but cannot account for the complete restoration of responses to NA by L-NMMA and L-NAME. These observations suggest that activation of nitric oxide formation from L-arginine makes a direct contribution to the production of vascular hyporeactivity by LPS in vivo.

Animals↗
PubMed1990

An L-arginine-derived factor mediates endotoxin-induced vascular hyposensitivity to calcium.

Aortas removed from rats treated with bacterial endotoxin displayed a reduced sensitivity to calcium (CaCl2, 10 microM-10 mM) in depolarizing medium (100 mM K+). Sensitivity was reduced further in the presence of L-arginine (1 mM) but restored to control by N omega-nitroarginine methyl ester (L-NAME, 300 microM) or NG-monomethyl-L-arginine (L-NMMA, 300 microM), inhibitors of nitric oxide synthesis from L-arginine. Furthermore, addition of methylene blue (10 microM), an inhibitor of soluble guanylate cyclase, restored the contractile response to 10 mM CaCl2. The results suggest that vascular hyposensitivity to calcium involves stimulation of guanylate cyclase subsequent to activation of the L-arginine pathway by endotoxin.

Animals↗
PubMed1990

Incubation with endotoxin activates the L-arginine pathway in vascular tissue.

Rat aortic rings incubated with a low dose of endotoxin (100 ng ml-1) for 5 h exhibited depressed reactivity to norepinephrine (NE) which was independent of the presence of endothelium. An inhibitor of nitric oxide synthesis from L-arginine NGmonomethyl-L-arginine (300 microM), but not the inactive D-enantiomer, restored the contractile response of endotoxin-treated rings to control. The effect of NGmonomethyl-L-arginine was reversed by L-arginine (1 mM). In the absence of NGmonomethyl-L-arginine, L- but not D-arginine relaxed endotoxin-treated rings but was without effect on control tissues. This response was reversed following inhibition of guanylate cyclase by methylene blue (3 microM). In addition, tissue cyclic GMP content was 10 times greater in endotoxin-treated compared to control tissue. These data indicate that endotoxin can act directly on vascular tissue to induce a hyporeactivity to NE which is secondary to the activation of the L-arginine pathway and subsequent activation of soluble guanylate cyclase.

Animals↗
PubMed1990

Local-regional non-rhabdomyosarcomatous soft tissue sarcomas of the head and neck.

Between 1962 and 1987, 112 consecutive patients were treated at St. Jude Children's Research Hospital for soft tissue sarcomas of the head and neck region; 18 of these children (16%) had histologic subtypes other than rhabdomyosarcoma. We evaluated the impact of surgery, postoperative chemotherapy, and irradiation on local control and survival in these cases. Three patients who had complete resection of tumors and received no further treatment are alive without disease at 36, 42, and 162 months. Local control was achieved in 1 of 2 patients with microscopic residual tumor and 4 of 9 patients with gross residual tumor who were treated with irradiation (2500-5040 cGy). Chemotherapy was the only postoperative treatment in three patients; only one achieved lasting local control. One patient was treated with irradiation only; his primary site showed no tumor cells at autopsy following an automobile accident. Overall, local control was achieved in 50% of patients; the disease-free survival rate at 3 years was 44%. The prognosis for patients with nonresectable tumors remains unsatisfactory because of the difficulty in securing local control. A revised therapeutic approach to these patients is presented.

Adolescent↗
PubMed1990

Evaluation of a community care project for people with learning difficulties.

The quality of life and adaptive behaviour of a group of 17 adults with learning difficulties who transferred from a long-stay hospital or hostel into small community-based group homes was assessed before and 1 year after the move. It was found that the increase in adaptive behaviour was largely dependent on structural staff procedures and there was a bias toward achievement in house-bound skills. Subjects had a low level of community presence and few meaningful relationships. Implications for service planning are discussed.

Activities of Daily Living↗
PubMed1990

Loss of vascular responsiveness induced by endotoxin involves L-arginine pathway.

The involvement of L-arginine-dependent nitric oxide (NO) production in the vascular failure observed in endotoxemia was investigated in male Wistar rats treated with Escherichia coli lipopolysaccharide (LPS). Contractile responses to norepinephrine (NE) were measured ex vivo in aortas isolated from rats treated with LPS (20 mg/kg ip, 4 h before experiments) and pressor responses to NE were recorded in vivo in rats infused with LPS (5 mg.kg-1.h-1 iv). LPS pretreatment induced a rightward shift of the concentration-response curve to NE and a reduction of the maximal contraction by approximately 43% and 54% (P less than 0.05) in aortic rings with and without functional endothelium, respectively. This was not modified by the presence of indomethacin (10 microM) during the contractile experiments. In contrast, in the presence of NG-monomethyl-L-arginine (L-NMMA, 300 microM) or methylene blue (10 microM), maximal contractions to NE were restored to control values whether functional endothelium was present or not. The effects of L-NMMA were reversed by L- but not by D-arginine. Additionally, the effects of LPS pretreatment on vascular contractility were potentiated by L-arginine. In vivo, LPS infusion produced a reduction in pressor responsiveness to NE (0.1-10 mg/kg), which was also abolished by L-NMMA (30 mg/kg iv). This effect of L-NMMA was reversed by L- but not by D-arginine (100 mg/kg iv). These results demonstrate that activation of the L-arginine pathway has a major role in the production of vascular hyporeactivity in endotoxemia, ex vivo as well as in vivo. Additionally, they suggest that endothelium-independent vascular production of NO may be involved.

Acetylcholine↗
PubMed1988

Reduced therapy for Wilms' tumor: analysis of treatment results from a single institution.

From 1968 to 1986, 192 patients from 0 to 17 years of age were enrolled in three consecutive protocol-controlled studies of Wilms' tumor at St Jude Children's Research Hospital. Tumors were completely excised at the time of diagnosis whenever possible, and patients were subsequently treated with chemotherapy and radiotherapy according to the initial extent of disease. All patients received dactinomycin and vincristine, with doxorubicin added to the regimens in studies 2 and 3. Chemotherapy was extended to 18 months in study 2 (n = 53), but was limited to 12 months for most patients in study 3 (n = 107). In the third study, radiation was eliminated altogether for patients with stage I or II tumors and was reduced to 12 Gy for those with more advanced disease. Intensification of chemotherapy in study 2 improved the 5-year relapse-free survival rate over that in study 1 (82% v 52%), but the accompanying increase in toxicity was considered unacceptable. Comparison of 2-year relapse-free survival rates in studies 2 and 3 indicated that the reduction of therapy in the latter trial did not jeopardize disease control: 88% v 86% for patients with stage II or III disease, favorable histology; 75% v 57% for the same stages, unfavorable histology; and 57% v 61% for stage IV patients. At least 80% of all patients enrolled in study 3 will be long-term survivors. We conclude that rescheduling of effective antitumor drugs and eliminating or reducing radiotherapy are feasible alternatives in the treatment of Wilms' tumor with favorable histologic features.

Adolescent↗
PubMed1987

Chronic stress as a factor in physiologic reactivity to challenge.

This study examined the hypothesis that chronic stress contributes to heightened cardiovascular reactivity. Chronic stress was operationalized as crowding stress associated with commercial-residential mixes in high-density neighborhoods. Seventeen residents of crowded neighborhoods and 24 residents of uncrowded neighborhoods worked on a challenging task while blood pressure and heart rate were measured. Self-report and biochemical measures indicated that the two groups differed in level of chronic stress. Results also indicated that chronic stress contributes to cardiovascular reactivity. Crowded residents showed greater increases in systolic and diastolic blood pressure and heart rate and took longer to return to baseline than did uncrowded residents. The few differences found between Type A and Type B residents were found only in the low-stress group.

Adult↗
PubMed1986

A primer on organosilicon chemistry.

Organosilicon chemistry is easily understood because a few generalizations allow us to compare it with the chemistry of carbon, hydrogen and the metals. A silyl group is used in organic synthesis as a metallic substitute for a hydrogen atom, metallic enough in character to control both the site of attack by an electrophile and the position of the final double bond. The silyl group can be thought of as a kind of super-proton. Organosilicon biochemistry is beginning to exist because of the possibility of incorporating silyl groups into drugs, and because the secondary metabolism of silicon-containing compounds is being studied.

Chemical Phenomena↗
PubMed1983

Limb salvage procedures for children with osteosarcoma: an alternative to amputation.

Amputation remains the standard surgical management for patients with osteosarcoma. However, in carefully selected patients, eradication of the primary tumor can be achieved by En-Bloc resection of the affected bone preserving both anatomical and functional status. Our criteria for limb salvage procedures are that patients must: (1) be age 12 years or older, (2) have no angiographic or clinical evidence of neurovascular involvement, (3) have low-grade osteosarcoma and/or good response to preoperative chemotherapy, and (4) be compliant. Between November 1980 and October 1982, 32 patients with osteosarcoma of an extremity were seen. Eight patients ranging in age from 13 to 21 years underwent limb salvage procedures. Five of these had Tikhoff-Linberg procedures for upper extremity lesions, two had En-Bloc resections for distal femur lesions, and one patient had a segmental arthrodesis for a distal tibial lesion. Of these eight patients, two had low-grade parosteal osteosarcoma. Follow-up ranged from 10 to 28 months (median 16 months). The two patients with parosteal osteosarcoma received no further therapy, while the other six patients received multiple agent chemotherapy. One patient died at 18 months with bilateral pulmonary disease. None have had local recurrences. Two of the eight patients had minor skin necrosis, requiring revision subsequently. Three patients have had transient nerve palsy. All have had good functional results. With careful selection of patients by rigid criteria, limb salvage procedures can be a viable alternative to amputation.

Adolescent↗
PubMedDate not supplied

Paracrine functions of the coronary vascular endothelium.

Coronary vascular endothelial cells control vascular tone by modulating the local concentration of circulating vasoactive substances (e.g. adenine nucleotides, biogenic amines and bradykinin) and by synthesising and releasing the vasoactive autacoids nitric oxide (NO) and prostacyclin (PGI2). The fluid shear stress exerted by the streaming blood is the physiologically most important stimulus for a continuous endothelial NO production, which counteracts neuro- and myogenic constriction. This shear stress-dependent NO release represents a highly effective local system for maintaining adequate blood flow to the myocardial tissue. At the transcriptional level endothelium-derived NO modulates the regulation of a number of genes (e.g. monocyte chemoattractant protein-1, P-selectin and vascular cell adhesion molecule-1) most probably by direct and/or indirect interaction with transcription factors. In addition to NO and PGI2, the coronary vascular endothelium is also able to release a factor which causes hyperpolarisation of the underlying smooth muscle. This so-called endothelium-derived hyperpolarising factor (EDHF) displays the characteristics of a cytochrome P450-derived arachidonic acid metabolite. However, since NO is able to attenuate production of this factor, EDHF may contribute to the regulation of vascular tone essentially in situations associated with an apparent dysfunction of the endothelium.

Acetylcholine↗