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Biomedical subjects

K M Bell

Publications and source records attributed to K M Bell.

At least 19 recordsLinked to original sources
PubMed2002

Insulin reduces serum glycosylphosphatidylinositol phospholipase D levels in human type I diabetic patients and streptozotocin diabetic rats.

The enzyme glycosylphosphatidylinositol phospholipase D has a postulated role in the insulin-mimetic signaling pathway of glycosylphosphatidylinositol compounds. We have investigated enzyme activity in the serum of human type I diabetic patients and plasma and tissues of streptozotocin-induced diabetic rats following insulin administration. In the human diabetic patients serum enzyme activity fell by an average of 10.6% (SEM = 2.7; P = 0.008; n = 20) following administration of insulin. In addition serum enzyme activity appeared to be depleted by 27% (SEM = 8.8; P = 0.011; n = 10) compared to nondiabetic controls. In untreated diabetic rats plasma enzyme activity gradually increased 0.3-fold over a 6-week period (P < 0.001; n = 8), this increase was reversed and activity normalized when these animals were treated with insulin. Cloning of the rat glycosylphosphatidylinositol phospholipase D cDNA enabled confirmation of the liver as the principal organ of synthesis. Analysis of mRNA levels in the livers of the diabetic rats showed that gene expression was reduced in the insulin-treated animals compared to the noninsulin-treated controls by 0.7-fold (P = 0.004; n = 4). Tissue enzyme activity was also reduced in the insulin-treated rats; in skeletal muscle enzyme activity was 0.3-fold lower (P = 0.001; n = 4). Insulin therefore decreases glycosylphosphatidylinositol phospholipase D synthesis in diabetic animals resulting in decreased serum enzyme levels, suggesting a relationship between this enzyme and the function of insulin.

Animals↗
PubMed2000

SOX14 is a candidate gene for limb defects associated with BPES and Möbius syndrome.

Members of the SOX gene family encode proteins with homology to the HMG box DNA-binding domain of SRY, the Y-linked testis-determining gene. SOX genes are expressed during embryogenesis and are involved in the development of a wide range of different tissues. Mutations in SRY, SOX9 and SOX10 have been shown to be responsible for XY sex reversal, campomelic dysplasia and Waardenburg-Hirschsprung disease, respectively. It is likely that mutations in other SOX genes are responsible for a variety of human genetic diseases. SOX14 has been identified from a human genomic library and the mouse and chicken sequences obtained by polymerase chain reaction amplification. The SOX14 amino acid sequence is highly conserved across these species, suggesting an important role for this protein in vertebrate development. SOX14 is expressed in the neural tube and apical ectodermal ridge of the developing chicken limb. This is the only SOX gene known to be expressed in the apical ectodermal ridge, a structure that directs outgrowth of the embryonic limb bud. Human SOX14 is localised to a 1.15-Mb yeast artificial chromosome on chromosome 3q23, close to loci for BPES (blepharophimosis, ptosis, epicanthus inversus syndrome) and Mobius syndrome. Although SOX14 maps outside these loci, its expression pattern and chromosomal localisation suggest that it is a candidate gene for the limb defects frequently associated with these syndromes.

Amino Acid Sequence↗
PubMed2000

SOX8 expression during chick embryogenesis.

We have isolated the SOX8 gene from the chicken embryo. This gene shows a high degree of sequence homology to SOX9 and SOX10. Detailed analysis of SOX8 expression by whole-mount in situ shows a dynamic and restricted expression pattern during chick development. SOX8 is expressed in the somitic derivative, the dermomyotome, the developing heart, pancreas, enteric neurone system, limb and the neural tube. This is the first detailed expression analysis of SOX8 in any species

Amino Acid Sequence↗
PubMed1999

Modification of blood flow in the HSN tumour and normal tissues of the rat by the endothelin ET(B) receptor agonist, IRL 1620.

Activation of endothelin receptors on the vasculature can produce a variety of responses from potent vasoconstriction to mild vasodilation, depending on the receptor complement within the tissue. To elucidate the potential role of endothelin analogues as tumour blood flow modifiers, we have evaluated the effect of the ET(B) receptor agonist, IRL 1620 ([Suc-(Glu9, Ala(11,15))-ET-1(8-21)]) in CBH/CBi rats bearing an HSN fibrosarcoma. Tissue blood flow and vascular resistance were determined, 20 min following administration of IRL 1620 (bolus intravenous), using the uptake of radiolabelled iodoantipyrine (125I-IAP). Blood flow was unchanged in most tissues. However, at doses > or = 1.0 nmol kg(-1) IRL 1620, blood flow in the brain and heart was increased, whereas in the small intestine it was reduced. Blood flow in the skeletal muscle was reduced at 1.0 nmol kg(-1) only. Tumour blood flow was significantly reduced at 3.0 and 5.0 nmol kg(-1). Vascular resistance was unchanged in most tissues although it was increased in the skeletal muscle at 1.0 nmol kg(-1), in the kidney at 1.0 and 3.0 nmol kg(-1) and in the brain and heart, it was reduced at 5.0 nmol kg(-1) IRL 1620. Vascular resistance was significantly increased in the tumour and the small intestine at doses > or = 1 nmol kg(-1) IRL 1620. Pretreatment of rats with BQ-788, an ET(B) receptor antagonist, selectively attenuated the tumour vascular response to 3 nmol kg(-1) IRL 1620 with no changes observed in the normal tissue responses. Our results demonstrate that the HSN tumour vasculature is selectively responsive to IRL 1620 at doses > 1 nmol kg(-1) compared with the majority of normal tissues with the exception of the small intestine, and that only the tumour response is highly sensitive to BQ-788 antagonism, under the experimental dosing regime investigated. These differences may be exploitable for therapeutic benefit.

Analysis of Variance↗
PubMed1998

Modification of tumor blood flow: current status and future directions.

Suboptimal drug distribution and hypoxia, which can contribute to treatment failure, are a direct consequence of the spatial and temporal heterogeneity in perfusion that occurs in solid tumors. Therefore, improvements in tumor blood flow have wide-ranging therapeutic importance. Paradoxically, controlled decreases in tumor blood flow can also be exploited and, if permanent, induce extensive tumor cell death on their own. We review the current knowledge of the factors controlling tumor blood flow with emphasis on the roles of the endogeneous vasodilator nitric oxide and the endogenous vasoconstrictor endothelin-1. The potential importance and application of approaches that irreversibly damage vascular function, so-called vascular targeting, are also discussed. Emphasis is given to the drug-based approaches to vascular targeting that are now entering clinical evaluation. There is no doubt that increased understanding of the processes that determine blood flow in tumors, coupled with the availability of techniques to monitor blood flow noninvasively in the clinic, will enable strategies for selectively modifying tumor blood flow to be transferred from the laboratory to the clinical setting.

Antineoplastic Agents↗
PubMed1998

The effect of oxygen and carbon dioxide on tumor cell endothelin-1 production.

Endothelin-1 (ET-1) is produced by some tumor cells, but the dependence of this production on pO2 and pCO2, conditions relevant within the tumor microenvironment, has not been described. HT29 colon adenocarcinoma cells and DU145 prostate carcinoma cells produce similar amounts of ET-1 in vitro under normal cell culture conditions of 21% O2/5% CO2 (normoxia). Exposure of HT29 cells to either 2% O2 or 0.2% O2 significantly reduced ET-1 production compared to cells in normoxia. In contrast, production of ET-1 by DU145 cells was usually unaffected by hypoxia and was even slightly increased in cells exposed to 2% O2 in HEPES-buffered EMEM (HEPES-EMEM). Exposure of cells to either 2.2% CO2 or 7.1% CO2 had no effect on the production of ET-1 by cells in bicarbonate-buffered EMEM (EMEM). However, in HEPES-EMEM, ET-1 production by both cell lines was reduced in 7.1% CO2. A slight reduction in ET-1 produced by DU145 cells was also observed in 2.2% CO2. These results illustrate that changes in ET-1 production by tumor cells in response to hypoxia and hypercapnia are tumor-dependent. It is clear that the production of ET-1 by tumor cells under normal culture conditions may not accurately reflect production within the tumor microenvironment. A greater insight into the in vivo situation, however, may be possible by modifying the cell culture conditions.

Adenocarcinoma↗
PubMed1998

Familial Kallmann syndrome: a novel splice acceptor mutation in the KAL gene.

Kallmann syndrome is an inherited disease which is characterised by anosmia (inability to smell) and hypogonadotropic hypogonadism both of which are thought to occur as a result of a failure of correct neuronal migration. To date the only genetic lesions identified are mutations in the X-linked gene, KAL. We conducted a mutation screen of the KAL gene in a family with Kallmann syndrome. This identified a new mutation in the KAL gene which removed an acceptor site at the junction of exon 6/intron 5. Exon 6 of the KAL gene encodes the C-terminal portion of a fibronectin type III domain may be involved in axonal pathfinding. We presume that the described mutation would result in the removal of exon 6 resulting in a frame shift which terminates the protein prematurely. It has been proposed that both mental illness and vesico-ureteric reflux are associated with mutations in the KAL gene. However, results from the family presented here do not show an association between either trait and the KAL gene mutation.

Child↗
PubMed1998

Dynorphin A(1-8): stability and implications for in vitro opioid activity.

The opioid binding profile and in vitro activity of the endogenous opioid peptide dynorphin A(1-8) have been studied. At opioid receptors in guinea-pig brain dynorphine A(1-8) was nonselective, although with some preference for the delta receptor (Ki 4.6 nM) over mu (Ki 18 nM) and kappa (Ki 40 nM) receptors. However, a high degree of metabolism was observed, with less than 10% of added dynorphin A(1-8) remaining at the end of the binding assay. In the presence of peptidase inhibitors to prevent breakdown of the N- and C-termini and the Gly3-Phe4 bond the major metabolite was [Leu5]enkephalin (representing 49% recovered material). This was reduced by inclusion of an inhibitor of endopeptidase EC 3.4.24.15. In the presence of all the peptidase inhibitors the affinity for kappa receptors (Ki 0.5 nM) relative to mu and delta receptors increased, but no selectivity of binding was observed. This lack of selectivity was confirmed using membranes from C6 glioma cells expressing rat opioid receptors. The agonist effect of dynorphin A(1-8) in the mouse vas deferens (EC50 116 nM) and guinea-pig ileum (EC50 38 nM) was mediated through the kappa receptor as evidenced by the rightward shifts afforded by the kappa-selective antagonist norbinaltorphimine. In the presence of peptidase inhibition potency was improved 2-fold in the mouse vas deferens and 20-fold in the guinea-pig ileum, but this agonist activity was mediated through delta receptors in the vas deferens and mu receptors in the ileum, as a result of the formation and stabilization of [Leu5]enkephalin. The results confirm the absence of receptor selectivity of dynorphin A(1-8) in binding assays but show that its agonist effects, at least in vitro, are mediated exclusively through the kappa opioid receptor.

Animals↗
PubMed1997

Vascular response of tumour and normal tissues to endothelin-1 following antagonism of ET(A) and ET(B) receptors in anaesthetised rats.

Modification of blood flow by endothelin-1 (ET-1) was examined in the s.c. HSN fibrosarcoma and compared to normal tissues of anaesthetised CBH/CBi rats. The ET receptor subtypes involved in the response were investigated using the ET(A) and ET(B) receptor antagonists BQ-610 and BQ-788, respectively. Blood flow and vascular resistance were determined using the uptake of radiolabelled iodo-antipyrine (125I-IAP). BQ-610 or BQ-788 was infused for 30 min prior to blood flow determination. ET-1 was administered 15 min into the infusion time. BQ-610 and BQ-788 infused alone did not modify any vascular parameters. Tumour blood flow increased slightly following ET-1, contrasting with most normal tissues, in which blood flow was reduced. Vascular resistance increased in all tissues, including the tumour. Neither antagonist significantly modified the ET-1-induced changes in tumour blood flow or vascular resistance, whereas in the majority of normal tissues BQ-610 attenuated and BQ-788 potentiated the vascular resonse to ET-1. Our results show that the HSN tumour vasculature is only weakly responsive to ET- 1 and antagonism of its effects by BQ-610 and BQ-788. This contrasts with the majority of normal tissues, in which ET- 1 induces an intense vasoconstriction.

Animals↗
PubMed1996

A comparative study of tumour blood flow modification in two rat tumour systems using endothelin-1 and angiotensin II: influence of tumour size on angiotensin II response.

Tumour blood flow modification following i.v. administration of angiotensin II (AT II, 0.19 nmol kg-1 min-1) or endothelin-1 (ET-1, 1 nmol kg-1) was compared in the P22 carcinosarcoma-bearing BD9 rat and the HSN fibrosarcoma-bearing CBH/CBi rat using the tissue uptake of radiolabelled iodoantipyrine. Results were compared with a range of normal tissues. HSN tumour blood flow was unmodified by either peptide, whereas P22 tumour blood flow was unmodified by ET-1 but was reduced to 80% of the control flow by AT II. Both peptides reduced absolute blood flow in the skin overlying the tumour, in contralateral skin, skeletal muscle, kidney and small intestine, whereas blood flow to the brain and heart was significantly increased by ET-1 and unmodified by AT II. Both peptides significantly increased vascular resistance (mean arterial blood pressure / tissue blood flow) in all normal tissues and both tumours, thus demonstrating the existence of vascular receptors for these 2 vasomodifiers, and the capacity of the vessels to respond to receptor activation. Dependency of response on tumour size was examined in the P22 tumour. In contrast to that in small P22 tumours (1.22 +/- 0.06 g), blood flow to large P22 tumours (7.18 +/- 0.25 g) was unmodified by AT II. Vascular resistance was equally increased in both tumour groups, thus illustrating little difference in the vascular response to AT II in the size range examined. Results show that the 2 rat tumours responded directly to ET-1 and AT II, but do not indicate any advantage of ET-1 over AT II in tumour blood flow modification. However, the existence of tumour vascular endothelin receptors suggests that the advent of less toxic and more controllable receptor ligands may make endothelin receptors of value in the modification of tumour blood flow.

Angiotensin II↗
PubMed1996

Spatial heterogeneity of tumour blood flow modification induced by angiotensin II: relationship to receptor distribution.

Angiotensin II (ATII) has potential for improving delivery of blood-borne anti-cancer agents to tumours by increasing tumour blood flow. However, ATII-induced hypertension is not always accompanied by an increase in tumour blood flow due to significant constriction of the tumour vasculature. Such unpredictability in tumour response to ATII limits the clinical usefulness of this approach. In this study, the potential of assessing numbers of binding sites for ATII as a predictor of tumour blood flow response to intravenous administration of ATII was investigated. The distribution of ATII receptors in the rat P22 carcinosarcoma was related to tumour blood flow distribution and blood flow response to ATII using an autoradiographic approach. ATII (0.2 microgram x kg-1 x min-1) increased mean arterial blood pressure of anaesthetized BD9 rats from 92.2 +/- 1.4 mmHG to 145.6+- 1.3 mmHg. Despite this increase in perfusion pressure, overall tumour blood flow to viable regions decreased by 20%, indicating significant constriction of tumour blood vessels. Autoradiographic localisation of tumour blood flow showed that the decrease in flow was confined to the tumour periphery, with no change at the tumour centre. This pattern was consistent with 10% more binding sites for ATII at the tumour periphery than at the tumour centre. Maximum number of binding sites (BLmax) for the P22 tumour was 0.38 +/- 0.09 fmol x mg-1, which is approximately a factor of 10 lower than published values for various normal tissues. The dissociation constant Kd was l.16 +/- 0.18 nM. These results encourage the development of techniques for analysis of receptor binding characteristics for predicting the response of individual tumours to blood flow manipulation using vasoactive agents.

Angiotensin II↗
PubMed1996

Reduced capacity of tumour blood vessels to produce endothelium-derived relaxing factor: significance for blood flow modification.

The effect of nitric oxide-dependent vasodilators on vascular resistance of tumours and normal tissue was determined with the aim of modifying tumour blood flow for therapeutic benefit. Isolated preparations of the rat P22 tumour and normal rat hindlimb were perfused ex vivo. The effects on tissue vascular resistance of administration of sodium nitroprusside (SNP) and the diazeniumdiolate (or NONO-ate) NOC-7, vasodilators which act via direct release of nitric oxide (NO), were compared with the effects of acetylcholine (ACh), a vasodilator which acts primarily via receptor stimulation of endothelial cells to release NO in the form of endothelium-derived relaxing factor (EDRF). SNP and NOC-7 effectively dilated tumour blood vessels after preconstriction with phenylephrine (PE) or potassium chloride (KCl) as indicated by a decrease in vascular resistance. SNP also effectively dilated normal rat hindlimb vessels after PE/KCl constriction. Vasodilatation in the tumour preparations was accompanied by a significant rise in nitrite levels measured in the tumour effluent. ACh induced a significant vasodilation in the normal hindlimb but an anomalous vasoconstriction in the tumour. This result suggests that tumours, unlike normal tissues are incapable of releasing NO (EDRF) in response to ACh. Capacity for EDRF production may represent a difference between tumour and normal tissue blood vessels, which could be exploited for selective pharmacological manipulation of tumour blood flow.

Acetylcholine↗
PubMed1996

Physician profiling: 12 critical points.

Physician profilers encompass an array of technological products that purport to evaluate individual clinician performance on utilization and other measures. Prior to installation, an organization should be familiar with a number of major concepts that encompass understanding of clinical practice processes, claims data limitations and idiosyncrasies, ethical issues, and mathematical principles. Twelve specific elements are described to assure that these concepts are addressed.

Ambulatory Care↗
PubMed1996

Tumour blood flow modification by endothelin-related peptides in the rat HSN fibrosarcoma.

Modification of tissue blood flow and tissue vascular resistance was examined in the female CBH rat, bearing a HSN fibrosarcoma, following bolus intravenous administration of 1 nM kg-1 endothelin-1 (ET-1) or 1 nM kg-1 sarafotoxin S6c (SX6c), selective agonists for endothelin A (ETA) and B (ETB) receptors respectively. Blood flow was measured 15 min after drug administration by the tissue uptake of 125I-labelled-iodoantipyrine. ET-1 and SX6c produced increases in mean arterial blood pressure (MABP) of 52 mmHg and 42 mmHg respectively. Blood flow to the tumour was unaffected by ET-1 treatment, whereas blood flow to normal tissues was reduced, the exception being the heart and the brain in which flow was increased. In contrast, tumour blood flow following SX6c was significantly increased, whereas blood flow in normal tissues was either unaltered or reduced. Vascular resistance was increased in all tissues and the tumour by ET-1 demonstrating that the tumour vasculature was constricting via ETA receptor activation. SX6c however, did not modify tumour vascular resistance, whereas it increased vascular resistance in all normal tissues, suggesting that the tumour lacks a functional population of ETB receptors. This discrepancy may provide a means for selectively modifying tumour blood flow.

Animals↗
PubMed1995

The influence of nitric oxide on tumour vascular tone.

Acetylcholine and sodium nitroprusside, which vasodilate via release of NO by endothelium-dependent and endothelium-independent mechanisms respectively, had little effect on tumour vascular resistance when administered to tissue-isolated tumours perfused in their normal state. However, under phenylephrine-induced vasoconstriction, sodium nitroprusside induced vasodilation whilst acetylcholine induced a small vasoconstriction. Phenylephrine itself induced an oscillatory change in tumour perfusion pressure. The nitric oxide synthase (NOS) inhibitor N omega-nitro-L-arginine (L-NNA) caused a dose-dependent increase in vascular resistance in ex vivo perfused tumours which was greater than that in normal perfused hindlimbs. Systemic administration of L-NNA caused a 50% decrease in tumour blood flow which was a larger effect than in any of the normal tissues studied except spleen and skeletal muscle. Modification of NOS activity in tumours is a promising means for selective tumour blood flow modification. Investigation of endothelium-dependent versus endothelium-independent methods for modifying tumour blood flow may provide methods for further selectivity.

Acetylcholine↗
PubMed1995

Effect of endothelin-1 and sarafotoxin S6c on blood flow in a rat tumor.

The modification of tumor blood flow resulting from administration of endothelin-1 (ET-1) and sarafotoxin S6c (SX6c) was examined in female CBH rats. Blood flow in subcutaneous HSN tumors and normal tissues was measured by tissue uptake of 125I-labeled iodoantipyrine ([125I])IAP). A 75% increase in tumor blood flow was observed after 1 nM/kg ET-1, contrasting with flow in normal tissue, which was unaffected or reduced. The exception to this was the brain, in which blood flow was increased by 30%, resulting from a rise in mean arterial blood pressure (MABP) and the absence of vasoconstriction. Paradoxically, a significant drop in the tumor vascular resistance was observed after 1 nM/kg ET-1, whereas in all other tissues the vascular resistance was significantly increased. Vascular responses to SX6c differed from those observed with ET-1. At 1 nM/kg SX6c, blood flow in the tumor was increased to 175% of the control as a result of the increase in MABP, which was similar to ET-1. However, unlike ET-1, there was no associated vasodilatation. Vascular resistance was increased in all normal tissues with 1 nM/kg SX6c, corresponding to decreases in blood flow in the contralateral skin, skeletal muscle, and small intestine. This study therefore demonstrates that the vascular responses to ET-1 and SX6c are unique in the HSN tumor compared to normal tissues. This atypical response of the tumor vasculature may therefore be exploitable to improve the delivery of blood-borne anti-cancer agents in therapy.

Animals↗
PubMed1994

Primary juvenile fibromyalgia syndrome and chronic fatigue syndrome in adolescents.

Chronic fatigue syndrome (CFS) and primary juvenile fibromyalgia syndrome (PJFS) are illnesses with a similar pattern of symptoms of unknown etiology. Twenty-seven children for whom CFS was diagnosed were evaluated for fibromyalgia by the presence of widespread pain and multiple tender points. Eight children (29.6%) fulfilled criteria for fibromyalgia. Those children who met fibromyalgia criteria had a statistically greater degree of subjective muscle pain, sleep disturbance, and neurological symptoms than did those who did not meet the fibromyalgia criteria. There was no statistical difference between groups in degree of fatigue, headache, sore throat, abdominal pain, depression, lymph node pain, concentration difficulty, eye pain, and joint pain. CFS in children and PJFS appear to be overlapping clinical entities and may be indistinguishable by current diagnostic criteria.

Adolescent↗