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H Cox

Publications and source records attributed to H Cox.

At least 19 recordsLinked to original sources
PubMed1995

Postprandial sympatho-adrenal activity: its relation to metabolic and cardiovascular events and to changes in meal frequency.

1. Sympatho-adrenal activity was measured after the consumption of a 3.15 MJ mixed meal. Whole-body noradrenaline spillover rates, forearm plasma noradrenaline spillover and adrenaline secretion rates were derived using isotope dilution methodology. Heart rate and blood pressure spectral analysis measurements were also made. The relation of sympathoadrenal activity to thermogenic and cardiovascular events was studied. Sympathetic nervous and thermogenic responses were measured for 120 min after the single 3.15 MJ meal and compared with those after three 1.05 MJ meals, given 30 min apart. 2. Whole-body and forearm plasma noradrenaline spillover, and the 0.1 Hz component of systolic pressure power all increased significantly postprandially, while the 0.1 Hz component of heart rate variability, an indirect index of cardiac sympathetic nervous activity, remained unaltered. Adrenaline secretion was unaltered postprandially. Whole-body plasma noradrenaline spillover and thermogenesis during the 120 min postprandial period were 37% and 36% higher after the single meal as compared with the multiple meals, although this was not statistically significant. 3. The sympathetic neural responses were delayed in relation to peak plasma insulin levels and sustained in the face of declining insulin levels. Energy expenditure increased significantly postprandially, but there was no direct quantitative relationship to plasma noradrenaline spillover. Forearm oxygen consumption did not increase postprandially despite significant increases in regional noradrenaline spillover. Thus, no close relation was demonstrated between postprandial sympathetic nervous activation and either insulin secretion or thermogenesis.

Adult↗
PubMed1992

Characterization of the interaction of the cervane alkaloid, imperialine, at muscarinic receptors in vitro.

The action of the cervane alkaloid, imperialine, has been assessed at M1, M2 and M3 receptors in functional assays and at M1, M2, M3 and putative M4 sites in binding studies. In functional studies, imperialine acted as a selective surmountable antagonist at M2 receptors in guinea-pig isolated atria and uterus (-log KB = 7.7 and 7.4, respectively), in comparison to M1 receptors in canine isolated saphenous vein (-log KB = 6.9) or M3 receptors in a range of guinea-pig isolated smooth muscles including ileum, trachea, fundus, seminal vesicle or oesophagus (-log KB = 6.6-6.8). In rat aorta, the -log KB value at the M3 receptor (5.9) was slightly, but significantly, lower. In competition radioligand binding studies, imperialine was also selective toward to M2 sites in rat myocardium (-log Ki = 7.2) with respect to M1 and M3 sites (rat cerebral cortex, rat submaxillary gland; -log Ki = 6.1 and 5.7, respectively). However, it did not significantly discriminate between rat cardiac M2 sites and putative M4 sites in rabbit lung (-log Ki = 6.9). Imperialine resembles the alkaloid himbacine in terms of its pharmacological profile at muscarinic receptor subtypes in that it acts as an M2 selective antagonist with respect to M1 or M3 sites. It may also provide a second, commercially available, antagonist with which to discriminate between M1 and M4 receptors.

Alkaloids↗
PubMed1992

Relationship between the sympatholytic action of nebivolol and hypotension.

Nebivolol, a chemically novel beta 1-adrenoceptor antagonist, acutely lowers blood pressure in spontaneously hypertensive rats, anaesthetised normotensive dogs, and hypertensive patients. We have investigated the actions of dl-nebivolol in five conscious normotensive rabbits (sham, mean blood pressure (BP) of 82.2 +/- 4.1 mm Hg, mean +/- SEM) and four hypertensive rabbits (renal wrap hypertension) (wrap, mean BP of 117.6 +/- 1.5 mm Hg). Nebivolol (1 mg/kg i.v.) did not significantly lower the BP or heart rate in either group 30 min after injection. In the same rabbits, on another day, after autonomic blockade (mecamylamine), nebivolol (0.1, 0.3, and 1.0 mg/kg i.v.) right shifted the bolus i.v. isoproterenol tachycardia dose-response curves by dose ratios of 5, 18, and 90 in sham rabbits, respectively, and 5, 11, and 23 in wrap rabbits, respectively, indicating significant cardiac beta 1-adrenoceptor antagonism. In guinea pig isolated right atria pretreated with atropine (1 microM) and desipramine (DMI, 0.1 microM), norepinephrine concentration-response curves were antagonised competitively by nebivolol (3-100 nM), giving a pKb of 7.90. In separate atria without DMI pretreatment, neither nebivolol (100 nM) nor propranolol (100 nM) had any significant effect on the increase in the rate of norepinephrine efflux following electrical field stimulation (0.5-2 Hz, 3 min). These findings suggest that at concentrations of nebivolol that show substantial beta 1-adrenoceptor antagonism, there is no evidence of hypotension or bradycardia nor additional effects on cardiac norepinephrine release. Why nebivolol lowers blood pressure in some species but not in the conscious rabbit is not known.

Adrenergic beta-Antagonists↗
PubMed1991

c-myc protein product is a marker of DNA synthesis but not of malignancy in human gastrointestinal tissues and tumours.

c-myc is a conserved cellular gene. The gene product is a nuclear-bound 62,000 molecular weight phosphoprotein (p62c-myc). Although p62c-myc levels have been measured in colorectal cancers, little is known about the expression of the protein in upper gastrointestinal tumours and tissues. Studies were performed on tumour and mucosal specimens from 87 patients with colorectal cancer, from two with polyposis coli, from six with squamous oesophageal carcinomas and from 18 with gastric carcinomas. The mean p62c-myc content was measured in units of fluorescence in the G1 diploid and G2 diploid peaks of the cell cycle by multiparameter flow cytometry using the 6E10 antibody. The nuclear p62c-myc content increased with DNA synthesis in tumours and mucosa. G2 levels of p62c-myc were higher in glandular mucosa than in adenocarcinomas. No differences in peak nuclear c-myc expression were found in relation to histological grade or to anatomical site of colorectal tumours. There was a broadly inverse relationship between G2 p62c-myc levels in tumours and mucosa and their in vivo 5-bromo-2'-deoxyuridine labelling indices. Nuclear p62c-myc levels are cell cycle related but the protein has not been shown to be a marker of increased tissue proliferation or of gastrointestinal malignancy. The reduction of the nuclear p62c-myc content of many adenocarcinoma cells compared with glandular mucosa cells suggests that reduced synthesis or nuclear retention of the normal protein may be a factor in the development of gastrointestinal adenocarcinomas, although the mechanism by which this may occur is not clear.

Adenocarcinoma↗
PubMed1991

Is adrenaline released by sympathetic nerves in man?

Radiotracer methods were used to measure the rates of regional release of adrenaline and noradrenaline into plasma in man. This was done as a partial test of a theory of essential hypertension pathogenesis which envisages an important cotransmitter function for neuronally released adrenaline. In healthy resting men no release of adrenaline could be detected from the heart, lungs or liver. Adrenaline was released into the right renal vein but an adrenal medullary source is suspected. With the relatively limited activation of the cardiac sympathetic outflow which accompanied mental challenge and isometric exercise, cardiac adrenaline release remained undetectable. During supine bicycle exercise, which increased cardiac noradrenaline release 10-30 fold, to a mean value of 197 ng/min, cardiac adrenaline release averaged 2.36 ng/min. In two clinical conditions associated with persistently elevated plasma adrenaline concentrations, cardiac failure and adrenaline-secreting phaeochromocytoma, regional release of adrenaline was clearly evident. Thus, in normal man during exercise, and in patients with cardiac failure at rest, adrenaline is released from non-adrenal sources, and probably from sympathetic nerves. Whether neuronal adrenaline release of the degree found would be sufficient to facilitate noradrenaline release, augment sympathetically-mediated cardiovascular responses and contribute to the development of arterial hypertension remains to be tested.

Adrenal Gland Neoplasms↗
PubMed1991

Adrenaline release by the human heart.

1. Radiotracer methods were used to measure the rates of regional release of adrenaline and noradrenaline to plasma in humans. 2. No release of adrenaline could be detected from the heart, lungs, liver and kidneys at rest. 3. With the relatively mild activation of the cardiac sympathetic outflow associated with mental challenge and isometric exercise, cardiac adrenaline release remained undetectable. 4. During supine bicycle exercise, which increased cardiac noradrenaline release 10-20 fold, to a mean value of 128 ng/min, cardiac adrenaline release averaged 1.63 ng/min. 5. Whether neuronal adrenaline release of this degree in the heart is sufficient to facilitate noradrenaline release and to augment sympathetically mediated cardiac responses remains to be tested.

Epinephrine↗
PubMed1991

Biochemical evidence of sympathetic hyperactivity in human hypertension.

Radiotracer measures of norepinephrine overflow to plasma are well suited for studying both human sympathetic nervous system responses to mental stress and sympathetic nervous pathophysiology in human hypertension. With an experimental laboratory stressor (cognitive challenge), we noted a preferential activation of the cardiac sympathetic outflow; however, in fainting reactions ("vasovagal syncope"), which occur infrequently during the course of central venous catheter placement under local anesthesia, the converse was seen--an almost total withdrawal of cardiac sympathetic activity. In primary human hypertension (particularly in younger patients), a differentiated activation of the sympathetic outflow to the heart and kidneys is present, based on measurements of norepinephrine spillover to plasma. It is uncertain whether this is attributable to behavioral factors and represents a component of the defense reaction. We previously reported overflow of norepinephrine into the cerebrovascular circulation (with high internal jugular venous sampling) in humans. Because this is resistant to ganglion blockade, brain neurons--not the cerebrovascular sympathetics--are the presumed source. In a preliminary study, we found higher rates of norepinephrine spillover into the cerebrovascular circulation in patients with essential hypertension than in healthy subjects, suggesting that an underlying increase in central nervous system norepinephrine turnover may be the basis for the increased sympathetic outflow.

Brain↗
PubMed1990

Tissue preparation for simultaneous flow cytometric quantitation of tumour associated antigens and DNA in solid tumours.

A multiparameter flow cytometric assay for the simultaneous study of tumour associated antigens (TAA) and DNA in fresh solid tumours was devised. Cell suspensions were prepared by disaggregating unfixed solid tumour samples mechanically over a stainless steel mesh. Indirect immunofluorescence was used to identify the TAA, and DNA was stained with propidium iodide. Cell morphology was well preserved, cell clumping was negligible, and high quality indirect immunofluorescence quality indirect immunofluorescence and DNA staining were obtained. The technique is simple, rapid, and reproducible. Multiparameter assays can be developed to study prognostic indicators such as membrane oncoproteins, receptors, and multidrug resistance in solid tumours. With a suitable panel of antibodies the technique might become an aid in the differential diagnosis and biochemical diagnosis of some solid tumours.

Antigens, Tumor-Associated, Carbohydrate↗
PubMed1989

Radial ray defects and associated anomalies.

In a series of 34 patients with defects of the radial ray, 24 individuals had additional clinical manifestations. A firm syndromic diagnosis could be reached in 17 persons (TAR syndrome 4, Holt-Oram syndrome 8, Fanconi anaemia 2, VATER association 2, Radial ray-choanal atresia 1). In the remainder, no specific diagnosis could be established. The heterogeneity of radial ray syndromes has important implications for prognostication and genetic counselling.

Abnormalities, Multiple↗
PubMed1988

Polar fluorescein derivatives as improved substrate probes for flow cytoenzymological assay of cellular esterases.

Fluorescein esters are employed in assays of cell viability, membrane permeability and esterase activity. The ester most widely used, fluorescein diacetate (FDA), has the disadvantage of rapid cellular efflux of its hydrolysis product fluorescein. This is particularly problematic for flow cytoenzymology (FCE), where fluorescence is measured in individual cells allowing identification of subpopulations differing in esterase activity and/or membrane characteristics. We present a comparison of FDA with two potentially improved substrate probes for FCE, carboxyfluorescein diacetate (CFDA) and bis(carboxyethyl)-carboxyfluorescein-tetra acetoxy methyl ester (BCECF-AM). Substrates were characterized in terms of reaction and product efflux kinetics in EMT6 mouse mammary tumour cells, together with inhibition kinetics for the carbamoylating agent BCNU. Intact viable cells were analysed by FCE and spectrofluorimetry, and the latter was also used for cell sonicates and purified esterase. CFDA and BCECF-AM enter cells and are hydrolysed more slowly than FDA. CFDA and FDA hydrolyses obey Michaelis-Menten kinetics with Km values of around 19 and 2 microM, respectively, whereas BCECF-AM hydrolysis deviates from this classical behaviour. BCNU (5 X 10(-4) M) inhibits FDA and BCECF-AM hydrolyses by approximately 50%, compared to 30% for CFDA. CFDA may be partly hydrolysed by membrane-bound esterases. Efflux half-lives were 16 min, 94 min and greater than 2 h for products of FDA, CFDA and BCECF-AM, respectively. We conclude that BCECF-AM is the optimal substrate probe for FCE. This study emphasizes the need to optimize various parameters when selecting a substrate for flow cytoenzymological assay or when loading other reporter fluorochromes into cells via lipophilic esters.

Animals↗
PubMed1987

Flow cytometric quantitation of the c-myc oncoprotein in archival neoplastic biopsies of the colon.

The c-myc oncogene encoded protein product, p62c-myc, was assayed simultaneously with DNA in populations of individual nuclei extracted from archival biopsies of colonic neoplasia. Both the protein and DNA were assayed fluorimetrically using flow cytometry with a synthetic peptide induced monoclonal antibody (MYC 1-6E10) for the protein and propidium iodide for DNA. The nuclear p62c-myc levels increased progressively from normal mucosa through polyps to carcinomas. However, there was a trend for the more poorly differentiated carcinomas to exhibit lower levels than moderately and well-differentiated tumours, p = 0.085. These results agree with those published previously with the same antibody using Western blotting for protein extracted from fresh frozen tissue and immunocytochemical assessment. Furthermore, flow cytometry is able to effect discriminations between subsets in heterogeneous populations using DNA as a second parameter which Western blot bulk studies cannot.

Biopsy↗
PubMed1987

Flow cytometric quantitation of DNA and c-myc oncoprotein in archival biopsies of uterine cervix neoplasia.

The c-myc nuclear associated oncoprotein has been quantitated simultaneously with DNA in nuclei extracted from archival biopsies of uterine cervix neoplasia. The oncoprotein and DNA were measured fluorimetrically in a flow cytometer using a mouse monoclonal antibody (MYC 1-6E10) and propidium iodide. Normal biopsies exhibited higher oncoprotein levels than carcinomas (P less than 0.00001). Furthermore, the maximum fluorescence signal in the normal tissue occurred at a lower antibody concentration compared with tumour tissue. There was no correlation between oncoprotein levels and histological grade, stage of disease, age of the patients or prognosis in the carcinomas. Aneuploidy, defined as a distinct second peak separate from the diploid distribution, was not a significant feature. The c-myc oncoprotein nuclear content does not appear to be a prognostic indicator in carcinoma of the cervix from the results of these studies but there is clearly diagnostic potential, particularly for automated analysis of cervical screening.

Cervix Uteri↗