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Biomedical subjects

G Lambert

Publications and source records attributed to G Lambert.

At least 145 records · Page 8Linked to original sources
PubMed1990

Evidence for increased renal norepinephrine overflow during sodium restriction in humans.

To investigate the differentiated pattern of efferent sympathetic nerve activity by means of analyzing norepinephrine kinetics in response to sodium restriction, cardiorenal sympathetic activity during rest and mental stress was studied in 12 subjects (33.3 +/- 2.6 years old, SEM) exposed to a low and a normal sodium diet; 5-40 mmol and 160-200 mmol/24 hours, respectively (crossover design). Organ norepinephrine release was calculated from organ plasma flow, arteriovenous plasma concentration gradient across the organ and the organ's fractional extraction of radiolabeled norepinephrine. Body weight and urinary sodium/24 hr fell significantly and urinary potassium/24 hr and both supine and standing blood pressure remained unchanged. Total norepinephrine release to plasma and norepinephrine plasma clearance were similar in both phases (approximately 460 ng/min and 1.90 l/min, respectively). A 138% increase in renal norepinephrine overflow was observed during sodium restriction (from 112 to 267 ng/min, p less than 0.025), which was due to elevated renal vein norepinephrine (434 versus 290 pg/ml, p less than 0.01) because renal plasma flow and renal norepinephrine extraction were unaltered. Similarly, sodium restriction caused a 168% elevation of renal renin secretion (p less than 0.05). Resting cardiac norepinephrine spillover and cardiac norepinephrine reuptake were unchanged between the two salt phases. Total and cardiac norepinephrine release, supine blood pressure, and heart rate increased to about the same extent in response to mental testing regardless of salt phase. In conclusion, sodium restriction induced a differential and physiological increase in resting renal sympathetic nervous activity, leaving cardiac norepinephrine overflow unchanged. Cardiac norepinephrine uptake was normal, which further supports the concept of a true increase of efferent renal nerve activity.

Adult↗
PubMed1990

Increased regional sympathetic nervous activity in human hypertension: causes and consequences.

Biochemical, electrophysiological, pharmacological and haemodynamic findings provide evidence for the existence of sympathetic nervous system activation in some patients with primary human hypertension, particularly younger ones. Sympathetic activation has been shown to involve neural outflows to the heart, kidneys and skeletal muscle. This sympathetic nervous stimulation, the cause of which remains obscure, appears to be commonly important in the pathogenesis of the hypertension. Whether the sympathetic overactivity has adverse effects in addition to its effect on blood pressure, by promoting left ventricular hypertrophy, cardiac arrhythmias and atherogenesis, is at present uncertain.

Blood Pressure↗
PubMed1989

Crystallization and preliminary X-ray diffraction studies of a complex between interleukin-2 and a soluble form of the p55 component of the high affinity interleukin-2 receptor.

Human recombinant interleukin-2 (IL-2) and a soluble recombinant form of the human p55 (Tac antigen) component of the IL-2 receptor (IL-2R) have been cocrystallized in 1.7-1.8 M ammonium sulfate, in the pH range 7.0-8.2. Variously glycosylated forms of both receptor and ligand can be cocrystallized under those conditions. The best crystals of the putative receptor-ligand complex involve the enzymatically desialylated receptor and unglycosylated IL-2. These crystals belong to the trigonal space group P3(1)2(1) or its enantiomorph, with unit cell dimensions a = b = 91 A and c = 119 A, and diffract to 3.5 A resolution. There is one receptor-ligand complex asymmetric unit, with a Matthews coefficient of 2.7, assuming the presence of one IL-2 molecule-receptor molecule. Interestingly, in addition to IL-2 (Mr = 14,000), the p55 IL-2 receptor (Mr = 44,000) and two fragments of the receptor, of apparent Mr = 35,000 and 25,000, respectively, in sodium dodecyl sulfate-polyacrylamide gel electrophoresis, the crystals are enriched in a reducible dimeric form of the desialylated receptor (apparent Mr = 90,000), as compared with protein solution from which the crystals grow. The overall amino acid content in the crystals is consistent with a 1:1 ratio of receptor to ligand. A native data set has been collected on a multiwire area detector and the search for suitable heavy atom derivatives is in progress.

Crystallization↗
PubMed1989

Measurement of overall and cardiac norepinephrine release into plasma during cognitive challenge.

Measurements of plasma norepinephrine concentrations and norepinephrine spillover into plasma were used to gauge sympathetic nervous system activation during cognitive challenge (forced mental arithmetic) in 12 human subjects. Norepinephrine levels were influenced by the sampling site, with the fractional increase being greatest for norepinephrine spillover from the heart (where norepinephrine release almost trebled), intermediate for the arterial plasma norepinephrine concentration and total body norepinephrine spillover (50-70% increase), and inconsequential for antecubital venous plasma norepinephrine levels (less than 20% increase). These findings are explained by patterning of the sympathetic response, which only minimally involves the sympathetic outflow to the skeletal muscle of the forearm but preferentially involves the heart. Antecubital venous plasma norepinephrine levels are not sufficiently sensitive to allow satisfactory monitoring of the sympathetic neural outflow to organs, such as the heart, which are selectively activated in the response to mental challenge.

Adult↗
PubMed1989

Noradrenaline release and the pathophysiology of primary human hypertension.

Measurements of the overflow of norepinephrine to plasma from individual organs (using radiotracer methodology) were used to delineate the pattern of sympathetic nervous system activation present in primary human hypertension. Mean total norepinephrine (NE) spillover in hypertensive patients was 418 ng/min, 42% (124 ng/min) higher than in subjects with normal blood pressure (BP)(P less than .05). Norepinephrine spillover among hypertensive patients was a function of age, only being elevated in patients under 40 years of age. Half of the excess in total norepinephrine release in hypertensive patients was accounted for by increased cardiorenal spillover. Mean renal norepinephrine spillover was 120 ng/min, compared with 69 ng/min in healthy subjects (P less than .02). Renal spillover was highest in younger patients. Corresponding cardiac norepinephrine spillover values were 12.6 ng/min and 5.1 ng/min (P less than .01). The balance of the excess total norepinephrine spillover comes from undetermined sites, but not the lungs or hepatomesenteric circulation. These measurements of regional norepinephrine overflow suggest that sympathetic nervous outflow to the kidneys and heart is selectively activated in early hypertension.

Humans↗
PubMed1989

Regional norepinephrine turnover in human hypertension.

Overall and regional rates of norepinephrine overflow to plasma were measured in 55 untreated patients with primary hypertension and in 40 healthy subjects, to study sympathetic nervous pathophysiology in human hypertension. Total norepinephrine spillover was increased in primary hypertension, particularly in patients aged less than 40 years, largely due to higher rates of renal and cardiac norepinephrine overflow. Renal renin release, and arterial plasma renin activity, were highest in these younger patients with increased renal sympathetic nervous activity. In older patients sympathetic activity and norepinephrine release was typically normal. A selective increase in the sympathetic nervous outflow to the heart and kidneys is commonly present in young patients with primary hypertension, and probably contributes materially to the early pathogenesis of the hypertension.

Female↗
PubMed1989

Parasitic conjoined twins with omphalocele and tetralogy of Fallot.

Human parasitic twins are very rare. Here we report a unique case of a partial twin attached to the host in the midline at the forehead, chin, chest, and epigastrium. The parasite lacked thoracic organs and major neural tube derivatives. However, it had small peripheral nerves and ganglia within perirenal and pericolonic connective tissue. Also present were a well-developed small intestine, colon, and appendix with normal submucosal and myenteric plexuses. These findings may represent either the initial presence of a neural tube that later regressed or migration of autosite neural crest cells. The parasite had a mature, functioning kidney with its ureter opening to skin and complete absence of urinary bladder or genital organs. This raises questions about the embryological development of the ureteric bud, which is an outgrowth of the mesonephric duct. The host had tetralogy of Fallot and omphalocele containing the parasitic kidney and bowel. Parasitic twinning occurs at 3 weeks of gestation, tetralogy of Fallot at 3-7 weeks, and omphalocele at 6-10 weeks. A single noxa acting at 3 weeks could have caused sequential malformations that initially seem unrelated.

Abnormalities, Multiple↗
PubMed1988

Norepinephrine spillover to plasma during steady-state supine bicycle exercise. Comparison of patients with congestive heart failure and normal subjects.

This study was performed to determine the relative contributions of plasma norepinephrine clearance and norepinephrine release to the increase in plasma norepinephrine concentration that occurs during exercise and to determine whether the high rates of cardiac norepinephrine release from the heart and kidney in patients with heart failure are associated with diminished reserve for regional sympathetic nervous stimulation. During supine steady-state bicycle exercise at 50% of maximum voluntary exercise capacity, the plasma norepinephrine concentration of six patients with congestive heart failure rose from 385 +/- 88 to 2,200 +/- 497 pg/ml, whereas that of nine normal subjects rose from 208 +/- 21 to 882 +/- 257 pg/ml. The change in plasma concentration in both groups was due to an increase in norepinephrine spillover to plasma without a change in plasma norepinephrine clearance. In patients with heart failure, cardiac spillover increased from 80 +/- 26 to 528 +/- 265 ng/min during exercise, and renal spillover rose from 146 +/- 71 to 418 +/- 69 ng/min. In the normal subjects, cardiac spillover rose from 5 +/- 2 to 73 +/- 23 ng/min, and renal spillover increased from 76 +/- 27 to 275 +/- 106 ng/min. There is no evidence of a reduced reserve for overall or regional sympathetic stimulation in patients with heart failure. Reduced reflex responses in these patients are more likely due to end-organ refractoriness than to inadequate stimulation.

Bicycling↗
PubMed1988

Molecular determinants for recognition of RU 24969 analogs at central 5-hydroxytryptamine recognition sites: use of a bilinear function and substituent volumes to describe steric fit.

The putative serotonin (5-HT) agonist RU 24969 [5-methoxy-3-1,2,3,6-tetrahydropyridin-4-yl)indole; 5-MeO-THPI] has been extensively used in the study and classification of 5-HT receptors. In order to study molecular determinants for recognition of THPIs at central 5-HT recognition sites, about 25 additional THPI derivatives were synthesized, incorporating, among others, 16 different indole-5-substituents and three different pyridine-N substituents in various combinations. Two saturated derivatives (piperidin-4-ylindoles) and two 2-methyl analogs were also included. Binding affinities at 5-HT1A, 5-HT2, and total 5-HT1 sites were obtained and the data were incorporated in quantitative structure-activity relationships (QSARs) using a combined linear free energy/molecular modeling approach. The QSAR analyses suggest distinct differences in the structural features that determine optimal potency at 5-HT1A sites versus those directing optimal potency for 5-HT2 sites. The parameter of the indole-5 substituent that almost exclusively determines potency for 5-HT1A sites is volume, the optimal size being about 24 cubic angstroms (calculated by fitting the activity versus volume data to a bilinear function). This is approximately the size of a carboxamide group. In contrast, at the 5-HT2 site both volume and hydrophobicity play major but opposing roles for the 5-substituent. A balance between the smallest possible volume and the greatest possible hydrophobicity is required for maximal 5-HT2 potency. Benzyl groups on the indole-1 or pyridyl-1 positions also favor potency at the 5-HT2 site (probably largely due to increased hydrophobic binding) while decreasing potency at the 5-HT1A site. A minor electronic contribution to the QSARs involving the charge on the indole 5-carbon is of opposite sign for 5-HT1A versus 5-HT2 sites and thus may also be useful for selective drug design. The data are consistent with the possibility that the indole and pyridyl rings are in a coplanar configuration when binding at both 5-HT1A and 5-HT2 sites, because the indole-2-methyl substituent, which provides a large energy barrier to the coplanar configuration, greatly reduces the potency of THPIs at both binding sites. Similarities in analog selectivity patterns suggest that the indolic portion of these compounds binds similarly to that of other indole derivatives such as tryptamines; thus, it is possible that optimally selective substituents predicted by these QSARs may be extrapolated to tryptamines and other indoles.

Animals↗
PubMed1987

[3H]spiroxatrine labels a serotonin1A-like site in the rat hippocampus.

[3H]Spiroxatrine was examined as a potential ligand for the labeling of 5-HT1A sites in the rat hippocampus. Analysis of the binding of [3H]spiroxatrine in the absence and presence of varying concentrations of three monoamine neurotransmitters revealed that serotonin (5-HT) had high affinity (IC50 = 20.7 nM for the [3H]spiroxatrine binding sites, consistent with the labeling of 5-HT1 sites, while dopamine and norepinephrine had very low affinity (IC50 = 57600 nM and greater than 10(-4) M respectively). Saturation studies of the binding of [3H]spiroxatrine revealed a single population of sites with a Kd = 2.21 nM. Further pharmacologic characterization with the 5-HT1A ligands 8-hydroxy-2-(di-n-propylamino)tetralin, ipsapirone, and WB4101 and the butyrophenone compounds spiperone and haloperidol gave results that were consistent with [3H]spiroxatrine labeling 5-HT1A sites. This ligand produced stable, reproducible binding with a good ratio of specific to nonspecific binding. The binding of [3H]spiroxatrine was sensitive to GTP, suggesting that this ligand may act as an agonist. This was supported by the finding that spiroxatrine inhibits forskolin-stimulated adenylate cyclase activity (a proposed 5-HT1A receptor model) in the rat hippocampus. Since [3H]spiroxatrine is structurally distinct from other currently available radioligands for the 5-HT1A site, it should provide new information about the properties of this putative serotonergic receptor.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1987

Modern lateral external beam (lens sparing) radiotherapy for retinoblastoma.

A standard 6 MV linear accelerator X-ray beam has been adapted to produce a non-divergent and almost penumbra-free beam edge by a beam splitting and extended collimation system. Using a contact lens to provide the reference point on the front surface of the eye and an attached rod-and-scale measuring system that is linked to the sharp beam edge system, it has proved possible to place this field border with an exactitude of within 0.5 mm at a required distance behind the front surface of the eye. This system has been developed for the treatment of small retinoblastomas not amenable to focal treatment methods; the technique may have other applications. Data in this manuscript corroborate an earlier Dutch publication and extend the observations on the physics beam profile obtainable, the immobilization of the patient, the anaesthetic procedure, the contact lens system and the dose prescription. Both scanning densitometry and TLC measurements in an anthropomorphic head shell (with extractable eye) confirm the extreme precision and sharp beam profile obtainable by this technique.

Eye Neoplasms↗
PubMed1986

Mechanism of elevated plasma noradrenaline in the course of essential hypertension.

Increased sympathetic nervous system tone may be the initiating pathophysiologic event in some patients with essential hypertension. We estimated sympathetic nervous activity from radiotracer-derived measurements of noradrenaline release to plasma in 34 patients with essential hypertension and 23 subjects with normal blood pressure. The plasma concentration of noradrenaline (32% increased) and the rate of release of noradrenaline to plasma (38% increased) were elevated overall in patients with essential hypertension, largely due to higher noradrenaline release in hypertensive patients aged less than 40 years. Noradrenaline release from the kidneys and heart was elevated; renal noradrenaline spillover was 2.4 times normal in patients aged less than 40 years. Increased renal noradrenaline spillover accounted for 42% and increased cardiac noradrenaline spillover for 4% of the excess total noradrenaline spillover in essential hypertension, leaving 54% unexplained. Total noradrenaline spillover to plasma was normal in hypertensive patients aged 60 years and over. The plasma noradrenaline concentration was similar in younger and older hypertensive patients, despite lower noradrenaline release in the latter due to an age-dependent fall in noradrenaline plasma clearance in essential hypertension. Cardiorenal sympathetic nervous system tone appears to be increased in essential hypertension, particularly in younger patients. This contributes substantially to the higher plasma noradrenaline values found.

Adult↗