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Biomedical subjects

D Robertson

Publications and source records attributed to D Robertson.

At least 217 records · Page 12Linked to original sources
PubMed1994

The effect of cycloheximide and ganglioside GM1 on the viability of retinotectally projecting ganglion cells following ablation of the superior colliculus in neonatal rats.

The time-course and extent of death of retinal ganglion cells (RGCs) following ablation of the superior colliculus (SC) in neonatal Wistar rats has recently been described [Harvey, A. R. and Robertson, D. (1992) J. Comp. Neurol., 325, 83-94]. Normal and pyknotic nuclei of retinotectally projecting ganglion cells were visualized using the fluorescent retrograde tracer diamidino yellow (DY), which had been injected into the SC at P2 (day of birth = P0), 2 days prior to tectal removal. The present report sets out to determine whether cycloheximide, an inhibitor of protein synthesis, or ganglioside GM1 reduced this lesion-induced RGC death. All surgery was carried out under ether anaesthesia; DY was injected into the left SC at P2 and the injected area was removed at P4. Cycloheximide (20-500 ng) was injected into the vitreous chamber of the right eye immediately after the lesion and again 11-12 h later. In some rats, cycloheximide administration was delayed until 12 h after the SC ablation. Control rats received SC lesions alone or lesions plus sham eye injections of saline. Different doses of GM1 were applied i.p. or intraocularly. Rats were perfused 24 h after the SC lesion, at the time of peak RGC death. Retinae of lesion only or sham eye injected rats contained approximately 11% pyknotic RGCs and the density of normal RGCs was approximately 3400/mm2. The rate of pyknosis in cycloheximide treated retinae was reduced to approximately 3%. Normal RGC density in these retinae was approximately 5500/mm2, similar to that found in retinae of unlesioned animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Manipulation of norepinephrine metabolism with yohimbine in the treatment of autonomic failure.

It has been postulated that alpha 2-adrenergic receptors play a modulatory role in the regulation of blood pressure. Activation of alpha 2-receptors located in the central nervous system results in inhibition of sympathetic tone and decrease of blood pressure. This indeed may be the mechanism of action of central sympatholytic antihypertensives such as alpha-methyldopa. Presynaptic alpha 2-receptors also are found in adrenergic nerve terminals. These receptors act as a negative feedback mechanism by inhibiting the release of norepinephrine. The relevance of alpha 2-adrenergic receptors for blood pressure regulation can be explored with yohimbine, a selective antagonist of these receptors. Yohimbine increases blood pressure in resting normal volunteers. This effect is associated with an increase in both sympathetic nerve activity, reflecting an increase in central sympathetic outflow, and in norepinephrine spillover, reflecting potentiation of the release of norepinephrine from adrenergic nerve terminals. These actions, therefore, underscore the importance of alpha 2-adrenergic receptors for blood pressure regulation even under resting conditions. Patients with autonomic failure, even those with severe sympathetic deprivation, are hypersensitive to the pressor effects of yohimbine. This increased responsiveness can be explained by sensitization of adrenergic receptors, analogous to denervation supersensitivity, and by the lack of autonomic reflexes that would normally buffer any increase in blood pressure. Preliminary studies suggest that the effectiveness of yohimbine in autonomic failure can be enhanced with monoamine oxidase inhibitors. Used in combination, yohimbine increases norepinephrine release, whereas monoamine oxidase inhibitors inhibit its degradation. Therefore, yohimbine is not only a useful tool in the study of blood pressure regulation, but may offer a therapeutic option in autonomic dysfunction.

Autonomic Nervous System Diseases↗
PubMed1994

Cisplatin induces apoptosis in a human ovarian carcinoma cell line without concomitant internucleosomal degradation of DNA.

After treatment of the human ovarian carcinoma cell line, CH1, with cisplatin, cells detached from the culture dish in a time- and dose-dependent fashion. These cells showed morphological changes indicative of apoptosis. Their DNA had not been degraded into oligonucleosomal fragments, but the DNA had been cut into larger fragments (30 kbp) of a size associated with chromatin loops. We conclude that cisplatin killed these ovarian cells by inducing apoptosis. However, in these cells, apoptosis was not accompanied by internucleosomal degradation of DNA. Our data are consistent with the hypothesis that the introduction of a double-strand break at a specific site in the chromatin loops is an early event in apoptosis. This degradation is accompanied by morphologically observable changes in chromatin structure. Internucleosomal degradation, when it occurs, is a late event.

Apoptosis↗
PubMed1994

The head and neck discomfort of autonomic failure: an unrecognized aetiology of headache.

Information concerning the frequency, severity, character, location, duration, diurnal pattern of headache and ancillary symptoms were obtained in 25 patients with autonomic failure and 44 control subjects. Precipitating and ameliorating factors were identified. Autonomic failure patients had more head and neck discomfort than controls. Their discomfort was much more likely to localize in the occiput, nape of the neck and shoulder, compared with controls. There was a greater tendency for the discomfort to occur in the morning and after meals. It was sometimes less than 5 min in duration and was often associated with dimming, blurring, or tunnelling of vision. It was provoked by upright posture and relieved by lying down. Patients with severe autonomic failure and orthostatic hypotension often present with a posture-dependent headache or neck pain. Because the relationship of these symptoms to posture is often not recognized, the fact that these findings may signal an underlying autonomic disorder is underappreciated, and the opportunity to consider this aetiology for the headache may be missed.

Autonomic Nervous System Diseases↗
PubMed1994

A sensitive radioimmunoassay for fludrocortisone in human plasma.

Fludrocortisone has been a mainstay of therapy for orthostatic hypotension for many years. Clinical experience suggests that there exists a substantial interindividual variation in responsiveness to the drug. To assess this, we have developed an assay that permits measurement of the low concentrations of fludrocortisone found in human plasma. Fludrocortisone was detected by radioimmunoassay. A polyclonal rabbit antibody, raised against dexamethasone which cross-reacts strongly with fludrocortisone, was reacted with either standard or unknown samples in the presence of [125I]fludrocortisone-3-TyrNH2 (synthesized by coupling tyrosine amide to fludrocortisone-3-oxime and iodinating with chloramine T oxidation). The ED10, ED50, and ED80 were 0.34, 5.0, and 30 ng/mL of plasma, respectively. The cross reactivity with other 9-fluorinated steroids was found as follows: dexamethasone, 340%; betamethasone, 230%; and triamicinolone, 8%. To preclude an erroneous result, subjects who were pregnant or receiving any steroid medication were excluded from the study. The percent cross-reactivity with the main naturally occurring steroids was as follows: 11-desoxycortisol 3.2%, cortisol 1.1%, DOC 0.3%, pregnenolone 0.1%, corticosterone 0.06%, progesterone 0.05%, and aldosterone < 0.05%. The only compound with potential for interference, because of its high level in the circulation in the early morning, was cortisol.(ABSTRACT TRUNCATED AT 250 WORDS)

Fludrocortisone↗
PubMed1994

The anemia of microgravity and recumbency: role of sympathetic neural control of erythropoietin production.

We hypothesize that reduced sympathetic stimulation of erythropoietin production may maintain the anemia which develops in virtually all space travellers. We tested this hypothesis in a human model of reduced sympathetic activity. Thirty-three patients with the Bradbury-Eggleston syndrome were divided into three groups according to their hemoglobin (Hgb) level. Patients with low Hgb had lower upright norepinephrine and lower upright renin. Patients with anemia also had inappropriately low plasma erythropoietin levels. We administered recombinant erythropoietin (Epogen) 25-50 units/kg s.c. 3 times per week and found that the anemia seen in autonomic failure could be reversed by this treatment. These results support the hypothesis that erythropoiesis is modulated by the sympathetic nervous system and that at such mechanisms may also operate in the microgravity environment where sympathetic activity is reduced.

Anemia↗
PubMed1994

Variable domain-identical antibodies exhibit IgG subclass-related differences in affinity and kinetic constants as determined by surface plasmon resonance.

We have analysed the binding of variable domain-identical mouse monoclonal antibodies (mAb) of the IgG3, IgG1 and IgG2b subclasses, as well as F(ab')2 fragments derived from the IgG3 and IgG1 mAb, to a multivalent glycoprotein target. Using a biosensor device (BIAcore, Pharmacia Biosensor) that measures the mass of the antibody (or other receptor molecule) deposited on a sensor chip displaying the relevant epitopes, we found that the IgG3 mAb binds more effectively than the other antibody species at a high but not a low epitope density. The greater functional affinity associated with the IgG3 mAb, at high epitope density, was correlated with both slower dissociation rate constants and faster association rate constants in comparison with the IgG1 and IgG2b mAb and the F(ab')2 fragments derived from the IgG3 and IgG1 mAb. Evidence for slower dissociation kinetics for the IgG3 mAb versus the IgG1 and IgG2b mAb was also obtained by ELISA and flow cytometry. These results demonstrate that: (1) differences in heavy chain constant (CH) domains can significantly influence apparent functional affinity for multivalent antigen, as determined without the use of covalently modified primary or secondary antibodies; (2) differences in CH domains can alter both association and dissociation rate constants for interactions between IgG antibodies and multivalent antigen; and (3) these effects of CH domains depend on epitope density. The effect of constant region differences on the apparent association rate constants suggests new approaches for achieving better binding or functional effectiveness through antibody engineering.

Acetylglucosamine↗
PubMed1994

An outbreak of Escherichia coli O157 associated with a children's paddling pool.

In May 1992, a small, circumscribed community outbreak of infection due to verotoxin-producing Escherichia coli O157 phage type 49 occurred in a semi-rural area of south-east Scotland. On the basis of stool cultures, six cases were identified, one of whom was asymptomatic. One child developed the haemolytic uraemic syndrome. Although the source of infection of the index case was not established nor could the extent of person-to-person spread be fully determined, the clinical, microbiological and epidemiological evidence available indicated that a children's paddling pool served as the focal point in the transmission of infection causing the outbreak.

Child, Preschool↗
PubMed1994

Dopamine beta-hydroxylase immunoreactivity in human cerebrospinal fluid: properties, relationship to central noradrenergic neuronal activity and variation in Parkinson's disease and congenital dopamine beta-hydroxylase deficiency.

1. Dopamine beta-hydroxylase is stored and released with catecholamines by exocytosis from secretory vesicles in noradrenergic neurons and chromaffin cells. Although dopamine beta-hydroxylase enzymic activity is measurable in cerebrospinal fluid, such activity is unstable, and its relationship to central noradrenergic neuronal activity in humans is not clearly established. To explore the significance of cerebrospinal fluid dopamine beta-hydroxylase, we applied a homologous human dopamine beta-hydroxylase radioimmunoassay to cerebrospinal fluid, in order to characterize the properties and stability of cerebrospinal fluid dopamine beta-hydroxylase, as well as its relationship to central noradrenergic neuronal activity and its variation in disease states such as hypertension, renal failure, Parkinsonism and congenital dopamine beta-hydroxylase deficiency. 2. Authentic, physically stable dopamine beta-hydroxylase immunoreactivity was present in normal human cerebrospinal fluid at a concentration of 31.3 +/- 1.4 ng/ml (range: 18.5-52.5 ng/ml), but at a 283 +/- 27-fold lower concentration than that found in plasma. Cerebrospinal fluid and plasma dopamine beta-hydroxylase concentrations were correlated (r = 0.67, P = 0.001). Some degree of local central nervous system control of cerebrospinal fluid dopamine beta-hydroxylase was suggested by incomplete correlation with plasma dopamine beta-hydroxylase (with an especially marked dissociation in renal disease) as well as the lack of a ventricular/lumbar cerebrospinal dopamine beta-hydroxylase concentration gradient. 3. Cerebrospinal fluid dopamine beta-hydroxylase was not changed by the central alpha 2-agonist clonidine at a dose that diminished cerebrospinal fluid noradrenaline, nor did cerebrospinal fluid dopamine beta-hydroxylase correspond between subjects to cerebrospinal fluid concentrations of noradrenaline or methoxyhydroxyphenylglycol; thus, cerebrospinal fluid dopamine beta-hydroxylase concentration was not closely linked either pharmacologically or biochemically to central noradrenergic neuronal activity. 4. Cerebrospinal fluid dopamine beta-hydroxylase was not changed in essential hypertension. In Parkinson's disease, cerebrospinal fluid dopamine beta-hydroxylase was markedly diminished (16.3 +/- 2.9 versus 31.3 +/- 1.4 ng/ml, P < 0.001) and rose by 58 +/- 21% (P = 0.02) after adrenal-to-caudate chromaffin cell autografts. In congenital dopamine beta-hydroxylase deficiency, lack of detectable dopamine beta-hydroxylase immunoreactivity in cerebrospinal fluid or plasma suggests absent enzyme (rather than a catalytically defective enzyme) as the origin of the disorder. 5. We conclude that cerebrospinal fluid dopamine beta-hydroxylase immunoreactivity, while not closely linked to central noradrenergic neuronal activity, is at least in part derived from the central nervous system, and that its measurement may be useful in both the diagnosis and treatment of neurological disease.

Adult↗
PubMed1994

Inhibition by ethanol of the cardiovascular effects of glutamate in the nucleus of the solitary tract.

This study investigates whether ethanol affects the cardiovascular changes evoked by the excitatory amino acid glutamate in the nucleus of the solitary tract (NTS). Male Sprague-Dawley rats were anesthetized with urethane and instrumented for microinjection of drugs into the NTS. In 28 animals, an initial dose-response curve for glutamate (37, 74, and 148 pmol/60 nL) was obtained. In eight animals (control group), the dose-response curve was unchanged when it was tested after microinjection of 60 nL of saline into the NTS. In contrast, the prior intra-NTS administration of ethanol (25 or 50 mM) consistently inhibited the hypotensive and bradycardic effects of glutamate. The specificity of this inhibitory response was corroborated by the inability of intra-NTS administrations of ethanol (50 mM) to affect the hypotensive and bradycardic responses to nicotine (922 pmol. 1.84 nmol, and 3.96 nmol). These results indicate that the cardiovascular effects of glutamate can be antagonized by ethanol in the NTS. This inhibitory effect, in turn, may provide a basis for the hypertensinogenic action of ethanol in humans.

Animals↗
PubMed1994

The sympathetic nervous system and the physiologic consequences of spaceflight: a hypothesis.

Many of the physiologic consequences of weightlessness and the cardiovascular abnormalities on return from space could be due, at least in part, to alterations in the regulation of the autonomic nervous system. In this article, the authors review the rationale and evidence for an autonomic mediation of diverse changes that occur with spaceflight, including the anemia and hypovolemia of weightlessness and the tachycardia and orthostatic intolerance on return from space. This hypothesis is supported by studies of two groups of persons known to have low catecholamine levels: persons subjected to prolonged bedrest and persons with syndromes characterized by low circulating catecholamines (Bradbury-Eggleston syndrome and dopamine beta-hydroxylase deficiency). Both groups exhibit the symptoms mentioned. The increasing evidence that autonomic mechanisms underlie many of the physiologic consequences of weightlessness suggests that new pharmacologic approaches (such as administration of beta-blockers and/or sympathomimetic amines) based on these findings may attenuate these unwanted effects.

Anemia↗
PubMed1994

Genetics and molecular biology of hypotension.

Major strides in the molecular biology of essential hypertension are currently underway. This has tended to obscure the fact that a number of inherited disorders associated with low blood pressure exist and that these diseases may have milder and underrecognized phenotypes that contribute importantly to blood pressure variation in the general population. This review highlights some of the gene products that, if abnormal, could cause hypotension in some individuals. Diseases due to abnormalities in the catecholamine enzymes are discussed in detail. It is likely that genetic abnormalities with hypotensive phenotypes will be as interesting and diverse as those that give rise to hypertensive disorders.

Animals↗
PubMed1994

Rapid isolation of nuclei from carrot suspension culture cells using a BioNebulizer.

The BioNebulizer is an instrument that breaks cells and large molecules using the shearing forces created by laminar flow of high-pressure gas in the microcapillary channels generated by the instrument. Within 4 min, 90% of the carrot suspension culture cells that passed through the nebulizer were broken. Cytosol and organelles were released from the broken cells leaving cell wall ghosts. Nuclei were further purified by means of a discontinuous Percoll gradient. This method yielded an average of 2 x 10(5) nuclei from 2 g of suspension culture cells (approximately 2 x 10(6) cells). The isolated nuclei actively incorporated [8,5'-3H]-GTP into RNA.

Cell Nucleus↗
PubMed1993

The diagnosis and treatment of baroreflex failure.

BACKGROUND: Baroreflexes originate in the great vessels of the neck and thorax and prevent arterial pressure from rising or falling excessively. METHODS: This study was undertaken to clarify the cause, clinical spectrum, and therapy of this disorder. We studied 11 patients with baroreflex failure presenting as severe, labile hypertension and hypotension, often with headache, diaphoresis, and emotional instability, and characterized by the failure of exogenous vasoactive substances to alter heart rate. Each underwent hemodynamic monitoring and biochemical, physiologic, and pharmacologic testing. RESULTS: The patients' maximal systolic blood pressures ranged from 164 to 280 mm Hg, and their minimal systolic pressures ranged from 58 to 96 mm Hg. Plasma norepinephrine and epinephrine concentrations were sometimes many times normal during blood-pressure surges. All the patients had excessive pressor and tachycardia responses to the mental-arithmetic and cold pressor tests and marked hypersensitivity to clonidine. The underlying causes of baroreflex failure included the familial paraganglioma syndrome, neck surgery or radiation therapy for pharyngeal carcinoma, bilateral lesions of the nucleus tractus solitarii, and surgical section of the glossopharyngeal nerves; in two patients the cause was unknown. Therapy with clonidine reduced the frequency of attacks by 81 percent and attenuated the elevated blood pressure and heart rate in the attacks that occurred. CONCLUSIONS: The syndrome of baroreflex failure should be considered in patients with otherwise unexplained labile hypertension. Clonidine attenuates the pressor and tachycardic surges in baroreflex failure.

Adult↗
PubMed1993

Effects of intra-cochlear perfusion of salicylates on cochlear microphonic and other auditory responses in the guinea pig.

The ototoxic action of salicylate was investigated in the guinea pig by perfusion of both salicylate and bromosalicylate through scala tympani. The results qualitatively confirmed experiments using intravenous administration in cats (Stypulkowski, 1990), showing dose-dependent elevations in compound action potential (CAP) thresholds, increases in cochlear microphonics (CM) and level-dependent reductions in 2f1-f2 acoustic distortion products. The endocochlear potential was not significantly affected and iontophoretic injection of salicylate into scala media had no measurable effect on CAP thresholds, consistent with an action on the basolateral walls of the hair cells. Perfusion with indomethacin produced effects similar to those of the salicylates, but at non-physiological doses. Together with the great effectiveness of 5-bromosalicylate, this suggests that salicylate does not act by inhibiting prostaglandin synthesis. The results are qualitatively consistent with the proposition that salicylates act on the basolateral walls of the outer hair cells. However, the magnitude of the CM increases, particularly at high drug concentrations, and the fact that salicylate reduced, but did not eliminate the effects of olivocochlear efferent stimulation on CM amplitude indicate that a simple explanation for salicylate effects based solely on a conductance increase in the outer hair cell membranes may be inadequate.

Acoustic Stimulation↗
PubMed1993

Ligaments of the lumbosacral spine and their role in possible extraforaminal spinal nerve entrapment and tethering.

The extraforaminal ligaments of the lumbosacral spine were studied in 34 cadavers. The corporotransverse ligament attached to the body and transverse process of the same vertebra. The ligament may entrap the exiting nerve root below it in rotary subluxation or in complete disk space loss. The lumbosacral ligament extends from the transverse process of L5 and the L5-S1 disk to the sacral ala, forming the roof of the lumbosacral tunnel through which the L5 spinal nerve passes. This may be the site of extraforaminal entrapment if lateral disk herniations, osteophytes, or tumor metastasis are also present. The nerve suspensory ligament attaches to the nerve sheath and to the disk and is felt to be significant as a vehicle for mechanoreception.

Genetic Variation↗