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Biomedical subjects

C Holmes

Publications and source records attributed to C Holmes.

At least 91 records · Page 5Linked to original sources
PubMed1995

Arteriovenous differences in plasma concentrations of catechols in rats with neuropathic pain.

BACKGROUND: Alterations in cutaneous temperature, sweating, and cutaneous blood flow in patients with pain states, such as reflex sympathetic dystrophy and causalgia, have been interpreted as evidence for exaggerated sympathetic outflow. It was determined whether pain behavior in a rat model of sympathetically maintained pain is associated with alterations in regional sympathoneural function. METHODS: Peripheral neuropathy was induced in 29 Sprague-Dawley rats by ligation of the left L5 and L6 spinal nerves. Sixteen other rats had sham surgery (nerve exposure without ligation). Animals were tested for behavioral signs of allodynia (decreased paw withdrawal thresholds to mechanical stimuli) at 2 and 4 weeks after the surgery. Arterial and iliac venous blood samples (left, affected; right, control) were obtained at 2 weeks (NP2, n = 14) and 4 weeks (NP4, n = 15) after neuropathic or sham (n = 8 at 2 and 4 weeks) surgery. Plasma concentrations of dihydroxyphenylalanine, dihydroxyphenylacetic acid, dopamine, norepinephrine, and the intraneuronal norepinephrine metabolite, 3,4-dihydroxyphenylglycol, were analyzed in arterial and left and right iliac venous samples. RESULTS: A decrease in paw withdrawal threshold was observed in neuropathic (NP2 and NP4) but not sham-operated rats. Affected and control limbs did not differ in arteriovenous differences in concentrations of dihydroxyphenylalanine, dihydroxyphenylacetic acid, dopamine, or 3,4-dihydroxyphenylglycol. No differences were observed between sham-operated and neuropathic animals in these arteriovenous increments. In contrast, affected limbs of NP2 rats had a reduced arteriovenous increment in norepinephrine concentrations, compared to that in the control side (P < 0.05). CONCLUSIONS: No neurochemical evidence of sympathetic hyperactivity is observed in the rat model of neuropathic pain; if anything, norepinephrine release is decreased in the affected limb. Autonomic disturbances in neuropathic pain are therefore more likely the result of receptor supersensitivity than increased local sympathoneural traffic.

Animals↗
PubMed1995

On the existence of functional angiotensin II receptors on vascular sympathetic nerve terminals in the human forearm.

OBJECTIVE: The existence of presynaptic angiotensin II receptors, modulating the release of the sympathetic neurotransmitter norepinephrine, was examined in the perfused human forearm model. DESIGN AND METHODS: In three groups out of a total of 20 healthy volunteers, intra-arterial infusions of tracer amounts of tritiated norepinephrine were given to measure forearm spillover and total plasma appearance rate of norepinephrine during intra-arterial infusions of angiotensin II (0.02, 0.2 and 2 ng/kg per min), methoxamine (0.08, 0.4 and 2 micrograms/kg per min) to produce vasoconstriction by stimulating alpha 1-adrenoceptors and saralasin (0.5 ng/kg per min) to block angiotensin II receptors. Postganglionic sympathoneural activity was stimulated by intravenous infusion of sodium nitroprusside (about 1.3 ng/kg per min) or attenuated by intravenous infusion of trimethaphan (about 1 mg/min). RESULTS: Angiotensin II failed to increase the spillover and total plasma appearance rate of norepinephrine, when given without additional treatment or during sodium nitroprusside or trimethaphan administration. In contrast, the spillover of norepinephrine even decreased during angiotensin II administration, both before and during intravenous sodium nitroprusside administration, probably because of angiotensin II-induced forearm vasoconstriction. Similar vasoconstrictor doses of angiotensin II and methoxamine produced similar changes in spillover and total plasma appearance rate of norepinephrine. The highest dose of angiotensin II increased diastolic blood pressure by 9% and decreased the pulse rate by 6%. Saralasin affected the spillover and total plasma appearance rate of norepinephrine neither before nor during intravenous sodium nitroprusside infusion. CONCLUSION: The present results fail to support the view that angiotensin II receptors exert stimulatory modulatory effects on norepinephrine release from sympathetic nerves in the human forearm, at rest or during changes in sympathoneural outflow.

Adult↗
PubMed1995

Thirst induced by a suckling episode during breast feeding and relation with plasma vasopressin, oxytocin and osmoregulation.

OBJECTIVE: There have been anecdotal reports of increased maternal thirst during breast feeding, but the physiological mechanisms remain obscure. We have assessed and quantified the stimulation of maternal thirst during breast feeding (suckling), and correlated the changes with plasma oxytocin and vasopressin levels. DESIGN: A within subject design was used with each subject acting as her own control. Each subject participated in a suckling period and a control non-suckling period the order of which was counterbalanced. SUBJECTS: Ten healthy breastfeeding women ranging from 28 to 52 days post partum. MEASUREMENTS: Thirst (assessed by a visual analogue scale), plasma vasopressin, plasma oxytocin (pOT), plasma osmolality and haematocrit, blood pressure, volume of milk transferred to baby, volume of water drunk immediately following each experimental period. RESULTS: Thirst increased significantly more over a suckling period than over a comparable control period (P = 0.013). The peak level of thirst correlated with the volume of water consumed to satiety following the suckling period (r = 0.7, P = 0.024). As expected, pOT levels rose significantly in response to suckling (P < 0.001). Six women demonstrated a close relation between thirst and oxytocin response during the suckling period. Despite significant changes in thirst during suckling there was no increase in plasma vasopressin or in osmoregulatory parameters. CONCLUSIONS: This study confirms that suckling is a potent stimulus to thirst in the mother, and is not associated with vasopressin release or dependent on any measurable alterations in osmoregulation. What actually stimulates thirst during breast feeding remains unknown, but there are two potential explanations for these observations: (1) suckling sends nerve impulses to the paraventricular and supraoptic nuclei in the hypothalamus which may have afferents within the central nervous system which stimulates a thirst response simultaneous with oxytocin release; (ii) a learned anticipation of thirst may be occurring in a situation associated with expectant fluid loss to preserve homeostasis.

Blood Pressure↗
PubMed1995

Production and metabolism of dopamine and norepinephrine in mesenteric organs and liver of swine.

Concentrations of catecholamines and their metabolites in plasma entering and exiting mesenteric organs, liver, and kidneys were examined to assess the regional production and metabolism of catecholamines in anesthetized swine. Higher portal venous than arterial plasma concentrations of norepinephrine and its metabolites, 3,4-dihydroxyphenylglycol (DHPG) and 3-methoxy-4-hydroxyphenylglycol (MHPG), and of dopamine and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), indicated substantial production of both catecholamines by mesenteric organs, representing 45-50% of total body production. Most dopamine was not metabolized to norepinephrine, suggesting a large nonnoradrenergic contribution to total body dopamine production. Concentrations of norepinephrine, DHPG, normetanephrine, and MHPG were lower in plasma exiting than entering the liver, whereas concentrations of the end-product of norepinephrine metabolism, vanillylmandelic acid (VMA), were higher in outflowing than inflowing plasma. Over 94% of the VMA removed by the kidneys was produced in the liver, consistent with the hepatic source of this metabolite. Removal of DOPAC and HVA by the liver exceeded removal by the kidneys or production by mesenteric organs, indicating greater hepatic than renal elimination of these metabolites from the body and underestimation of mesenteric organ dopamine production based on summed spillovers of dopamine metabolites from the liver into the systemic circulation.

Animals↗
PubMed1995

Catecholaminergic effects of prolonged head-down bed rest.

Prolonged head-down bed rest (HDBR) provides a model for examining responses to chronic weightlessness in humans. Eight healthy volunteers underwent HDBR for 2 wk. Antecubital venous blood was sampled for plasma levels of catechols [norepinephrine (NE), epinephrine, dopamine, dihydroxyphenylalanine, dihydroxyphenylglycol, and dihydroxyphenylacetic acid] after supine rest on a control (C) day and after 4 h and 7 and 14 days of HDBR. Urine was collected after 2 h of supine rest during day C, 2 h before HDBR, and during the intervals 1-4, 4-24, 144-168 (day 7), and 312-336 h (day 14) of HDBR. All subjects had decreased plasma and blood volumes (mean 16%), atriopeptin levels (31%), and peripheral venous pressure (26%) after HDBR. NE excretion on day 14 of HDBR was decreased by 35% from that on day C, without further trends as HDBR continued, whereas plasma levels were only variably and nonsignificantly decreased. Excretion rates of dihydroxyphenylglycol and dihydroxyphenylalanine decreased slightly during HDBR; excretion rates of epinephrine, dopamine, and dihydroxyphenylacetic acid and plasma levels of catechols were unchanged. The results suggest that HDBR produces sustained inhibition of sympathoneural release, turnover, and synthesis of NE without affecting adrenomedullary secretion or renal dopamine production. Concurrent hypovolemia probably interferes with detection of sympathoinhibition by plasma levels of NE and other catechols in this setting. Sympathoinhibition, despite decreased blood volume, may help to explain orthostatic intolerance in astronauts returning from spaceflights.

Adult↗
PubMed1995

Production and characterisation of monoclonal and polyclonal antibodies to different regions of the cystic fibrosis transmembrane conductance regulator (CFTR): detection of immunologically related proteins.

We have raised mouse monoclonal antibodies to eight synthetic peptides corresponding to different regions of the human cystic fibrosis transmembrane conductance regulator (CFTR) and rabbit polyclonal antisera to beta-galactosidase fusion proteins which encompass three different regions of CFTR. Immunoblot, immunoprecipitation, immunofluorescence and immunocytochemical experiments demonstrate that, in addition to recognising CFTR, these antibodies recognise one or more immunologically related proteins with a similar molecular mass, calcium responsiveness and tissue distribution to CFTR.

Amino Acid Sequence↗
PubMed1995

The chief scientist reports ... An analysis of patients attending two emergency dental clinics in Edinburgh.

Two studies of self-referred patients attending emergency dental clinics in Edinburgh have shown that almost half of the patients have been to the dentist in the last year and 60% had routine treatment on their last dental visit. Despite this contact with dental services, over 40% of patients with a dental emergency who attend the emergency dental clinics say that they do so because of actual or perceived difficulty in obtaining immediate care from the general dental services. Some 17% attend the clinics for reasons of convenience and 19% of patients attend the emergency clinic at the Dental Hospital because they prefer to be treated in a 'centre of excellence'. In September 1994 the School of Dentistry is to close and the Dental Hospital relocated. Changes may have to be made to the organisation of general dental practice in the Edinburgh area to accommodate patients with a dental emergency. The majority of emergency dental patients in Edinburgh are not put off attending for the relief of their problem by the cost of National Health Service treatment.

Adolescent↗
PubMed1994

Synovial sarcoma. Uniform response of metastases to high dose ifosfamide.

BACKGROUND: This report describes the unusually high response rate of metastatic synovial sarcoma to high dose ifosfamide (14-18 g/m2) when that drug was used to treat 13 consecutive patients with recurrent metastatic synovial sarcoma before surgery (or thoracotomies) to provide optimal salvage therapy for these patients. PATIENTS AND METHODS: Thirteen patients with recurrent or pulmonary metastatic synovial sarcoma seen at the Cedars-Sinai Comprehensive Cancer Center (Los Angeles, CA) from April, 1989 through January, 1993 were treated with high dose ifosfamide (14-18 g/m2). Ifosfamide was infused at the dose of 2 g/m2 over a 4-hour bolus infusion, followed by 2-g/m2 24-hour continuous infusions of ifosfamide, for a total of 14 or 18 g/m2 (6-8 days). Mesna (Mesnex, Bristol-Myers Oncology, Princeton, NJ) was infused with the ifosfamide at equimolar doses. Supplemental sodium bicarbonate (180 mEq) was given daily to prevent severe acidosis. Nine of the thirteen patients were treated with prior chemotherapy for their primary tumors. Prior chemotherapy consisted of doxorubicin (Adriamycin, Adria Labs, Dublin, OH) in all patients and doxorubicin combined with cisplatin in eight of them. RESULTS: All 13 patients had objective responses to high dose ifosfamide chemotherapy. There were nine partial responses and four complete responses. Five of the patients died of disease at 20-40 months (median, 27 months) from initial therapy. Eight patients have survived from 2 to 43 months (median, 20 months) from initial therapy, and three of these patients are disease free. Those patients surviving disease free had successful surgical removal of their residual metastatic disease after chemotherapy. CONCLUSION: Metastatic synovial sarcoma appears to be particularly sensitive to high dose ifosfamide chemotherapy. This experience suggests that there is a role for high dose ifosfamide chemotherapy in preoperative and postoperative adjuvant chemotherapy for primary synovial sarcoma, which is usually always a high grade malignant lesion with a poor prognosis after surgery alone.

Adolescent↗
PubMed1994

Improved assay for plasma dihydroxyphenylacetic acid and other catechols using high-performance liquid chromatography with electrochemical detection.

Several modifications of an HPLC-electrochemical assay method for plasma levels of norepinephrine (NE), epinephrine (EPI), dopamine (DA), dihydroxyphenylglycol (DHPG), dihydroxyphenylalanine (DOPA) and dihydroxyphenylacetic acid (DOPAC) that improve the accuracy and reliability of DHPG, DOPA, and DOPAC measurements are described. In batch alumina extractions, increasing the amount of alumina decreased analytical recoveries of DHPG, DOPA, and especially DOPAC, and increasing the strength of the eluting acid increased recoveries of these catechols, without affecting recoveries of the amines NE, EPI and DA. Refrigeration (4 degrees C) until injection stabilized DOPAC in aqueous solution and therefore improved the reproducibility of plasma DOPAC measurements. Circulation of chilled water (15 degrees C) around the column using a water jacket decreased variability in retention times of the catechols and thereby facilitated identification of peaks, while enhancing separation of DHPG from the solvent front. Use of 6-fluoro-DOPA and 6-fluoro-DOPAC as internal standards did not improve inter-assay reliability. We recommend that in assays of plasma catechols including DOPAC, small (5 mg), precisely measured amounts of alumina be used, with a relatively strong eluting solution (e.g. 0.04 M phosphoric acid-0.2 M acetic acid, 20:80, v/v), and that the samples be refrigerated until injection, with column temperature held constant at less than 20 degrees C.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1994

beta-Amyloid precursor protein isoforms show correlations with neurones but not with glia of demented subjects.

Post-mortem cerebral cortex from 15 demented patients was specially collected to minimise autolysis and two membrane fractions and one soluble fraction were quantitatively examined for the major species of beta-amyloid precursor protein (APP) of high apparent molecular mass (> or = 80 kDa) together with the major mRNA species encoding APP isoforms. The number of pyramidal neurones and astrocytes, putative biochemical indices of interneurones and pyramidal neurones, and choline acetyl transferase activity were also determined. Multiple regression analysis has been used to investigate intercorrelations of APP species with biochemical and morphometric measures, free of any effects of confounding demographic variables. Subjects with Alzheimer's disease showed a loss of cholinergic activity and D-aspartate uptake compared with patients with other causes of dementia. The major finding of the study is that measures of neurones rather than astrocytes most closely correlate with the concentration of APP. Pyramidal cell numbers were positively correlated with mRNA for APP695. APP in the soluble fraction showed a negative correlation with pyramidal cell numbers and cholinergic activity. These results indicate that neurones within the cerebral cortex are the major source of APP, and that secretion of APP is dependent upon cortical pyramidal neuronal activity and cholinergic activity.

Aged↗
PubMed1994

OHM3295: a fentanyl-related 4-heteroanilido piperidine with analgesic effects but not suppressive effects on splenic NK activity in mice.

The immunoregulatory effects of fentanyl and a fentanyl-related compound, OHM3295, were studied in mice. Male CD1 mice treated with a range of fentanyl doses (0.1-1.0 mg/kg, subcutaneously) showed suppression of splenic natural killer (NK) activity following 0.25-0.50 mg/kg fentanyl dose but not higher (0.75-1.0 mg/kg) or lower (0.1 mg/kg) doses. Fentanyl (0.01-32.0 mg/kg) also induced dose-related analgesia as measured by an increase in tail flick latency; these analgesic effects were antagonized by naltrexone (1.0-10.0 mg/kg). Pretreatment with naltrexone (1.0-3.2 mg/kg) resulted in significant suppression of splenic NK activity following fentanyl (10.0-32.0 mg/kg) administration. In comparison to fentanyl, OHM3295 (3.2-25.0 mg/kg) augmented splenic NK activity in a naltrexone-reversible manner. Similar to fentanyl, OHM3295 (1.0-32.0 mg/kg) also induced a naltrexone-sensitive, dose-related analgesia as measured by an increase in tail flick latency. These results with OHM3295 demonstrate a novel profile of effects which includes naltrexone-sensitive analgesic effects in the absence of immunosuppressive effects. In addition, this is the first reported case in which a compound with opioid analgesic effects has been shown to potentiate natural killer cytolytic activity following in vivo administration.

Analgesics↗
PubMed1994

The effect of clozapine on plasma norepinephrine: relationship to clinical efficacy.

Clozapine is an atypical neuroleptic medication with superior efficacy to conventional antipsychotic agents for patients with chronic, symptomatic schizophrenia. Neurochemical characteristics that distinguish clozapine from other neuroleptics and contribute to its differential efficacy are not known. We assessed the effects of clozapine on plasma levels of norepinephrine (NE) in a double-blind, parallel groups comparison of clozapine (n = 11) and haloperidol (n = 15) in chronic schizophrenic outpatients who had been previously treated with fluphenazine. Simultaneous measurements were obtained for plasma levels of the catecholamine precursor dopa, the dopamine metabolite dihydroxyphenylacetic acid (DOPAC), the NE metabolite 3,4-dihydroxyphenylglycol (DHPG), adrenocorticotropin (ACTH), cortisol, and hemodynamic parameters. Clozapine produced marked increases (471%) in plasma NE levels, whereas haloperidol had no significant effects on plasma NE levels. Clozapine also increased dopa and tended to increase DOPAC levels, without effects on DHPG, ACTH, or cortisol levels and without consistent changes in blood pressure. Across patients, the magnitude of clozapine-induced increments in plasma NE levels was positively related to improvement in positive symptoms and global symptomatology and was unrelated to the occurrence of extrapyramidal symptoms. The results suggest that clozapine differs importantly from other neuroleptics in increasing plasma NE levels, with the peripheral noradrenergic stimulation related to its superior efficacy profile. The unchanged DHPG levels and absence of hypertension suggest a more complex mechanism of action of clozapine than heightened NE release alone.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1994

Comparison of the Howmedica and Synthes military external fixation frames.

To direct the U.S. military purchase of deployable external fixation gear, a project was designed to compare the biomechanical properties and ease of clinical application of military external fixators developed by Synthes and Howmedica. The project assessed (a) ease of application, (b) biomechanics, (c) heat stability, and (d) product line compatibility. Pretrained general surgery residents were provided with fresh cadaver limbs with simulated grade IIIB tibial fractures and 5-cm middiaphyseal defects. All chose the Howmedica Ultra-X for its ease of application but, on manual testing, noted that the Synthes Trauma-Fix was more stable. The frames were biomechanically tested in a previously validated model with strictly controlled parameters. The Howmedica Ultra-X demonstrated only 75% of the compressive stiffness, 29% of the anteroposterior bending stiffness, and 51% of the torsional stiffness of the Synthes Trauma-Fix. The Ultra-X failed to withstand steam sterilization and was significantly weaker than, and incompatible with, Howmedica's commercially available product. The Trauma-Fix demonstrated no statistically significant difference from Synthes' commercially available product. The Howmedica Ultra-X is unsuitable for military external fixation: The biomechanical properties are not equivalent to those of the unilateral Hoffmann frame, it is incompatible with commercially available Howmedica external fixators, and it fails to withstand heat sterilization.

Biomechanical Phenomena↗
PubMed1993

Neurotransmitters and second messengers in aging and Alzheimer's disease.

A substantial loss of cortical cholinergic nerve endings, along with a much more circumscribed cortical degeneration of pyramidal neurons, almost certainly causes glutamatergic hypoactivity in live Alzheimer's patients. These selective pathologies are discussed in terms of therapy. An additional effect of some proposed treatments is emerging as there is evidence that processing pathways for beta-amyloid precursor proteins in cortical pyramidal neurons, a target cell for acetylcholine, are affected by neuronal activity.

Aging↗
PubMed1993

Plasma and cerebrospinal fluid neurochemical pattern in Menkes disease.

Menkes disease is a neurodegenerative disorder of copper metabolism. Because the enzyme dopamine-beta-hydroxylase requires copper to catalyze the conversion of dopamine to norepinephrine, we reasoned that patients with Menkes disease would have a neurochemical pattern similar to that seen in patients with congenital absence of dopamine-beta-hydroxylase, i.e., high levels of dopamine, the dopamine metabolite dihydroxyphenylacetic acid (DOPAC), and the catecholamine precursor dihydroxyphenylalanine (DOPA), and low levels of norepinephrine and its neuronal metabolite dihydroxyphenylglycol (DHPG). We measured plasma and cerebrospinal fluid (CSF) levels of catechols in 10 patients ranging in age from 9 days to 27 months. In contrast to patients with congenital absence of dopamine-beta-hydroxylase, norepinephrine levels were normal in plasma of 4 Menkes patients and in CSF of all 10 patients. However, the ratios of DOPA:DHPG and DOPAC:DHPG in plasma and CSF of Menkes patients were invariably increased beyond the ranges of control values. These neurochemical findings indicate partial deficiency of dopamine-beta-hydroxylase in Menkes patients, with compensatory increases in catecholamine biosynthesis in sympathetic nerves and in the brain. Increased tyrosine hydroxylation and increased exocytotic release of norepinephrine may be responsible for preservation of plasma and CSF norepinephrine levels in Menkes patients. The abnormal neurochemical pattern, including high ratios of DOPA:DHPG and DOPAC:DHPG, may serve as a biochemical marker for Menkes disease and provide a baseline against which the influence of proposed therapies can be judged.

Adult↗
PubMed1993

Positron emission tomographic imaging of cardiac sympathetic innervation using 6-[18F]fluorodopamine: initial findings in humans.

OBJECTIVES: This study evaluated the safety, efficacy and validity of 6-[18F]fluorodopamine positron emission tomographic scanning of cardiac sympathetic innervation and function in humans. METHODS: Positron emission tomography (PET) scans, arterial blood and urine were obtained after a 3-min intravenous infusion of 6-[18F]fluorodopamine (1 to 4 mCi, 188 to 809 mCi/mmol) in healthy volunteers, with or without pretreatment with oral desipramine to inhibit neuronal uptake of catecholamines. RESULTS: 6-[18F]Fluorodopamine PET scanning visualized the left ventricular myocardium. Blood pressure increased slightly and transiently. The estimated absorbed radiation dose to the main target organ, the wall of the urinary bladder, was 0.8 to 1.0 rad/mCi of injected 6-[18F]fluorodopamine. By 24 h after the injection, the main 6F-compound in urine was 6F-vanillymandelic acid, a metabolite of 6F-norepinephrine. Desipramine attenuated accumulation of myocardial 6-[18F]fluorodopamine-derived radioactivity and plasma 6F-dihydroxyphenylacetic acid. CONCLUSIONS: 6-[18F]Fluorodopamine produces negligible hemodynamic effects and acceptable radiation exposure at doses that visualize the left ventricular myocardium. Sympathetic nerves take up 6-[18F]fluorodopamine, which is translocated from the axoplasm into storage vesicles, where is it beta-hydroxylated to the fluorinated analogue of the sympathetic neurotransmitter norepinephrine. Therefore, the basis for visualization of myocardium after 6-[18F]fluorodopamine injection in humans is radiolabeling by 6-[18F]fluorodopamine and 6-[18F]fluoronorepinephrine of vesicles in sympathetic terminals. 6-[18F]Fluorodopamine PET scanning provides a novel means for assessing sympathetic innervation and function noninvasively in the human heart.

Adult↗