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R A Hawkins

Publications and source records attributed to R A Hawkins.

At least 37 records · Page 2Linked to original sources
PubMed1998

Glutamine transport by the blood-brain barrier: a possible mechanism for nitrogen removal.

Glutamine and glutamate transport activities were measured in isolated luminal and abluminal plasma membrane vesicles derived from bovine brain endothelial cells. Facilitative systems for glutamine and glutamate were almost exclusively located in luminal-enriched membranes. The facilitative glutamine carrier was neither sensitive to 2-aminobicyclo(2,2,1)heptane-2-carboxylic acid inhibition nor did it participate in accelerated amino acid exchange; it therefore appeared to be distinct from the neutral amino acid transport system L1. Two Na-dependent glutamine transporters were found in abluminal-enriched membranes: systems A and N. System N accounted for approximately 80% of Na-dependent glutamine transport at 100 microM. Abluminal-enriched membranes showed Na-dependent glutamate transport activity. The presence of 1) Na-dependent carriers capable of pumping glutamine and glutamate from brain into endothelial cells, 2) glutaminase within endothelial cells to hydrolyze glutamine to glutamate and ammonia, and 3) facilitative carriers for glutamine and glutamate at the luminal membrane may provide a mechanism for removing nitrogen and nitrogen-rich amino acids from brain.

Animals↗
PubMed1998

Diurnal rhythm returns to normal after elimination of portacaval shunting.

Previous studies showed that portacaval shunting causes metabolic and behavioral changes in rats. Most metabolic changes reversed within 1-2 wk after restoration of normal circulation. However, the rate of cerebral glucose metabolism (CMRGlc) remained depressed in some areas. The question arose whether complete recovery was possible. Therefore, a long-term behavioral study was undertaken to determine the time course of recovery. Diurnal activity was monitored for 48 h each week over a period of 14 wk: 2 wk before shunting, 6 wk after shunting, and 6 wk after restoration of normal hepatic circulation. Nighttime activity was depressed within 1 wk of shunting and did not change. Normal circulation to the liver was reestablished after 6 wk. The diurnal cycle was normal 3 wk later. Thus, although recovery of the diurnal rhythm is possible, the relatively long period necessary suggests the correction of a significant structural or chemical abnormality. A study of CMRGlc was made using the behavioral study as an index of the time necessary for recovery. CMRGlc returned to normal throughout the brain 6 wk after cessation of shunting except in the hippocampus and amygdala (7-8% decrease).

Ammonia↗
PubMed1998

Clinical utility of positron emission tomography with 18F-fluorodeoxyglucose in detecting residual/recurrent squamous cell carcinoma of the head and neck.

PURPOSE: The use of positron emission tomography with 18F-fluorodeoxyglucose (FDG-PET) to detect residual/recurrent squamous cell carcinoma of the head and neck has been tested only in small groups of patients. Our purpose, therefore, was to evaluate the ability of this technique to detect the presence of tumor at both primary and nodal sites in a large cohort of patients. METHODS: All patients referred for PET scanning over a 2.5-year period with a question of residual or recurrent squamous cell carcinoma of the head and neck were identified. Thirty-five of 44 patients had sufficient follow-up to be meaningful to our analysis (range, 6-33 months). PET scans were interpreted visually with knowledge of the clinical history and correlative anatomic imaging findings. Detection of disease involving primary and nodal sites was assessed independently. Additionally, because each patient had been referred in an attempt to resolve a specific clinical problem, the usefulness of PET in accurately addressing these questions was assessed. RESULTS: At the primary site, sensitivity and specificity for residual/recurrent disease were 100% and 64%, respectively; for nodal disease, sensitivity and specificity were 93% and 77%, respectively. In helping to resolve the clinical question being asked, the positive predictive value of the test result was 65% and the negative predictive value was 91%. CONCLUSION: The high sensitivity and negative predictive value of PET scanning in our cohort of patients suggest an important role for this technique in the care of patients with suspected residual/recurrent head and neck carcinoma. The lower figures obtained for specificity and positive predictive value reflect the fact that increased FDG uptake may be due to either tumor or inflammation.

Adult↗
PubMed1998

Functionality of the progesterone receptor in ovarian cancer and its regulation by estrogen.

Here, we sought to obtain evidence that the progesterone receptor (PR) may be functional in ovarian cancer and regulated by estrogen. Megestrol acetate inhibited growth of the PR-positive PE04 ovarian carcinoma xenograft but not the PR-negative HOX 60 xenograft. PR concentration was higher in early-stage (I/II) tumors than in advanced-stage (III/IV) tumors (P = 0.007) and in tumors of endometrioid histology compared to other carcinoma subtypes (P = 0.009). Patients with a tumor PR concentration of >40 fmol/mg protein had significantly improved survival over those patients whose tumors contained <40 fmol/mg (P = 0.0007; log-rank). Evidence of PR regulation by estrogen was obtained by endocrine manipulation of the PE04 xenograft. PR content of PE04 xenografts fell from 145 to 7 fmol/mg protein in ovariectomized mice and was 2 fmol/mg in male mice. Administration of 17-beta-estradiol increased PR content to 745 fmol/mg. In primary ovarian carcinomas, PR was significantly associated with ER concentrations (P < 0.0001), suggesting regulation of PR levels by estrogen. This association was present for tumors of endometrioid histology (P < 0.0001) but not for those with serous histology (P = 0.31). These data point to the regulation of PR levels by estrogen in ovarian cancer and to a mediatory role for PR in the inhibition of growth induced by progestin.

Animals↗
PubMed1997

Presurgical multimodality neuroimaging in electroencephalographic lateralized temporal lobe epilepsy.

The purpose of this study was to compare 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET), hippocampal volumetry (HV), T2 relaxometry, and proton magnetic resonance spectroscopic imaging (1H-MRSI) in the presurgical neuroimaging lateralization of patients with nonlesional, electroencephalogram (EEG)-defined unilateral temporal lobe epilepsy (TLE). Twenty-five patients were prospectively studied, along with age-matched controls. T2 relaxometry examinations were performed in 13 patients. Comparison of FDG-PET, HV, and 1H-MRSI was possible in 23 patients. FDG-PET lateralized 87% of patients, HV 65%, N-acetyl aspartate (NAA)/(choline [Cho] + creatine [Cr]) 61%, and [NAA] 57%. Combined HV and NAA/(Cho + Cr) results lateralized 83% of the patients, a value similar to PET. Of 10 patients with normal magnetic resonance imaging (MRI) scans, 2 were lateralized with HV, 6 with FDG-PET, 4 with NAA/(Cho + Cr), and 3 with [NAA]. T2 relaxometry lateralized no patients without hippocampal atrophy. Bilateral abnormality was present in 29 to 33% of patients with 1H-MRSI measures and 17% with HV. Only hippocampal atrophy correlated with postoperative seizure-free outcome. FDG-PET remains the most sensitive imaging method to correlate with EEG-lateralized TLE. Both FDG-PET and 1H-MRSI can lateralize patients with normal MRI, but only the presence of relative unilateral hippocampal atrophy is predictive of seizure-free outcome. Bilaterally abnormal MRI and 1H-MRSI measures do not preclude good surgical outcome.

Adult↗
PubMed1997

Primary systemic therapy for operable breast cancer--10-year survival data after chemotherapy and hormone therapy.

Between 1984 and 1990, 94 women presenting to the Edinburgh Breast Unit with operable breast cancer of 4 cm or greater in diameter (T2, T3, N0, N1, M0) were given preoperative systemic therapy. Initially, all women received hormone therapy, with CHOP (cyclophosphamide 1 g m(-2), doxorubicin 50 mg m(-2), vincristine 1.4 mg m(-2) to a maximum of 2 mg and prednisolone 40 mg per day orally for 5 days) chemotherapy being administered to those who failed to respond by 3 months. After April 1987, first-line hormone therapy was only offered to women with oestrogen receptor (ER)-moderate/-rich (> 20 fmol mg(-1) protein) tumours, and CHOP was reserved for those women whose tumours failed to respond to hormone therapy and for those with ER-negative/-poor tumours. Response data have been published previously (Anderson et al, 1991). After a median follow-up of 7.5 years, there is no difference in survival between those women given initial hormone therapy and those given chemotherapy, with neither group having yet reached its median survival. The two key factors that predicted for a poor survival were the number of involved axillary nodes after preoperative systemic therapy (P < 0.00001) and a lack of response to preoperative therapy (P < 0.05). These data suggest that many women with ER-moderate/-rich tumours will have a good prognosis after preoperative hormone therapy alone. However, it is possible to identify, by their post-systemic therapy axillary node status, a group of women who still have an appalling prognosis after preoperative chemotherapy or hormone therapy.

Adult↗
PubMed1997

Glucose transport by isolated plasma membranes of the bovine blood-brain barrier.

Luminal and abluminal endothelial plasma membrane vesicles were isolated from bovine cerebral microvessels, the site of the blood-brain barrier. Glucose transport across each membrane was measured using a rapid-filtration technique. Glucose transport into luminal vesicles occurred by a stereospecific energy-independent transporter [Michaelis-Menten constant (K(m)) = 10.3 +/- 2.8 (SE) mM and maximal velocity (Vmax) = 8.6 +/- 2.0 nmol.mg protein(-1).min-1]. Kinetic analysis of abluminal vesicles also showed a transport system with characteristics similar to the luminal transporter (K(m) = 12.5 +/- 2.3 mM and Vmax = 10.0 +/- 1.0 nmol.mg protein-1.min-1). These functional, facilitative glucose transporters were symmetrically distributed between the luminal and abluminal membrane domains, providing a mechanism for glucose movement between blood and brain. The studies also revealed a Na-dependent transporter on the abluminal membrane with a higher affinity and lower capacity than the facilitative transporters (K(m) = 130 +/- 20 microM and Vmax = 1.59 +/- 0.44 nmol.mg protein-1.min-1. The abluminal Na-dependent glucose transporter is in a position to transport glucose from the brain extracellular fluid into the endothelial cells of the blood-brain barrier. The functional significance of its presence there remains to be determined.

Animals↗
PubMed1997

Penetration of glutamate into brain of 7-day-old rats.

The permeability of the blood-brain barrier to glutamate was measured by quantitative autoradiography in brains of 7-day-old rats (average plasma glutamate 114 microM) and rats injected subcutaneously with glutamate (average plasma glutamate 2,670 microM). Measurements of glutamate permeability were initiated by the injection of [14C]glutamate into the inferior vena cava and the 7-day-old rats sacrificed at 1 minute to avoid the accumulation of [14C]glutamate metabolites in plasma. Glutamate entered the brain at a slow rate, with an average permeability-surface area product of 12 microl x min(-1) x g(-1), except in those areas known to have fenestrated capillaries. Thus, glutamate readily entered and accumulated in circumventricular organs where the radioactivity was localized. Although three areas with a blood-brain barrier, the cerebral cortex, the hypothalamus and the midbrain, of 7-day-old rats had permeabilities similar to adult rats, the other areas of the brain with a blood-brain barrier had a permeability about 1.5-1.9 times that of adult rats. The greater permeability of the brain of 7-day-old rats may reflect the degree of immaturity of the blood-brain barrier.

Animals↗
PubMed1996

Role of oxoproline in the regulation of neutral amino acid transport across the blood-brain barrier.

Regulation of neutral amino acid transport was studied using isolated plasma membrane vesicles derived from the bovine blood-brain barrier. Neutral amino acids cross the blood-brain barrier by facilitative transport system L1, which may allow both desirable and undesirable amino acids to enter the brain. The sodium-dependent amino acid systems A and Bo,+ are located exclusively on abluminal membranes, in a position to pump unwanted amino acids out. gamma-Glutamyl transpeptidase, the first enzyme of the gamma-glutamyl cycle, is an integral protein of the luminal membrane of the blood-brain barrier. We demonstrate that oxoproline, an intracellular product of the gamma-glutamyl cycle, stimulates the sodium-dependent systems A and Bo,+ by 70 and 20%, respectively. Study of system A showed that 2 mM oxoproline increased the affinity for its specific substrate N-methylaminoisobutyrate by 50%. This relationship between the activity of the gamma-glutamyl cycle and system A transport may provide a short term regulatory mechanism by which the entry of potentially deleterious amino acids (i.e. neurotransmitters or their precursors) may be retarded and their removal from brain accelerated.

Amino Acids↗
PubMed1996

Randomised comparison of 5 years of adjuvant tamoxifen with continuous therapy for operable breast cancer. The Scottish Cancer Trials Breast Group.

In 1985 a second randomisation was initiated for women in the treatment arm of the Scottish Tamoxifen Trial either to stop tamoxifen at 5 years or to continue indefinitely. A preliminary analysis of outcome in 342 patients at a median follow-up of 6 years suggests that a worthwhile gain in disease control from continuing adjuvant tamoxifen beyond 5 years is unlikely. [Hazard ratio for events (relapse or death without relapse) is 1.27, 95% CI = 0.87 - 1.85.] There is a suggestion that therapy for longer than 5 years may increase the risk of endometrial carcinoma (P = 0.064).

Adult↗
PubMed1996

Prospective evaluation of prognostic factors in operable breast cancer.

In 215 patients with operable breast cancer (T1-T3, N0-1, M0) and no other or previous cancer, presenting to a single breast unit, sufficient tumour was available for the prospective determination of four putative biochemical markers of prognosis: oestrogen receptor (ER) activity, cathepsin D (cath D), epidermal growth factor receptor (EGFR) activity and cyclic AMP-binding proteins (c-AMP-b). There were significant inter-relationships between ER and EGFR (r = -0.26), c-AMP-b and cath D (r = +0.32) and ER and c-AMP-b (r = +0.14). After follow-up (median 36.2 months), a total of 55 recurrences (18 locoregional only) and 35 deaths were recorded. By univariate analysis, up to 10 of 18 biochemical, clinical and histopathological variables of potential prognostic value were significantly related to disease-free interval or death, but by multivariate analysis only oestrogen receptor concentration and node status contributed significantly to risk of both distant recurrence/death; in addition, tumour size made a small contribution to the risk for a distant recurrence only. Only two parameters, tumour grade and ER concentration, were significantly related to risk of locoregional recurrence by univariate analysis, but by multivariate analysis, only tumour grade was important. It is concluded that tumour ER concentration, axillary nodal status and tumour grade remain as the most important prognostic factors in the early years after presentation of operable breast cancer, with a minor influence of tumour size. At this time, the prognostic significance of quantitative measurements of ER concentration, carefully controlled for the quality of both assay and tumour specimen, is probably greater than is generally appreciated. We have yet to identify other factors, which add significantly to the short-term prognostic value of these key features.

Age Factors↗
PubMed1996

Optimized sampling and parameter estimation for quantification in whole body PET.

Whole-body positron emission tomography (PET) has recently emerged as an important imaging tool for cancer detection and staging. Initial applications of the technique have been primarily qualitative. One of the major reasons is the limits imposed by kinetically undersampled data over the whole body, as opposed to the standard method of continuous dynamic sampling in one body location. In this paper, a new estimation method using weighted nonlinear least squares (WNLS) for the first bed position and Bayesian regression (BR) for subsequent positions is proposed. A general criterion for designing optimal sampling schedules which maximizes the measurement information with multiple bed positions is developed. The overall approach is illustrated with the problem of estimating the metabolic rate of glucose (MRGLu) in tumors at different axial positions (image bed positions) in the body by using computer simulations and patient data. The results show that estimates of MRGLu using sparse data and the optimized Bayesian approach are comparable with those obtained by standard methods and fully sampled data. This study demonstrates the potential of the technique described for quantification where several bed positions have to be used to image all the regions of interest (ROI).

Abdominal Muscles↗
PubMed1996

Eliminating metabolic abnormalities of portacaval shunting by restoring normal liver blood flow.

Portacaval shunting causes a variety of anatomic, metabolic, and physiological changes. However, it has not been determined whether, and to what degree, these changes are permanent after a sustained period of shunting. We prepared three groups of rats for study of the recovery process. One group had side-to-side shunts for 3 wk, one group had side-to-side shunts for 2 wk followed by the restoration of normal liver circulation for 1 wk, and one group (control) had sham operations. Side-to-side shunting causes liver atrophy, increased plasma ammonia, altered plasma and brain amino acid spectra, decreased plasma glucose, and increased transport of neutral amino acids across the blood-brain barrier. After restoration of the normal pattern of liver circulation by shunt repair, the liver regained its normal size within 1 day. All abnormalities associated with liver dysfunction disappeared with the exception of plasma glucose, which remained approximately 15% lower than control values.

Amino Acids↗
PubMed1996

Reversal of portacaval shunting normalizes brain energy consumption in most brain structures.

The cerebral metabolic rate of glucose consumption (CMRGlc) was measured throughout brains of rats with 1) portacaval shunts created for 2 wk, followed by restoration of normal blood circulation for 2 wk; 2) portacaval shunts created for 2 wk, followed by a sham operation and 2 wk of recovery; 3) two sham operations, each with 2 wk of recovery times. Portacaval-shunted rats had diminished CMRGlc (decreases of 7-23%) throughout the brain in agreement with previous studies. After restoration of normal liver blood flow, the CMRGlc of most structures returned to near-normal values, although a few structures, notably the hippocampus, remained 11-13% lower. These data suggest that the consequences of portacaval shunting to brain energy metabolism can be markedly improved, if not completely reversed, by restoring the normal pattern of blood flow to an otherwise healthy liver. Other metabolic and physical data collected (liver weight, liver-to-body weight, plasma ammonia) returned to normal except plasma glucose concentrations, which remained lower by 11%, suggesting a persistent, albeit mild, defect in glucose homeostasis.

Animals↗
PubMed1996

Comparison of the metabolic disturbances caused by end-to-side and side-to-side portacaval shunts.

Portacaval shunting causes liver atrophy, hyperammonemia, and hepatic encephalopathy. A fundamental question is whether the changes, especially those to brain, are permanent. To answer this, it is necessary to have a model whereby a portacaval shunt can be created for a period of time and then the normal pattern of circulation to the liver restored at will. An end-to-side shunt, the most extensively studied model of liver dysfunction, is permanent. However, a side-to-side shunt can be constructed that results in a somewhat different pattern of circulation but with the potential to be reversed. The purpose of the present study was to compare the severity of the metabolic disturbances caused by the two models. Rats with an end-to-side shunt, a side-to-side shunt, or sham operation were prepared and studied after 14-19 days. Both models of shunting caused the same degree of liver atrophy, hyperammonemia, and indistinguishable disturbances in the amino acid content of plasma and brain. Furthermore, both models produced the same degree of cerebral depression as measured by glucose consumption.

Amino Acids↗
PubMed1996

Quantification of serial tumor glucose metabolism.

UNLABELLED: We developed a method to improve the quantitative precision of FDG-PET scans in cancer patients. The total-lesion evaluation method generates a correlation coefficient (r) constrained Patlak parametric image of the lesion together with three calculated glucose metabolic indices: (a) the total-lesion metabolic index ("KT-tle", ml/min/lesion); (b) the total-lesion voxel index ("VT-tle", voxels/lesion); and (c) the global average metabolic index ("KV-tle", ml/min/voxel). METHODS: The glucose metabolic indices obtained from conventional region of interest (ROI) and multiplane evaluation were used as standards to evaluate the accuracy of the total-lesion evaluation method. Computer simulations and four patients with metastatic melanoma before and after chemotherapy were studied. RESULTS: Computer simulations showed that the total-lesion evaluation method has improved precision (% s.d. < 0.6%) and accuracy (approximately 10% error) compared with the conventional ROI method (% s.d. approximately 5%; approximately 25% error). The KT-tle and VT-tle indices from human FDG-PET studies using the total-lesion evaluation method showed excellent correlations with the corresponding values obtained from the conventional ROI methods and multiplane evaluation (r approximately 1.0) and CT lesion volume measurements. CONCLUSION: This method is a simple but reliable way to quantitatively monitor tumor FDG uptake. The method has several advantages over the conventional ROI method: (a) less sensitive to the ROI definition, (b) no need for image registration of serial scan data and (c) includes tumor volume changes in the global tumor metabolism.

Computer Simulation↗
PubMed1995

Biochemical discrimination between luminal and abluminal enzyme and transport activities of the blood-brain barrier.

Luminal and abluminal membrane vesicles derived from bovine brain endothelial cells, the site of the blood-brain barrier, were fractionated in a discontinuous Ficoll gradient. A mathematical analysis was developed to determine the membrane distribution of membrane marker enzyme activities as well as the ratio of luminal to abluminal membrane in each fraction of the gradient. The results of this analysis indicate that gamma-glutamyl transpeptidase and amino acid transport system A are located on the luminal and abluminal membranes, respectively. Conversely, 5'-nucleotidase and alkaline phosphatase activities are evenly distributed between both membranes. Although Na+/K(+)-ATPase activity is primarily located on the abluminal membrane, approximately 25% of the activity is of luminal origin. Na+/K(+)-ATPase activities associated with each membrane showed different ouabain sensitivities, suggesting that different isoenzymes are located in luminal and abluminal membranes. The analytical procedure used in this study provides a quantitative means to determine the distribution of marker enzymes and transport proteins in partially purified membrane vesicle populations.

5'-Nucleotidase↗