Biomedical subjects
Publications and source records attributed to M Salter.
Primary lymphoma of bone (PLB) is an uncommon neoplasm representing only 5% of all extranodal non-Hodgkin's lymphomas. The precise role of magnetic resonance imaging (MRI) scanning is unknown. A review of the literature and a recent case treated at the University of Alabama at Birmingham in which MRI unveiled other foci of disease undetected by routine staging studies is presented.
The aromatic amino acids are, inter alia, substrates for the synthesis of important neurotransmitters. Although the factors controlling the synthesis of these transmitters are not fully understood, there is evidence that the concentrations, both relative and absolute, of the precursor amino acids in the blood are of some significance. The article reviews the biochemical pathways involved in tryptophan, phenylalanine, and tyrosine metabolism in liver, brain, and other tissues and discusses (1) the major regulatory events in the maintenance of blood concentrations and (2) the effects of diet, load dosing, hormones, and other circulating substances on the fate of the amino acids and on events in the central nervous system.
Studies using simultaneous radiation therapy and conventional doses of cisplatin have suggested improvement in local control and patient survival. This study was undertaken to determine toxicity and patient tolerance to concomitant high-dose cisplatin (40 mg/m2 per day X 5) and radiation (60 Gy in 6 wk +/- 10-Gy boost to residual tumor). Seventeen patients with advanced, inoperable squamous cell cancer primary tumor in the head and neck were treated (15 males and 2 females; median age, 57 yr). Cisplatin was started on day 1 of radiation therapy and repeated every 28 days for three cycles. Normal saline infusion (250 ml/hr) was started 12 hours prior to the first dose and continued 12 hours after the fifth dose. The daily dose of cisplatin was dissolved in 250 ml of 3% NaCl and given over 30 minutes. The cisplatin dose for subsequent cycles was reduced 10 mg/m2 per day only for a nadir granulocyte count less than 500/mm3 or fever greater than 101 degrees F during leukopenia. Of the 17 patients who started therapy, 15 have completed therapy; 1 patient died after one cycle, and 1 died after two cycles. Eleven patients received three cycles of cisplatin, and 10 patients required one dose reduction (6 at course 2 and 4 at course 3). Seven possible infections were successfully treated. Grade 2 neuropathy occurred in 3 patients, and renal toxicity greater than grade 1 occurred in 1 patient. Additional toxic effects were median WBC count nadir of 1.8 X 10(3)/mm3, platelet count nadir of 128 X 10(3)/mm3, hemoglobin nadir of 9.8 g/dl, and median weight loss of 5%.(ABSTRACT TRUNCATED AT 250 WORDS)
The objective of this study was to quantitate and characterize the variants of bombesin-like immunoreactivity in the alimentary canal of the rat, rabbit, hawk, owl, dog, monkey and human. Bombesin-like immunoreactivity was found throughout the entire gastrointestinal tract of all species studied. In the rat, the highest concentration of bombesin-like immunoreactivity was found in the colon. Gel chromatography showed that bombesin-like immunoreactivity corresponded to gastrin-releasing peptide (GRP-27) and GRP-10. In the dog, the greatest concentration of bombesin-like immunoreactivity was observed in the mucosal layer of the fundus, whereas the concentration of bombesin-like immunoreactivity in the muscle layer of the dog did not vary significantly from region to region. Gel chromatography showed that bombesin-like immunoreactivity in the dog corresponded to GRP-27, bombesin, GRP-10, and a smaller fragment. In the human, the concentration of bombesin-like immunoreactivity did not vary significantly from region to region in the mucosal and muscular layers. Gel chromatography of human fundal mucosa showed that bombesin-like immunoreactivity peaks occur in the regions of GRP-27, bombesin and GRP-10. These findings substantiate the observation that bombesin-like peptides play a variety of roles in the regulation of gut function.
At saturating concentrations of tryptophan, the activity of tryptophan 2,3-dioxygenase was the same in isolated liver cells and in extracts with added haematin. Intraperitoneal injection of haematin did not increase tryptophan oxidation in livers subsequently perfused in situ. Preincubation of liver cells with physiological concentrations of tryptophan caused maximal saturation of tryptophan 2,3-dioxygenase with haem in liver cells. In cell-free extracts tryptophan 2,3-dioxygenase exhibited complex kinetics with haem. The results have important implications for the understanding of the role of haem in tryptophan metabolism.
The quantitative importance of the individual steps of aromatic amino acid metabolism in rat liver was determined by calculation of the respective Control Coefficients (Strengths). The Control Coefficient of tryptophan 2,3-dioxygenase for tryptophan degradation was determined in a variety of physiological conditions and with a range of activities of tryptophan 2,3-dioxygenase. The Control Coefficient varied from 0.75 with basal enzyme activity to 0.25 after maximal induction of the enzyme by dexamethasone. The remainder of the control for tryptophan degradation was associated with the transport of the amino acid across the plasma membrane, with only very small contributions from kynureninase and kynurenine hydroxylase. The Control Coefficients of tyrosine aminotransferase for tyrosine degradation were approx. 0.70 and 0.20 with basal and dexamethasone-induced tyrosine aminotransferase activities respectively; the Control Coefficients of the transport of the amino acid into the cell were 0.22 and 0.58 respectively. Phenylalanine hydroxylase was found to have a Control Coefficient for the degradation of phenylalanine of approx. 0.50 under conditions of basal enzyme activity; after maximal activation by glucagon, the Control Coefficient decreased to 0.12. The transport of phenylalanine was responsible for the remaining control in the pathway. These results have important implications, directly for the regulation of aromatic amino acid metabolism in the liver, and indirectly for the regulation of neuroamine synthesis in the brain.
The transport of the aromatic amino acids into isolated rat liver cells was studied. There was a rapid and substantial binding of the aromatic amino acids, L-alanine and L-leucine to the plasma membrane. This has important consequences for the determination of rates of transport and intracellular concentrations of the amino acids. Inhibition studies with a variety of substrates of various transport systems gave results consistent with aromatic amino acid transport being catalysed by two systems: a 2-aminobicyclo(2,2,1)heptane-2-carboxylic acid (BCH)-insensitive aromatic D- and L-amino acid-specific system, and the L-type system (BCH-sensitive). The BCH-insensitive component of transport was Na+-independent and facilitated non-concentrative transport of the aromatic amino acids; it was unaffected by culture of liver cells for 24 h, by 48 h starvation, dexamethasone phosphate or glucagon. Kinetic properties of the BCH-inhibitable component were similar to those previously reported for the L2-system in liver cells. The BCH-insensitive component was a comparatively low-Km low-Vmax. transport system that we suggest is similar to the T-transport system previously seen only in human red blood cells. The results are discussed with reference to the importance of the T- and L-systems in the control of aromatic L-amino acid degradation in the liver.
A system for the parallel determination of enzyme phosphorylation and expressed activity in rat liver cells, and its application to studies of phenylalanine hydroxylase and tyrosine aminotransferase, is described. Phenylalanine hydroxylase is phosphorylated by agents which stimulate cyclic AMP- and Ca2+-dependent protein kinase activity. The phosphorylation site(s) appear to be the same for both kinases. Phosphorylation is accompanied by increased metabolic flux at low, physiologically relevant, substrate concentrations. Insulin and spermine both inhibit the phosphorylation of the enzyme, possibly by increasing dephosphorylation. Tyrosine aminotransferase is phosphorylated in liver cell incubations but the rate is slow and insensitive to additions to the medium. No parallel changes in flux could be detected. Both enzymes are subject to complex regulatory mechanisms, short- and long-term. Their activities may be coordinated in vivo by control exerted at the level of the plasma membrane where both amino acids share the same transport processes. Determination of the control coefficients for the several components indicates that membrane transport may be a major limitation on flux.
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The total activity of three key enzymes and the flux through eight steps of aromatic amino acid metabolism have been determined in liver cells isolated from rats fed either control or pyridoxine-free diet for 5-6 weeks. The pyridoxine-free diet caused a decrease in the catabolism of tyrosine and phenylalanine because of a drop in the flux through tyrosine aminotransferase. This decrease of expressed cellular tyrosine aminotransferase activity can be fully explained in terms of loss of cofactor. Larger decreases in the catabolism of tryptophan were seen after pyridoxine deprivation. The decreased extent of tryptophan catabolism can be solely attributed to loss of cofactor or increased degradation of kynureninase. Inhibition of tryptophan 2,3-dioxygenase was seen in pyridoxine deficiency, probably because of the buildup of the kynurenine metabolites. The control strength of kynureninase, for flux through kynureninase, was calculated to be less than or equal to 0.004, but 0.41 after pyridoxine deprivation. The sensitivity of the three pathways to pyridoxine deprivation is interpreted and discussed in terms of the different affinities for pyridoxal phosphate and the control strengths of the pyridoxal phosphate-dependent enzymes, tyrosine aminotransferase and kynureninase.
The metabolism of L-tryptophan by isolated liver cells prepared from control, adrenalectomized, glucocorticoid-treated, acute-diabetic, chronic-diabetic and insulin-treated chronic-diabetic rats was studied. Liver cells from adrenalectomized rats metabolized tryptophan at rates comparable with the minimum diurnal rates of controls, but different from rates determined for cells from control rats 4h later. Administration of dexamethasone phosphate increased the activity of tryptophan 2,3-dioxygenase (EC 1.13.11.11) 7-8-fold, and the flux through the kynurenine pathway 3-4-fold, in cells from both control and adrenalectomized rats. Increases in flux through kynureninase (EC 3.7.1.3) and to acetyl-CoA can be explained in terms of increased substrate supply from tryptophan 2,3-dioxygenase. The metabolism of tryptophan was increased 3-fold in liver cells isolated from acutely (3 days) diabetic rats, with a 7-8-fold increase in the maximal activity of tryptophan 2,3-dioxygenase. The oxidation of tryptophan to CO2 and metabolites of the glutarate pathway increased 4-5-fold, consistent with an increase in picolinate carboxylase (EC 4.1.1.45) activity. Liver cells isolated from chronic (10 days) diabetic rats metabolized tryptophan at rates comparable with those of cells from acutely diabetic rats, but with a 50% decrease in the activity of tryptophan 2,3-dioxygenase. The proportion of flux from tryptophan 2,3-dioxygenase to acetyl-CoA, however, was increased by 50%; this was indicative of further increases in the activity of picolinate carboxylase. Administration of insulin partially reversed the effects of chronic diabetes on the activity of tryptophan 2,3-dioxygenase and flux through the kynurenine pathway, but had no effect on the increased activity of picolinate carboxylase. The role of tryptophan 2,3-dioxygenase in regulating the blood tryptophan concentration is discussed with reference to its sensitivity to the above conditions.
The rate of tryptophan metabolism in isolated liver cells from animals fed on a high-leucine diet was greater than for cells from control animals. Leucine inhibited tryptophan metabolism and tryptophan uptake in isolated liver cells, probably by competing for membrane transport. Leucine had no effect on tryptophan 2,3-dioxygenase in vitro. 4-Methyl-2-oxovalerate increased tryptophan oxidation in incubations containing albumin, by displacing bound tryptophan and increasing the availability of the amino acid to the cell. The results suggest that, under extreme conditions, when the availability of tryptophan is low, leucine may be pellagragenic.
Detailed information regarding the kinetics of thermal inactivation of Pichinde, an arenavirus, is presented. Inactivation of virus infectivity proceeded as a first order reaction over the temperature range 22-53 degrees C. The determined inactivation rates analysed as a function of absolute temperature revealed that two different reactions were involved. Below 37 degrees C, the energy of activation was determined to be compatible with RNA degradation, whereas at higher temperatures a correspondingly greater value suggests that protein inactivation contributes significantly to loss of infectivity. Both inactivation reactions were retarded in the presence of foetal calf serum to a final concentration of 1%. The relatively short half-life of 12-24 h at 22 degrees C suggests transmission in nature via contaminated foodstuffs and soil may be inefficient.
Monoclonal antibodies prepared against Tacaribe and Junin viruses have been used to define further the serological relationships between arenaviruses of the Tacaribe complex. A close relationship was found between these two viruses and the heterologous Amapari and Machupo viruses, with Pichinde virus and Parana virus being more distantly related. Among the antibodies specific for Tacaribe virus, five were found to react with viral antigens at the surface of infected cells and to neutralize virus infectivity in vitro. These five antibodies could be differentiated by competitive immunoassay as recognizing at least two antigenically distinct epitopes. The kinetics of reaction between antibody and virus were examined for all five neutralizing antibodies. One antibody (2.25.4) effectively neutralized all infectious virus. The remaining four directed against a second epitope gave significant persistent fractions which could be reduced by addition of complement, anti-mouse immunoglobulin, or antibody 2.25.4. Variants of Tacaribe virus resistant to neutralization by antibody 2.25.4 were obtained by growth in the presence of this antibody and neutralization kinetics were reexamined using the heterologous monoclonal neutralizing antibodies. Several different neutralization profiles were obtained, suggesting that point mutations resulted in conformational changes at topographically selected distinct epitopes recognized by the remaining antibodies.
Liver cells from fed Sprague-Dawley rats metabolized phenylalanine, tyrosine and tryptophan at rates consistent with the known kinetic properties of the first enzymes of each pathway. Starvation of rats for 48 h did not increase the maximal activities of phenylalanine hydroxylase, tryptophan 2,3-dioxygenase and tyrosine aminotransferase in liver cell extracts, when results were expressed in terms of cellular DNA. Catabolic flux through the first two enzymes was unchanged; that through the aminotransferase was elevated relatively to enzyme activity. This is interpreted in terms of changes in the concentrations of 2-oxoglutarate and glutamate. Cells from tryptophan-treated animals exhibited significant increases in the catabolism of tyrosine and tryptophan, but not of phenylalanine. The activities of tyrosine aminotransferase and tryptophan 2,3-dioxygenase were also increased, although the changes in flux and enzyme activity did not correspond exactly. These results are discussed with reference to the control of aromatic amino acid catabolism in liver; the role of substrate concentration is emphasized.
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Conventional treatment for high grade and large sarcomas uses a radical surgical approach, including amputation, in many patients. We evaluated a limb-sparing treatment approach using preoperative regional Adriamycin chemotherapy and rapid-fraction radiation therapy. Thirty patients with soft tissue or skeletal sarcoma were treated in a prospective, nonrandomized clinical trial to evaluate local disease control and limb salvage in these patients who would otherwise require amputation or face a high risk of local recurrence with surgical excision. Almost all patients had large tumors with grade III histologic findings. All patients had a three day intra-arterial regional chemotherapy infusion with Adriamycin (100 milligrams total dose), followed within ten days by rapid-fraction irradiation (3,000 rads over a two week period) prior to surgical excision of the tumor. The size and location of the sarcoma permitted only a marginal resection in one-half of the patients, while the remainder could be excised in a three dimensional en bloc manner. Almost all patients received post-operative systemic Adriamycin chemotherapy (450 milligrams per square meter given intravenously over a six month period). Two of six patients with significant wound complications later required amputation. Only one patient (3 per cent) has had a local recurrence of sarcoma develop after a mean follow-up of 22 months (range nine to 42 months), and 90 per cent of the patients have a useful extremity. The three year survival rate was 68 per cent for soft tissue sarcomas, compared with an expected survival rate of 38 per cent for published historical control studies. The patient with osteogenic sarcoma has a projected 83 per cent survival rate at 18 months after treatment. This multimodality approach is an effective treatment for local disease control in patients with high risk sarcoma. It permits limb salvage in most patients without compromising the survival rates.