Search PubMed⌕ Search

Biomedical subjects

S Kaufman

Publications and source records attributed to S Kaufman.

At least 307 records · Page 17Linked to original sources
PubMed1983

Ligand effects on the limited proteolysis of phenylalanine hydroxylase: evidence for multiple conformational states.

The effects of phenylalanine and tetrahydrobiopterin on the limited proteolysis of rat liver phenylalanine hydroxylase by chymotrypsin have been examined. The presence of tetrahydrobiopterin inhibits the proteolytic activation of native phenylalanine hydroxylase. In contrast, phenylalanine causes a stimulation of proteolytic activation under these conditions. Neither phenylalanine nor tetrahydrobiopterin affect the rate of hydrolysis of a synthetic substrate by chymotrypsin. Both tetrahydrobiopterin and phenylalanine inhibit the release of soluble radioactivity from [32P]phosphorylated phenylalanine hydroxylase. These results confirm the existence of multiple conformational states of phenylalanine hydroxylase.

Animals↗
PubMed1983

The development of tetrahydrobiopterin and guanosine-5'-triphosphate cyclohydrolase: differential patterns in rat brain and pineal gland.

The developmental patterns of appearance of 5,6,7,8-tetrahydrobiopterin (BH4) and the first enzyme in BH4 biosynthesis, guanosine-5'-triphosphate cyclohydrolase (GTPcyc), were examined in rat brain and pineal gland. A parallel relationship between BH4 content and GTPcyc activity was evident in both tissues during development. In brain, the maximal content of BH4 and activity of GTPcyc was observed 2 days prior to, and 10 days after, birth. In contrast, both pineal BH4 content and GTPcyc activity became maximal postnatally. The influence of neural input on the developmental appearance of pineal BH4 was examined in rats that had been superior cervical ganglionectomized shortly after birth. It was found that this procedure did not alter the developmental appearance of BH4.

Aging↗
PubMed1983

Tetrahydropterin therapy for hyperphenylalaninemia caused by defective synthesis of tetrahydrobiopterin.

A patient with hyperphenylalaninemia caused by a defect in the synthesis of tetrahydrobiopterin was treated with 6-methyltetrahydropterin. This synthetic analog of the naturally occurring hydroxylation cofactor tetrahydrobiopterin, when given orally at a daily dose of 20 mg per kilogram of body weight increased depressed plasma and cerebrospinal fluid levels of norepinephrine. At a daily dose of 8 mg/kg, this pterin increased depressed cerebrospinal fluid levels of the biogenic amine metabolites dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindoleacetic acid. At these doses of 6-methyltetrahydropterin, there was an improvement of the patient's neurological symptoms, including a pronounced decrease in eye rolling and drooling and a marked increase in muscle strength, coordination, and physical activity.

Biopterins↗
PubMed1983

Combined modality treatment of gastric cancer.

In a series of 46 patients with localized gastric cancer treated at Massachusetts General Hospital, problems with excessive acute or chronic toxicity due to combination treatment with irradiation (XRT) and chemotherapy (CT) were not seen. Forty of the 46 received combined treatment with 2 regimens: 1) Irradiation plus concomitant 3 days of 5-FU followed by maintenance 5-FU or combined drugs--26 patients; 2) In the other 14 patients, the sequence of irradiation and chemotherapy was altered. A single course of combined drug chemotherapy was given prior to irradiation and 5-6 additional courses were administered after completion of XRT (CT-XRT-CT). The drug combination was initially 5-FU-BCNU but this was changed to FAM (5-FU, Adriamycin, Mitomycin C). Irradiation was delivered to tightly contoured portals using shaped blocks to spare as much small bowel, kidney and marrow as possible while giving 4500-5200 rad in 25 to 29 fractions over 5 to 6 weeks. In this series, there were no cases of septicemia or any deaths related to treatment. A 3 year survival rate of about 20% was achieved for the total group of patients and 43% in the group with resection but at high risk for later failure. Our inability to improve these numbers is undoubtedly a result of dose limitations with external beam irradiation combined with a systemic failure problem. When irradiation is combined with surgical resection of all or a majority of tumor, both survival and local control appear to be better than in the unresected patient group. Only 4 of 29 patients (14%) with curative resection, or resection but residual disease, had later evidence of failure within the irradiation field as opposed to 6 of 9 or 66% in the group with unresectable disease.

Adenocarcinoma↗
PubMed1983

Disseminated herpes simplex infection with retinitis in a renal allograft recipient.

An immunosuppressed recipient of a renal allograft developed bilateral necrotizing retinitis. Disseminated herpes simplex infection was documented by clinical findings and serologic and viral culture studies. Cultures and serologic tests for cytomegalovirus were negative. The evidence strongly favored the diagnosis of herpes simplex retinitis. Tapering of immunosuppressive drugs and administration of adenine arabinoside appeared to halt temporarily the progression of the disease in one eye and resulted in healing of the retinitis in the other eye. Subsequent progression of the more severely involved right eye resulted in an exudative retinal detachment and loss of vision prior to the patient's death from meningoencephalitis. Herpes simplex retinitis must be considered in the differential diagnosis of necrotizing retinitis in an immunosuppressed patient.

Adult↗
PubMed1983

Plasma prolactin levels and body fluid deficits in the rat: causal interactions and control of water intake.

A study was made of the responses of chronically hyperprolactinaemic rats to selected dipsogenic stimuli. Measurements were also made of the correlation between the state of hydration of the animal and the plasma prolactin levels. After 24 h water deprivation. S.C. isoprenaline (10 micrograms/kg body wt.) or I.P. injection (5 ml/kg body wt.) of a hypertonic solution (50% w/w) of polyethylene glycol (mol. wt 20000) there was no difference between the hyperprolactinaemic and control rats with respect to the total water intake, the time course of drinking or the urine output. After I.V. injection of 2 M-NaCl (5 ml/kg body wt.) there was no difference between the hyperprolactinaemic and control rats with respect to the total water intake or urine output. However, the hyperprolactinaemic rats drank more slowly than the controls. When angiotensin II was infused I.V. at a rate of 0.2 micrograms/min, the water intake was greater and the threshold to drinking lower in the hyperprolactinaemic than control rats. After 24 h water deprivation, plasma prolactin levels rose significantly in both the control and hyperprolactinaemic rats. When the rats were injected I.V. with hypertonic saline (5 ml, 2 M-NaCl/kg body wt.) and denied access to water, plasma prolactin levels had not changed 1 h later in either the control or hyperprolactinaemic animals. It is concluded that there is no interaction either between the plasma osmolality and prolactin secretion or between the plasma prolactin levels and the amount of water drunk in response to intracellular fluid deficits. However, prolactin secretion is stimulated by the combined intra- and extracellular deficits resulting from water deprivation and there is a clearly demonstrated interaction between prolactin and the extracellularly mediated stimulus of angiotensin II.

Angiotensin II↗
PubMed1982

Specificity of amino acids as activators and substrates for phenylalanine hydroxylase.

Rat liver phenylalanine hydroxylase can be markedly activated by a variety of different procedures including those that lead to covalent modification of the enzyme, such as limited proteolysis by alpha-chymotrypsin and alkylation of sulfhydryl groups by N-ethylmaleimide, and those that lead to reversible changes, such as the interaction of the enzyme with lysolecithin and related compounds. These treatments not only lead to increased activity toward the normal substrate for the enzyme, phenylalanine, but they lead to even greater increases in activity toward normally poor substrates such as m-tyrosine. Activations of this type, therefore, in effect, appear to broaden the amino acid specificity of the enzyme. We have now found that the extent of the change in substrate specificity on activation of the enzyme is much greater than had been heretofore realized. Indeed, the lysolecithin-activated enzyme is able to act on nonaromatic amino acids such as methionine and norleucine, catalyzing their conversion to methionine sulfoxide and epsilon-hydroxynorleucine, respectively. These amino acids are also substrates for phenylalanine hydroxylase that has been activated by limited proteolysis with alpha-chymotrypsin and by reaction with N-ethylmaleimide. By contrast, the unactivated hydroxylase as little or no activity toward methionine and norleucine. Rat liver phenylalanine hydroxylase can also be activated by its substrate, phenylalanine. We have now found that the novel substrates, methionine and norleucine, are also able to activate the enzyme. On a molar basis, however, they are not as active as phenylalanine. A model that can account for the broadened substrate specificity of the activated enzyme is discussed.

Amino Acids↗
PubMed1982

Spontaneous activation of phenylalanine hydroxylase in rat liver extracts.

A wide variety of modifications of rat liver phenylalanine hydroxylase, such as limited proteolysis and phosphorylation, leads to a selective increase in the tetrahydrobiopterin-dependent hydroxylase activity without affecting the 6-methyltetrahydropterin or the 6,7-dimethyltetrahydropterin-dependent activity. The ratio of hydroxylase activity in the presence of tetrahydrobiopterin and one of these synthetic pterins, therefore, can serve as an indicator of the state of activation of the enzyme. Comparisons of this ratio for the crude and the pure liver enzyme, indicated that the purified enzyme has undergone activation. We have studied this activation under controlled conditions and have found that it is a Mn2+-sensitive process that occurs in liver extracts that have been freed of small molecules. The activation appears to be different from any of those that have been described previously.

Animals↗
PubMed1982

Clinical trial of Corynebacterium parvum (intra-lymph-node and intravenous) and radiation therapy in the treatment of head and neck carcinoma.

Fifty-seven patients with previously untreated squamous cell carcinoma of the head and neck region of all clinical stages were entered a trial to evaluate the effectiveness of Corynebacterium parvum combined with radiation therapy in improving local and survival results. Twenty-nine patients were randomized to receive radiation therapy alone, and 28 patients were randomized to receive radiation therapy combined with C. parvum. The C. parvum was administered into the tumor-bearing lymph nodes of the neck or into the cervical node region in non-node-positive patients (4 mg/m2) and by intravenous routes (at 2, 2, 4, 4 and 4 mg/M2) at days -10, -7, and -3 before, and at +7 and +14 days after the start of radiation therapy. The study began in July 1975 and was terminated after 2 1/2 years of patient accession. The statistical analysis showed that those receiving C. parvum were not doing better than controls and, in fact, in some subgroups there was concern that they might be doing less well. Pertinently, analysis showed that those receiving C. parvum would not experience the 25% point improvement in disease-free survival frequency which had been stipulated in the design of the protocol.

Aged↗