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Biomedical subjects

J W Keller

Publications and source records attributed to J W Keller.

At least 19 recordsLinked to original sources
PubMed1995

Structural and mechanistic analysis of two refined crystal structures of the pyridoxal phosphate-dependent enzyme dialkylglycine decarboxylase.

Two refined structures, differing in alkali metal ion content, of the bifunctional, pyridoxal phosphate-dependent enzyme dialkylglycine decarboxylase (DGD) are presented in detail. The enzyme is an alpha 4 tetramer, built up as a dimer of dimers, with a subunit molecular mass of 46.5 kDa. The fold of DGD is similar to those of aspartate aminotransferase, omega-amino acid aminotransferase and tyrosine phenol-lyase. The structure has two binding sites for alkali metal ions. DGD with potassium in site 1 (near the active site) and sodium in site 2 (at the surface of the molecule) has been refined against 2.6A resolution data (R-factor = 17.6%), and DGD with sodium at both sites has been refined against 2.1 A resolution data (R-factor = 17.8%). The proximity of site 1 to the active site accounts for the dependence of enzyme activity on potassium ions, and the observed active site structural changes caused by ion exchange at this site explain the inhibition of activity by sodium. DGD catalyzes both the decarboxylation of dialkylglycine species and the transamination of L-amino acids in its normal catalytic cycle. The active site structure of DGD is moderately homologous to that of aspartate aminotransferase, which catalyzes only transamination; both the differences and similarities provide mechanistic guidelines for the DGD-catalyzed reactions. Models of the L-isovaline and L-alanine external aldimine intermediates suggest mechanisms by which the decarboxylation and transamination reactions could be accomplished within the single active site. Decarboxylation is proposed to be at least partially catalyzed by stereoelectronic activation of the C alpha-carboxylate bond achieved by orienting this bond perpendicular to the plane of the pyridinium ring in the dialkylglycine external aldimine intermediate. Transamination is proposed to be catalyzed by a similar effect on the C alpha-H bond of the L-amino acid external aldimine intermediate, combined with general base catalysis provided by Lys272, in analogy to the mechanism of aspartate aminotransferase.

Amino Acid Sequence↗
PubMed1995

Definitive radiation therapy for extrahepatic bile duct carcinoma.

PURPOSE: To evaluate retrospectively the role of radiation therapy for extrahepatic bile duct (EHBD) carcinoma. MATERIALS AND METHODS: Twenty-seven patients with local-regional EHBD carcinomas were treated with definitive radiation therapy. Radiation therapy was delivered by means of external beam radiation therapy (EBRT) alone or combined with transcatheter iridium-192 brachytherapy. The median total dose was 54 Gy (range, 30-144 Gy). Survival rates were calculated and compared by using the log-rank test. Possible prognostic factors affecting survival were evaluated by means of univariate analysis. RESULTS: The median survival of all patients was 13 months, with 1- and 2-year actuarial survival rates of 52% and 10%, respectively. Univariate analysis revealed that men, patients with tumors limited to the bile duct, and patients receiving EBRT doses of at least 45 Gy had significantly better outcomes. Local-regional recurrence was the main cause of treatment failure (82%). Two patients developed gastric outlet obstruction. CONCLUSION: Patients with locally advanced EHBD carcinomas have a low survival rate. Certain factors, however, appear to have prognostic significance.

Adenocarcinoma↗
PubMed1995

Use of dreams in therapy: a survey of clinicians in private practice.

A literature review indicated a dearth of research on how dreams are used in therapeutic settings so a questionnaire was sent to a random sample of 500 members of the Florida Psychological Association to assess (a) the extent of dream use in therapy, (b) theoretical approaches applied to dream interpretation, and (c) basis for experience and expertise in dream work. Of the 500 potential clinicians, 228 returned survey forms for a response rate of 46%. Analysis indicated that 83% of the respondents used dream material at least occasionally in their practice and that Freudian and Gestalt approaches were most often used in dream interpretation. Interestingly, most respondents gained their 'experience' in dream work through self-study and continuing education workshops and seminars.

Adult↗
PubMed1994

An alkali metal ion size-dependent switch in the active site structure of dialkylglycine decarboxylase.

The pyridoxal 5'-phosphate-dependent enzyme dialkylglycine decarboxylase (DGD) is activated by K+ and Rb+ ions, whereas Li+ and Na+ ions are inhibitory. A binding site for alkali metal ions close to the active site (site 1) was discovered in the crystal structure of DGD, and an exchange of K+ for Na+ at this site was shown to affect the conformation of two active site residues [Toney, M. D., Hohenester, E., Cowan, S. W., & Jansonius, J. N. (1993) Science 261, 756-759]. We have investigated the effects of alkali metal ions on DGD activity and have determined the crystal structures at 2.8 A resolution of DGD with Li+ and Rb+ bound at site 1. Due to the weak scattering of the Li+ ion, its position had to be modeled using information from small molecule structures. A comparison of the DGD structures with Li+, Na+, K+, and Rb+ bound at site 1 reveals a striking correlation between active site structure and enzymatic activity. The small, inhibitory ions Li+ and Na+ are accommodated by replacing two protein-derived ligands of the larger, activating ions K+ and Rb+ by a single water molecule. This actuates a two-state structural switch between active and inactive enzyme that involves a concerted reorientation of the active site residues Ser80 and Tyr301 and a small change in the quaternary structure of the DGD tetramer. An important role of the essential K+ ion in both cofactor binding and the organization of a catalytically competent active site structure is proposed. In the structure of DGD with Rb+ bound at site 1, a second Rb+ ion has partially replaced the structural Na+ ion at metal binding site 2 on the surface of the DGD molecule, without significantly altering the protein structure. In contrast to Na+, the Rb+ ion is bound with unfavorable geometry, and it is proposed that the rigid site 2 structure results in a pronounced selectivity for Na+ ions.

Binding Sites↗
PubMed1992

Nondetectable prostate-specific antigen in moderately differentiated adenocarcinoma of prostate.

Prostate-specific antigen (PSA) is a glycoprotein derived from prostatic ductal and acinar epithelial cells. The main clinical use of PSA is as a marker of prostate tumor progression/recurrence. We present a case of a sixty-nine-year-old patient with recurrent endometrioid carcinoma of the prostate (status post-radical prostatectomy, hormonal therapy, and external beam radiation therapy) with normal serum PSA.

Adenocarcinoma↗
PubMed1992

The prognostic significance of race and survival from prostate cancer based on patients irradiated on Radiation Therapy Oncology Group protocols (1976-1985).

A number of studies have identified race as a prognostic factor for survival from prostate cancer. To evaluate the prognostic significance of race in a controlled setting, we evaluated 1294 patients treated on three prospective randomized trials conducted by the Radiation Therapy Oncology Group between 1976 to 1985. One-hundred and twenty (9%) of the patients were coded as black, while 1077 (83%) of the patients were coded as white. Protocol 7506 included 607 patients with clinical Stage T3-T4Nx or T1b-T2N1-2. Protocol 7706 included 484 patients with clinical Stage T1b or T2 who were node negative. Protocol 8307 included 203 Stage T2b-T4 patients with no lymph node involvement beyond the pelvis. Univariate and multivariate analyses were used to assess the possible independent significance of race and other prognostic factors, including Gleason score, serum acid phosphatase, nodal status, and hormonal status. Protocols 7706 and 8307 revealed that race was not of prognostic significance for disease-free or overall survival by either univariate or multivariate analysis. Univariate analysis of Protocol 7506 revealed that the median survival for blacks was somewhat shorter (5.4 years vs. 7.1 years, p = 0.02). This difference persisted after a multivariate analysis. A higher percentage of blacks treated on 7506 had an abnormally elevated serum acid phosphatase compared to whites (p = 0.006), and the time to distant failure tended to be shorter (p = 0.07). These findings suggest that blacks treated on 7506 may have had more extensive disease at presentation. Based on these prospective randomized trials, it is most likely that the lower survival noted for black Americans with prostate cancer reflects the tendency for blacks to present with more advanced disease. Differences in access to care, the quality of care received, and the impact of co-morbid conditions may explain the lower survival reported for black Americans elsewhere in the literature.

Black or African American↗
PubMed1991

Crystallization and preliminary X-ray diffraction studies of dialkylglycine decarboxylase, a decarboxylating transaminase.

The pyridoxal phosphate-dependent enzyme dialkylglycine decarboxylase (E.C. 4.1.1.64) has been crystallized by vapor diffusion from a 15% polyethyleneglycol solution with sodium pyruvate as coprecipitant. The space group of the crystals is either P6(2)22 or the enantiomorph, P6(4)22, with one subunit of 46,500 Da per asymmetric unit. The unit cell has dimensions a = b = 152.7 A, c = 86.6 A, alpha = beta = 90 degrees, gamma = 120 degrees, and a solvent content of approximately 61%. diffraction extends to 2.3 A resolution.

Burkholderia cepacia↗
PubMed1990

Pseudomonas cepacia 2,2-dialkylglycine decarboxylase. Sequence and expression in Escherichia coli of structural and repressor genes.

A 3969-base pair PstI-PstI fragment of Pseudomonas cepacia DNA containing the gene for the pyridoxal 5'-phosphate dependent 2,2-dialkylglycine decarboxylase (pyruvate) (EC 4.1.1.64) was cloned in Escherichia coli. The insert was sequenced by the dideoxy method using nested deletions from both ends, revealing a central 1302-base pair region that codes for the decarboxylase subunit. The recombinant enzyme was expressed in E. coli, purified to homogeneity, and sequenced at the amino terminus. Also, a cofactor-labeled active site peptide was sequenced. The carboxyl terminus of the deduced amino acid sequence is homologous with the carboxyl terminus of mammalian ornithine aminotransferase; the active site sequence is similar to the active site sequences of several other aminotransferases. No homologies with known decarboxylase sequences could be found. Expression of the decarboxylase gene is negatively controlled by a 687-nucleotide sequence upstream of and diverging from the structural gene. Expression is induced by S-isovaline, 2-methylalanine, and D-2-aminobutanoic acid, but not by glycine, D- or L-alanine, L-2-aminobutanoic acid, R-isovaline, or other alkyl amino acids.

Amino Acid Sequence↗
PubMed1990

Effects of cigarette smoke and nicotine on platelets and experimental coronary artery thrombosis.

The causal link between smoking, atherosclerosis and an increased risk for acute platelet mediated coronary events such as acute platelet thrombus formation, myocardial infarction, and sudden coronary death is not clear. Our studies suggest that there may be a transient increase in in vivo platelet activity with each exposure to cigarette smoke or elevated plasma nicotine. It is thought that platelets may contribute to the acceleration of the atherosclerotic process by several mechanisms (5). Thus it may be that each time a person increases their platelet activity, by smoking or some other means, and given other predisposing conditions such as elevated lipids and/or acute intimal damage, such as rupture of an atherosclerotic plaque, the atherosclerotic process may be enhanced. In addition it appears that cigarette smoke makes a developing thrombus more adherent and less likely to embolize distally, although the effect is transient. Finally, cigarette smoke may provide the final stimulus for an occlusive coronary thrombus in a stenosed coronary artery already predisposed to thrombosis by other risk factors. This may account for the fact that the risk of coronary occlusion and myocardial infarction decreases markedly in the first year after quitting (65). It may be that smoking has a greater likelihood of precipitating a fatal thrombus than it does of accelerating the altherosclerotic process. This would be reflected in the inability of aspirin to prevent the smoking induced enhancement of CFR's in our model (23) or the enhancement of platelet function in men with coronary artery disease (66).

Animals↗
PubMed1990

Combined inhibitory effects of aspirin and ethanol on adrenaline exacerbation of acute platelet thrombus formation in stenosed canine coronary arteries.

STUDY OBJECTIVE: This study was performed to see whether ethanol could potentiate the inhibitory effect of aspirin on recurrent platelet thrombus formation and subsequent embolisation, which have been shown to cause cyclic reductions in blood flow in 70% of mechanically stenosed dog coronary arteries. DESIGN: After mechanical stenosis of the circumflex coronary artery in open chest dogs, cyclic variations in blood flow were measured during treatment with aspirin, ethanol, or both. SUBJECTS: 20 adult mongrel dogs were used: in group 1 (n = 5) each dog was given aspirin 5 mg.kg-1; in group 2 (n = 5) each was given 1.2 ml.kg-1 ethanol; in group 3 (n = 10) each was given aspirin 1 mg.kg-1 combined with either 0.3 or 0.6 ml.kg-1 ethanol. MEASUREMENTS AND MAIN RESULTS: In group 1, aspirin 5 mg.kg-1 abolished cyclic reductions in circumflex blood flow, but an intravenous infusion of adrenaline (0.4 microgram.kg-1.min-1 for 15 min) caused them to return. In group 2, ethanol 1.2 ml.kg-1 abolished cyclic flow reductions but they returned after adrenaline infusion challenge. In group 3, aspirin 1 mg.kg-1 combined with either 0.6 or 0.3 mg.kg-1 ethanol abolished cyclic flow reductions and protected against their return during adrenaline infusion challenge in 9/10 dogs. CONCLUSIONS: The results suggest that ethanol potentiates the inhibitory effects of aspirin on platelet thrombus formation in our model of simulated coronary artery disease.

Animals↗
PubMed1988

Relative effects of cigarette smoke and ethanol on acute platelet thrombus formation in stenosed canine coronary arteries.

In 10 open chest dogs with mechanically stenosed coronary arteries acute platelet thrombus formation with subsequent embolisation reduced coronary blood flow cyclically by -10.2(3.3) ml.min-2 (as measured with an electromagnetic flow probe). Ventilating the dogs with cigarette smoke increased the flow reduction to -13.5(4.6) ml.min-2. Ethanol 1.0 ml.kg-1 iv completely abolished acute thrombus formation and flow reductions in all 10 dogs. Repeat ventilation with cigarette smoke after ethanol failed to renew flow reductions in nine of the 10 dogs. It is suggested that ethanol effectively inhibits the exacerbating effects of cigarette smoke on acute platelet thrombus formation when both are being used simultaneously.

Animals↗
PubMed1987

Weekly mitoxantrone therapy of Hodgkin's disease, non-Hodgkin's lymphoma, and chronic lymphocytic leukemia. A Southeastern Cancer Study Group Trial.

A weekly schedule of mitoxantrone was evaluated in chronic lymphoproliferative disorders. One of 11 patients with Hodgkin's disease, 2 of 12 with favorable-histology non-Hodgkin's lymphoma, 4 of 27 with unfavorable-histology non-Hodgkin's lymphoma, and 1 of 11 with chronic lymphocytic leukemia showed a response. Since the use of a larger single dose every 3 weeks is well tolerated, simpler, and probably more effective, we do not recommend further evaluation of the weekly dose schedule.

Adolescent↗
PubMed1986

Treatment of chronic lymphocytic leukemia using chlorambucil and prednisone with or without cycle-active consolidation chemotherapy. A Southeastern Cancer Study Group Trial.

Patients with untreated chronic lymphocytic leukemia (CLL) received protocol treatment with 6 months of chlorambucil (CB) (30 mg/M2) and prednisone (P) (80 mg/d X 5) every 2 weeks. Complete and partial responders (CR, PR) were then randomized to consolidation with six more courses of CB and P or to four courses of cytosine arabinoside (25 mg/M2 every 12 hours X 8, subcutaneously) and cyclophosphamide (25 mg/M2 every 12 hours X 8, orally) every three weeks. Of the 178 eligible patients entered, 138 (78%) were evaluable for induction therapy which produced a 22% hematologic CR and an overall response rate (CR + PR) of 74%. Eighty-two patients received adequate consolidation, at the end of which 43 were in CR. No difference was seen in response or survival between the two consolidation treatments. Responders had longer survival than nonresponders (P = 0.0001) even when a 6-month "guarantee time" was excluded, but there was no survival difference between CR and PR. Thus, intermittent CB and P is a well-tolerated, useful therapy for CLL but the addition of cyclophosphamide and cytosine arabinoside does not improve results.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1986

Percutaneous needle biopsy in the diagnosis and classification of lymphoma.

Results of percutaneous needle biopsies were evaluated retrospectively in 58 patients in whom a diagnosis of lymphoma was suspected. The biopsy specimen was diagnostic in 94% of the 36 patients with lymphoma, 20 of whom had recurrent disease and 16 of whom had newly diagnosed lymphoma. Sufficient tissue was obtained in 94% of these positive biopsy specimens to allow histologic subtyping of the lymphoma. Immunohistochemical studies performed on seven of the biopsy specimens allowed immunologic subclassification into B-cell and T-cell types of lymphoma. Our results suggest that the percutaneous needle biopsy is a useful and reliable tool in the diagnosis and classification of lymphoma.

Adolescent↗
PubMed1985

Comparison of enzyme immunoassay and gas-liquid chromatography for the rapid diagnosis of invasive candidiasis in cancer patients.

Three proposed quantitative markers for candidiasis, arabinitol, mannose, and mannan in serum, are compared in 50 normal blood donors and 38 high-risk patients, 23 with and 15 without invasive candidiasis. Arabinitol concentrations in serum, the arabinitol/creatinine ratio, and mannose concentrations in serum were significantly greater in the 15 patients without candidiasis than in the normal blood donors (P less than 0.05). The sensitivities and specificities were 26 and 87% for arabinitol, 13 and 93% for the arabinitol/creatinine ratio, and 39 and 87% for mannose. On the other hand, mannan concentrations in serum were less than 1 ng/ml in normal blood donors and patients without candidiasis (P = 0.344), and the sensitivity and specificity were 65 and 100%, respectively. Of 23 patients with proven or probable candidiasis, 16 had mannan levels in serum greater than the mean + 2 standard deviations (0.46 ng/ml) for the 15 controls. In 16 patients with invasive candidiasis and positive blood cultures for the Candida spp., only 13 had elevated levels of at least one of the three markers. The arabinitol/creatinine ratio, the mannose level, and the mannan level became elevated an average of 4 days before, 1 day before, and on the same day that the blood cultures were drawn, respectively. Conversely, mannan was detected in the sera of six of seven patients with invasive candidiasis and negative blood cultures. We conclude that the best approach to diagnosing invasive candidiasis involves obtaining blood cultures and carrying out serial assays for mannan in serum.

Candidiasis↗
PubMed1985

Psychodiagnostic test usage: a survey of the society for personality assessment.

The present survey investigated psychodiagnostic test usage and practices of the Society for Personality Assessment. A brief questionnaire was forwarded to 400 SPA members and 206 responded for a 51.5% rate of return. Projective techniques found popular in previous surveys of Division 12 were the major assessment instruments utilized by SPA members. Exner's comprehensive system was the preferred mode of Rorschach analysis, followed by the Klopfer and Beck systems. The Wechsler Scales and the MMPI were frequently included in conducting a psychological battery. Personality assessment was mainly utilized for diagnostic purposes and as an indicator for type of therapy.

Humans↗
PubMed1984

Perspectives on death: a developmental study.

While prior research has focused on death anxiety in general, more recent studies have recognized the need for multilevel measures for assessing the fear of death. A 12-item questionnaire used in the present cross-sectional investigation produced three factors--Evaluation of Death in General (Factor I), Belief in the Hereafter (Factor II), and Death Anxiety Related to Self (Factor III). The sample consisted of 874 Ss categorized into six age groups from young adult to old age. A two-way ANOVA on each of the factor scores was performed for the variables age and sex. Middle-age and late middle-age persons were significantly less anxious in regard to Evaluation of Death in General than their younger and older counterparts. Old age groups showed the least Death Anxiety Related to Self. Sex differences were found for Factors II and III. Future research should differentiate the concept of death from the process of dying.

Adolescent↗