TIP30, a cofactor for HIV-1 Tat-activated transcription, is homologous to short-chain dehydrogenases/reductases.
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Acetyltransferases↗
Biomedical subjects
M E Baker
Publications and source records attributed to M E Baker.
A common ancestor for a subunit in the mitochondrial proton-translocating NADH:ubiquinone oxidoreductase (complex I) and short-chain dehydrogenases/reductases.
The proton-translocating NADH:ubiquinone oxidoreductase or complex I is located in the inner membranes of mitochondria, where it catalyzes the transfer of electrons from NADH to ubiquinone. Here we report that one of the subunits in complex I is homologous to short-chain dehydrogenases and reductases, a family of enzymes with diverse activities that include metabolizing steroids, prostaglandins and nucleotide sugars. We discovered that a subunit of complex I in human, cow, Neurospora crassa and Aquifex aeolius is homologous to nucleotide-sugar epimerases and hydroxysteroid dehydrogenases while seeking distant homologs of these enzymes with a hidden Markov model-based search of Genpept. This homology allows us to use information from the solved three-dimensional structures of nucleotide-sugar epimerases and hydroxysteroid dehydrogenases and our motif analysis of these enzymes to predict functional domains on their homologs in complex I.
Amino Acid Sequence↗
Esophagectomy with gastric reconstruction for achalasia.
PURPOSE: Achalasia is a degenerative esophageal disorder that may result in esophageal failure necessitating resection for restoration of gastrointestinal function. This study evaluates a protocol of esophageal resection and gastric reconstruction for end-stage achalasia. METHODS: Hospital records, radiographic studies, and resection specimens of patients undergoing esophagectomy and gastric reconstruction were reviewed. Patient outcome was defined by an evaluation of symptoms (early satiety, dysphagia, regurgitation, and reflux), dietary restrictions, and ability to maintain or gain weight. Preoperative, operative, and postoperative variables and pathologic features in the resection specimens were analyzed to determine predictors of outcome. RESULTS: In a 10-year period, 32 patients underwent esophagectomy with gastric reconstruction for achalasia; 30 (94%) underwent elective surgery and 2 (6%), emergency surgery. No postoperative deaths occurred. Of 29 patients completing telephone interviews, 24 (83%) had no or mild dysphagia; 21 (72%), no or mild regurgitation; 20 (69%), no or mild reflux; and 19 (66%), no or mild early satiety. Twenty-four (83%) patients had no or minimal dietary restrictions; 26 (90%) had no or minimal social dietary restrictions. Postoperative weight was not different from preoperative weight. Of 30 patients, 26 (87%) felt better after esophagectomy and 25 (83%) would have the operation again. There were few predictors of outcome. Younger patients were more likely to have dysphagia ( P =.03). CONCLUSIONS: Esophagectomy with gastric reconstruction relieves preoperative dysphasia and regurgitation in the majority of patients. Dietary function and weight maintenance are excellent, attesting to the durability of the procedure in patients with end-stage achalasia.
Adult↗
Esophageal diverticula: patient assessment.
Esophageal diverticula are best classified by their anatomic location: pharyngoesophageal (Zenker's diverticula), midthoracic, and epiphrenic. Most diverticula result from esophageal motility disorders. Although some patients are asymptomatic and diverticula are incidental findings, most patients are symptomatic. Dysphagia, regurgitation, and pain are common complaints, however, symptoms are often nonspecific and may be the result of an associated esophageal motility disorder. Contrast radiography is the prime diagnostic tool; evaluation of the diverticulum, associated esophageal abnormalities, and complications are assessed by a barium esophogram. Esophagoscopy adds little to the evaluation of the diverticulum but may be indicated in the assessment of other esophageal abnormalities. Motility studies, which may be difficult or hazardous to perform, are of little use in the diagnosis and treatment of Zenker's diverticula. Manometric evaluation of midthoracic or epiphrenic diverticula usually show an associated motility disorder and may influence treatment decisions.
Diverticulum, Esophageal↗
Midthoracic esophageal diverticula.
Periesophageal inflammation, most commonly secondary to tuberculosis, was a frequent cause of midthoracic diverticula. Today, the majority of these diverticula are the result of esophageal motility disorders. Although many patients are asymptomatic, it is the underlying motility disturbances that produce most symptoms. A barium esophagogram is the best study to show midthoracic diverticula. Esophageal manometry may be difficult to perform because of the obstruction of passage of the motility catheter by the diverticulum, but it is useful in defining the cause of the diverticulum and directing therapy. Esophagoscopy is helpful in the assessment of complications or associated esophageal abnormalities. It adds little to the evaluation of the diverticulum. In patients requiring surgery, a diverticulectomy with a myotomy performed on the esophageal wall opposite the diverticulum is the preferred treatment. Lesser procedures have been reported to be successful in select patients.
Barium Sulfate↗
Assessment of esophageal emptying post-pneumatic dilation: use of the timed barium esophagram.
OBJECTIVES: The reported success rate of pneumatic dilation in patients with achalasia varies from 50% to 93%. This wide variability may be due to using symptom relief post-dilation as the only assessment of success. There are no studies comparing subjective symptom improvements to objective improvement in esophageal emptying after pneumatic dilation. METHODS: Patients with achalasia undergoing pneumatic dilation from 1995 to 1997 were evaluated. Pre- and post-dilation symptoms were recorded using a standardized scoring system. Barium column height was measured 1 min and 5 min after upright ingestion to assess esophageal emptying. Based on percentage of total symptom and barium height improvement post-dilation, patients were grouped according to one of nine outcomes; the association between subjective and objective parameters of improvement was tested. RESULTS: A total of 37 patients underwent 53 pneumatic dilations. There was a significant association (p < 0.001) between improvement in patient symptoms and barium height. In 38 of 53 (72%) pneumatic dilations, the degree of symptom and barium height improvement was similar. Near complete symptom resolution was reported after 26 dilations. In eight of 26 (31%) patients however, there was < 50% improvement in barium height (group A). Compared with the 16 patients with 91-100% improvement in both symptoms and barium height (group B), forward stepwise regression identified age as the only difference between the two groups, with group A patients being significantly (p = 0.04) older. CONCLUSIONS: Objective assessment of esophageal emptying pre- and post-dilation identifies an important subset of patients with poor esophageal emptying who report near complete symptom resolution. This group may benefit from any early repeat pneumatic dilation.
Adult↗
Botulinum toxin versus pneumatic dilatation in the treatment of achalasia: a randomised trial.
BACKGROUND: Intrasphincteric injection of botulinum toxin is a new treatment option for achalasia. AIMS: To compare the immediate and long term efficacy of botulinum toxin with that of pneumatic dilatation. METHODS: Symptomatic patients with achalasia were randomised to botulinum toxin (22 patients, median age 57 years) or pneumatic dilatation (20 patients, median age 56 years). Symptom scores were assessed initially, and at one, three, six, nine, and 12 months after treatment. Objective assessment included oesophageal manometry initially and at one month, and barium oesophagram initially and at one, six, and 12 months post-treatment. RESULTS: Pneumatic dilatation resulted in a significantly (p=0.02) higher cumulative remission rate. At 12 months, 14/20 (70%) pneumatic dilatation and 7/22 (32%) botulinum toxin treated patients were in symptomatic remission (p=0.017). Failure rates were similar initially, but failure over time was significantly (p=0.01) higher after botulinum toxin (50%) than pneumatic dilatation (7%). Pneumatic dilatation resulted in significant (p<0.001) reduction in symptom scores, and lower oesophageal sphincter pressure, oesophageal barium column height, and oesophageal diameter. Botulinum toxin produced significant reduction in symptom scores (p<0.001), but no reduction in objective parameters. CONCLUSIONS: At one year pneumatic dilatation is more effective than botulinum toxin. Symptom improvement parallels objective oesophageal measurements after pneumatic dilatation but not after botulinum toxin treatment for achalasia.
Adult↗
Comparison of two barium suspensions for dedicated small-bowel series.
OBJECTIVE: The in vivo radiographic features of two commercially available formulations of barium used as contrast media in dedicated small-bowel series were compared. SUBJECTS AND METHODS: Fifty-six consecutive outpatients referred for a dedicated small-bowel series were randomly administered either E-Z-Paque or Entrobar. Representative survey radiographs from each examination were randomized and reviewed by six gastrointestinal radiologists from three institutions. Each observer assigned a numeric score (1 = poor, 2 = fair, 3 = good, and 4 = excellent) that rated the quality of the radiograph with respect to these characteristics: definition of fold pattern, translucency, distention, and integrity of the barium column. Statistical analysis was performed for each characteristic using Wilcoxon's two-sample rank sum test. RESULTS: All six observers found a statistically significant difference between the two barium formulations for mean scores for definition of fold pattern and translucency. Mean scores for fold pattern were 3.3, 3.0, 3.2, 3.6, 3.3, and 3.4 for Entrobar and 2.1, 2.3, 2.4, 3.2, 2.6, and 2.7 for E-Z-Paque. Mean scores for translucency were 2.5, 2.7, 2.8, 3.1, 2.7, and 3.3 for Entrobar and 1.6, 1.7, 2.1, 2.3, 1.9, and 2.7 for E-Z-Paque. No statistically significant difference was found for mean score for distention or integrity of the barium column. CONCLUSION: On radiographs, Entrobar was found to have superior characteristics for visualization of fold pattern and translucency but offered no advantages for distention or integrity of the barium column. Improved translucency and definition of fold pattern may translate into improved sensitivity and confidence in diagnosing small-bowel abnormality.
Barium Sulfate↗
Albumin's role in steroid hormone action and the origins of vertebrates: is albumin an essential protein?
Albumin, the major serum protein, binds a wide variety of lipophilic compounds including steroids, other lipophilic hormones and phytochemicals that bind to hormone receptors. Albumin has a low affinity for these lipophilic compounds. However, due to albumin's high concentration in serum, albumin is a major carrier of steroids and lipophilic hormones and regulator of their access to their receptors. Moreover, albumin functions as a sink for phytochemicals, which prevents their binding to hormone receptors and other cellular proteins, protecting animals from disruptive phytochemical-mediated endocrine effects. We propose that these properties of albumin were important in protochordates and vertebrates about 550 to 520 million years ago, just before and during the Cambrian. At that time, animal body sizes and exposure to phytochemicals in food were increasing, and animals in which albumin expression was high had a selective advantage in surviving and reproducing in the presence of toxic phytochemicals. This hypothesis that albumin has essential function(s) in mammalian endocrine physiology can be tested by comparing the effects of phytochemicals in Nagase rats that have 1/1000 the normal albumin concentration or in mice in which the albumin gene is knocked out with those in normal rats and mice.
Animals↗
Mutation of tyrosine-194 and lysine-198 in the catalytic site of pig 3alpha/beta,20beta-hydroxysteroid dehydrogenase.
Pig 3alpha/beta,20beta-hydroxysteroid dehydrogenase is an NADPH-dependent enzyme that catalyses the reduction of ketones on steroids and aldehydes and ketones on various xenobiotics, like its homologue carbonyl reductase. 3alpha/beta,20beta-Hydroxysteroid dehydrogenase and carbonyl reductase are members of the short-chain dehydrogenases/reductase family, in which a tyrosine residue and a lysine residue have been identified as catalytically important. In pig 20beta-hydroxysteroid dehydrogenase these residues are tyrosine-194 and lysine-198. Here we report the effect on the reduction of two ketone and two aldehyde substrates by pig 3alpha/beta,20beta-hydroxysteroid dehydrogenase in which tyrosine-194 has been mutated to phenylalanine and cysteine, and lysine-198 has been mutated to isoleucine and arginine. Mutants with phenylalanine-194 or isoleucine-198 are inactive. Depending on the substrate, the mutant with cysteine-194 has a catalytic efficiency of 0.4-1% and the mutant with arginine-198 has a catalytic efficiency of 4-23% of the wild-type enzyme. We also mutated tyrosine-81 and tyrosine-253 to phenylalanine. Although both tyrosines are conserved in 3alpha/beta,20beta-hydroxysteroid dehydrogenase and carbonyl reductase, depending on the substrate, the mutant enzymes are as active as, or more active than, wild-type enzyme.
20-Hydroxysteroid Dehydrogenases↗
Characterization of Ke 6, a new 17beta-hydroxysteroid dehydrogenase, and its expression in gonadal tissues.
The abnormal regulation of the Ke 6 gene has been linked to the development of recessive polycystic kidney disease in the mouse. In this report, we have shown that Ke 6 is a 17beta-hydroxysteroid dehydrogenase and can regulate the concentration of biologically active estrogens and androgens. The Ke 6 enzyme is preferentially an oxidative enzyme and inactivates estradiol, testosterone, and dihydrotestosterone. However, the enzyme has some reductive activity and can synthesize estradiol from estrone. We find that the Ke 6 gene is expressed within the ovaries and testes. The presence of Ke 6 protein within the cumulus cells surrounding the oocyte places it in a strategic location to control the level of steroids to which the egg is exposed. Previously, it had been shown that glucocorticoids can induce renal cysts in the neonatal rodent, only when given at a narrow time window of postnatal kidney development. We propose that the reduction in the level of Ke 6 enzyme, which occurs in the cpk, jck, and pcy mice, may lead to abnormal elevations in local level of sex steroids, which either directly or indirectly via abnormal glucocorticoid metabolism result in recessive renal cystic disease, a developmental disorder of the kidney.
17-Hydroxysteroid Dehydrogenases↗
Spinach CSP41, an mRNA-binding protein and ribonuclease, is homologous to nucleotide-sugar epimerases and hydroxysteroid dehydrogenases.
Spinach CSP41 is part of a protein complex that binds to the 3' untranslated region (UTR) of petD precursor-mRNA, a chloroplast gene encoding subunit IV of the cytochrome b6/f complex. CSP41 cleaves the 3'-UTR of petD mRNA within the stem-loop structure, suggesting a key role in the control of chloroplast mRNA stability. We discovered that CSP41 is homologous to nucleotide-sugar epimerases and hydroxysteroid dehydrogenases while seeking distant homologs of these enzymes with a hidden Markov model-based search of Genpept. This analysis identified Synechocystis ORF, Accession 1652543 as a homolog. Subsequent analyses show that spinach CSP41 and Arabidopsis thaliana 2765081 are homologous to the Synechocystis ORF. Information from the solved 3D structures of epimerases and dehydrogenases and our motif analysis of these enzymes is used to predict domains on CSP41 that are important in binding and metabolism of mRNA. Cyanobacteria are among the earliest life forms, indicating that the divergence from a common ancestor of nucleotide-sugar epimerases and an mRNA binding protein with ribonuclease activity was ancient.
Amino Acid Sequence↗
Evolution of mammalian 11beta- and 17beta-hydroxysteroid dehydrogenases-type 2 and retinol dehydrogenases from ancestors in Caenorhabditis elegans and evidence for horizontal transfer of a eukaryote dehydrogenase to E. coli.
Physiological responses due to steroid hormones and retinoids are regulated by their cognate receptors and dehydrogenases. The origins of either regulatory mechanism are not fully understood. Here we examine the origins of the human 11beta-hydroxysteroid dehydrogenase-type 2, which regulates access of glucocorticoids to cells, and 17beta-hydroxysteroid dehydrogenase-type 2, which regulates access of androgens and estrogens to cells. Sequence comparisons trace their ancestry to homologs in Caenorhabditis elegans. These C. elegans proteins most closely resemble mammalian all-trans and 11-cis-retinol dehydrogenases. The similarity is sufficient -37% to 43% identity to suggest that one or more of the C. elegans homologs metabolizes a retinoid. Receptors for retinoids, but not for androgens, estrogens or glucocorticoids have been identified in C. elegans, suggesting that retinoid-mediated gene transcription is more ancient than that for adrenal and sex steroids. We propose that the hydroxysteroid dehydrogenase-type 2 mechanism for regulating the androgen, estrogen and glucocorticoid concentrations in mammals descended from that for regulating retinoid concentrations. Interestingly, E. coli contains a protein with strong sequence similarity to mammalian retinol dehydrogenases. Sequence comparisons and phylogenetic analysis indicate that the E. coli protein may be an example of horizontal transfer from a eukaryote ancestor.
11-beta-Hydroxysteroid Dehydrogenases↗
An NADPH-dependent reductase in neonatal pig testes that metabolizes androgens and xenobiotics.
We have isolated an NADPH-dependent reductase from neonatal pig testes that metabolizes androgens and a variety of xenobiotics. This enzyme is distinct from 3alpha/beta,20beta-hydroxysteroid dehydrogenase or its homologue, carbonyl reductase, as judged by its immunological and molecular properties and its much narrower specificity for steroids. This reductase and 3alpha/beta,20beta-hydroxysteroid dehydrogenase may be part of a mechanism for regulating androgen levels the neonatal pig testes. Interestingly, we could not find multiple isoforms of 3alpha/beta,20beta-hydroxysteroid dehydrogenase/carbonyl reductase in pig testes unlike human and rat testes and other organs in which multiple isoforms are expressed.
Androgens↗
Comparison of examination times between CT scanners: are the newer scanners faster?
OBJECTIVE: The purpose of this study was to determine if a newer technology helical CT scanner can reduce CT examination times. MATERIALS AND METHODS: Data from 1049 CT examinations were recorded prospectively during a 5-week period. "Room time" was defined as the time each patient spent in the CT room (time patient exited minus time patient entered) and "scanner time" was defined as the time a scanner was dedicated to a specific patient (longer of either time that image processing was complete minus time patient entered room, or total time that patient spent in the scanner room). Data to calculate the room and scanner times were recorded along with the scanner type, examination protocol, and five other covariates. Both times were calculated for the 10 most common examination protocols (n = 769 patients) and compared between the older and newer model CT scanner using analysis of covariance models. The most common protocols were abdomen and pelvis (n = 211); head (n = 146); chest (n = 99); simple sinus (n = 99); and chest, abdomen, and pelvis (n = 68). RESULTS: The mean room and scanner times, adjusted for covariates, were both significantly shorter for the newer scanner (p = .0001). The results for room time were statistically significant for six of the 10 examination protocols (84% of examinations). Likewise, the results for scanner time were statistically significant for four examination protocols (68% of examinations). Examination times were longer for inpatients (p = .0001) and when problems occurred during the examination (p = .0001). Sex and age did not significantly affect examination times (p > .08). CONCLUSION: The newer helical CT scanner we studied significantly reduced the time for many types of examinations.
Cost Control↗
Cost accounting in radiology: building a cost model using hospital-based, commercially available software.
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Accounting↗
Flavonoids inhibit estrogen binding to rat alpha-fetoprotein.
There is considerable interest in the role(s) of plant-derived compounds such as bioflavonoids in regulating steroid hormone action in mammals, and in particular, the possible effects of the bioflavonoids on the growth of steroid-dependent breast and prostate tumors and on possible abnormal development of steroid-sensitive tissues. Studies of the hormone-like actions of bioflavonoids often use fetal or neonatal rats, which contain high levels of serum alpha-fetoprotein (AFP), a protein that binds estradiol with a Kd approximately 5 x 10(-9) M. Interaction of bioflavonoids with AFP could affect the availability of estrogens to estrogen-responsive cells, as well as the actions of bioflavonoids. These considerations motivated us to study the effect of several flavonoids (quercetin, rutin, naringenin, chrysin, apigenin, kaempferol, myricetin, morin, fisetin) and isoflavonoids (daidzein, genistein) on estrogen binding to rat AFP. We found that naringenin, a flavanone, and quercetin and kaempferol, flavonols, inhibit estrogen binding to AFP with apparent Kds of about 5 x 10(-7) M. To our surprise, the two isoflavonoids, daidzein and genistein, have Kds of about 5 x 10(-6) M for AFP. This 10-fold [correction of 1Q-fold] difference in affinity for AFP between flavonoids and isoflavonoids suggests that AFP has a specificity for the flavonoid structure. Moreover, the affinities of bioflavonoids for rat AFP are sufficiently high to suggest that flavonoids and isoflavonoids could modulate estradiol and estrone binding to rat AFP in vivo, when present at dietary levels. Additionally, the potency of the plant estrogens may be altered by binding to AFP. The flavonoids that we tested have different hydroxyl and glucoside substituents on the A, B, and C rings, which allows us to define some of the spatial requirements for binding to AFP. We find that 5,7-hydroxyl groups in ring A and a 4'-hydroxyl group in ring B are important for binding to AFP. This information, combined with molecular modeling studies, may elucidate the molecular basis for recognition of flavonoids and estrogens by AFP. Also, these findings indicate that the flavonoid levels in the diet need to be considered in studies of the effects of various xenobiotics and endocrine manipulations on experimental animals, particularly during development when serum estrogen binding protein concentrations are often elevated. Finally, bioflavonoids should be useful tools for understanding the variety of estrogen actions initiated by different structural classes of estrogens.
Animals↗
Flavonoids as hormones. A perspective from an analysis of molecular fossils.
Although for centuries plants have been known to have hormone-like actions in humans, the mechanism(s) by which plant-derived compounds act in humans is still being elucidated, a goal that has assumed more importance due to interest in the protective actions of fruits and vegetables in diseases such as cancer. Here I use the "molecular fossil record" of amino acid sequences of proteins involved in regulating the actions steroids, retinoids, thyroid hormone and prostaglandins to propose some mechanisms by which flavonoids in fruits and vegetables can have hormone-like actions in humans. I focus on: i) hormone receptors that bind to DNA and regulate gene transcription and ii) the enzymes that regulate the concentrations of these hormones. Comparative analyses of amino acid sequences show that nuclear receptors for steroids, retinoids, thyroid hormone and prostaglandins in humans and insects are descended from a common ancestor. Similar analyses of dehydrogenases that regulate the concentrations of steroids, retinoids and prostaglandins reveal strong sequence similarity to enzymes in plants, insects, fungi, and bacteria. The similarity is sufficient to suggest that some compounds that bind receptors or enzymes in invertebrates, plants or unicellular organisms may also bind to mammalian homologs that are involved in endocrine physiology. Among the phytochemicals that are candidates for such activity are flavonoids because they are involved in plant-insect and plant-bacteria interactions and have some structural and chemical similarities to steroids, retinoids, thyroid hormone, prostaglandins and fatty acids. These similarities and the kinship of human, plant, insect and bacterial proteins involved in signal transduction provide a conceptual framework for investigating flavonoids for hormone-like actions in humans. Understanding these modes of action may be useful in developing protocols for preventing hormone-dependent diseases such as breast and prostate cancer.
Animals↗