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Biomedical subjects

C A Brown

Publications and source records attributed to C A Brown.

At least 163 records · Page 9Linked to original sources
PubMed1991

ACS general surgeons participate in payment reform activities.

As reported in the Bulletin at various times over the past several years, the American College of Surgeons has frequently been called upon by federal agencies and commissions to provide clinical information and advice on issues that are associated with implementation of the Medicare physician payment system reforms mandated by the Omnibus Budget Reconciliation Act of 1989 (OBRA '89). In doing so, the College has often relied on the expertise of Fellows who are deeply committed both to the practice of general surgery and to the College. The purpose of this article is to provide a review of the College's participation in activities related to implementation of the Medicare reforms, as viewed by some of the general surgeons who shared in those efforts.

Centers for Medicare and Medicaid Services, U.S.↗
PubMed1990

Translation initiation in the HEXB gene encoding the beta-subunit of human beta-hexosaminidase.

The human lysosomal enzyme beta-hexosaminidase (EC 3.2.1.52) is a glycoprotein composed of dimers of alpha- and/or beta-subunits. The subunits of the enzymes are synthesized in the rough endoplasmic reticulum and transported through the Golgi apparatus to the lysosome. As such, each subunit contains an amino-terminal signal peptide that directs the nascent polypeptide into the lumen of the endoplasmic reticulum. The signal peptide cleavage site of the beta-polypeptide is known, but its NH2 terminus has not been determined due to the presence of three candidate initiation codons upstream of the cleavage site. In this study, we identified the mRNA cap site, confirming the presence of all three AUGs in the majority of HEXB mRNA. To identify the site of translation initiation, we mutated the three ATGs by deletion and site-directed mutagenesis and showed that all three AUG codons can be used for translation initiation after expression in COS cells. Furthermore, in each case, a fully processed, i.e. mature lysosomal, and enzymatically active beta-hexosaminidase was produced indicating that a functional signal peptide was synthesized. However, expression of a frameshift mutation in the normal construct, created by insertion of a single nucleotide between the first and second ATG, resulted in no significant enzyme activity or beta-subunit protein. We conclude, therefore, that the first in-frame ATG is used exclusively in vivo, in keeping with the scanning model of eukaryotic translation initiation. Interestingly, substitution of all three ATGs with CTG resulted in a significant amount of mature beta-hexosaminidase, showing that under these conditions, initiation could occur from non-AUG codons. Translation initiation from the first AUG gives the prepro-beta-polypeptide a signal peptide of 42 amino acids that has an unusually long hydrophobic core more typical of membrane spanning domains. Such a large hydrophobic core has not been found in other cleavable signal peptides.

Amino Acid Sequence↗
PubMed1990

Suspected familial renal disease in chow chows.

Renal disease was diagnosed in 6 young Chow Chows. Clinical abnormalities included vomiting, polyuria, polydipsia, and weight loss. Common abnormal laboratory findings were azotemia, hyperphosphatemia, hypocalcemia, nonregenerative anemia, and low urine specific gravity. All 6 dogs had similar microscopic renal lesions. characterized by interstitial fibrosis, a population of small glomeruli, and lack of inflammatory cells. A familial basis for the renal disease is suggested because of its development in 4 closely related dogs.

Animals↗
PubMed1990

Mitogenic effects of transforming growth factor type e on epithelial and fibroblastic cells--comparison with other growth factors.

Transforming growth factor type-e (TGFe) is a novel TGF which was first described as a growth factor possibly involved in autocrine stimulation of anchorage-independent growth of carcinoma cells. Its later identification in normal tissues, plasma, and platelets suggested a role for TGFe in normal cell growth. This study shows that TGFe stimulates both anchorage-dependent and -independent growth of epithelial and fibroblastic cells of nonneoplastic origin. The mitogenic activity of TGFe in monolayer is slightly less than that of basic fibroblast growth factor, equipotent to that of epidermal growth factor, and greater than that of IGF-1. TGFe acts as a progression factor for both AKR-2B and Balb-3T3 cells. TGFe is also a potent mitogen for normal human epidermal keratinocytes and may therefore play a role in epidermal growth and regeneration.

Animals↗
PubMed1990

Partitioning of amino acids in lactating cows: oxidation to carbon dioxide.

The rate and extent of oxidation of 20 different amino acids has been evaluated as part of a study on partitioning of amino acids in normal lactating cows. Only four amino acids--glutamate, aspartate, alanine and glutamine--were extensively oxidized, and when expressed as a percentage of the injected dose oxidized during 3 h after intravenous injection, the value for these four amino acids was not significantly different from those obtained with the volatile fatty acids. The oxidation of all other amino acids was significantly slower, effectively prolonging their availability for protein synthesis. The pattern of oxidation among the amino acids supports the hypothesis that catabolized protein can provide a protracted source of anaplerotic precursors that augment the metabolic role of the tricarboxylic acid cycle and would have survival advantage in both acute and chronic exigencies. Glutamate and aspartate provide the earliest and largest influx to the tricarboxylic acid cycle, with alanine and, especially, glutamine appearing to serve as reservoirs of amino-nitrogen. Several dispensable amino acids are metabolized as slowly as the indispensable ones, indicating that metabolic conservation is not restricted to the latter group.

Amino Acids↗
PubMed1989

Introduction of the alpha subunit mutation associated with the B1 variant of Tay-Sachs disease into the beta subunit produces a beta-hexosaminidase B without catalytic activity.

Lysosomal beta-hexosaminidase (beta-N-acetylhexosaminidase, EC 3.2.1.52) occurs in two major isozyme forms, hexosaminidase A (alpha beta) and hexosaminidase B (beta beta). Although dimer formation is required for enzymatic activity, both subunits contain active sites which share many common substrates. However, the alpha subunit alone confers on hexosaminidase A the specificity for negatively charged substrates, e.g. GM2 ganglioside. Recently, a point mutation, producing a single amino acid substitution in the alpha subunit (Arg178-His), has been found to be associated with the B1 variant phenotype of Tay-Sachs disease (Ohno, K., and Suzuki, K. (1988) J. Neurochem. 50, 316-318). This variant is characterized by normal levels of hexosaminidase A as measured by a common artificial substrate, but an absence of activity toward alpha subunit-specific substrates. However, because of the presence of an active beta subunit in the mutant hexosaminidase A, it has not been possible to determine whether the affected alpha subunit has undergone a change in substrate specificity or become totally inactive. In order to define the full effect of the B1 mutation we have taken advantage of the common evolutionary origin of the genes coding for the alpha and beta subunits. Since the B1 mutation occurs in a region of extended identity between the two subunits, we have duplicated the Arg178-His mutation in a cDNA coding for the human beta subunit (Arg211-His). By expression of the mutant construct in monkey COS cells we have been able to examine the effect of this mutation on beta subunits which are capable of forming stable, active homodimers, an experiment that could not readily be accomplished with heterodimeric hexosaminidase A. Our data show that beta homodimers containing the Arg211-His substitution are formed and are transported into the lysosome in a manner identical to that of normal pro-hexosaminidase B. However, the mutant homodimers are processed at a slower rate and are less stable in the lysozyme. Their most striking feature was a total lack of normal hexosaminidase B activity. We conclude that while the effect of the Arg178-His substitution is not strictly limited to the active site, the severe B1 phenotype results from a totally inactive alpha-subunit in hexosaminidase A.

Amino Acid Sequence↗
PubMed1989

Membrane topology of mammalian cytochromes P-450 from liver endoplasmic reticulum. Determination by trypsinolysis of phenobarbital-treated microsomes.

We have studied the membrane topology of liver microsomal cytochromes P-450 derived from phenobarbital-treated rabbits via trypsinolysis of intact microsomes, recovery of solubilized peptide fragments by ultracentrifugation and liquid chromatography, primary structure determination by Edman microsequence analysis, and database searching to match isolated fragments with parent sequences. Relative to the primary structure of isozyme 2, the major phenobarbital-inducible form, fragments were isolated beginning at residues Glu86, Ile101, Arg126, Cys152, Leu198, Ser211, Asn237, Glu327, Asn385, Thr407, Phe408, Phe413, and Thr444. Such results show that this family of structurally related cytochromes is bound to the endoplasmic reticulum membrane by only one or two transmembrane segments, located at the NH2-terminal end of the polypeptide chain. The remainder of the protein, from residue approximately 50 to the COOH terminus must exist as a catalytic, heme-containing domain exposed on the cytosolic side of the membrane. Furthermore, our results indicate that the catalytic domain must be peripherally associated with the membrane surface. This would imply that substrates might have access to the active site of the cytochrome P-450 either by diffusion from the cytosol or from within the lipid bilayer.

Amino Acid Sequence↗
PubMed1989

A Canadian multicenter study with Zaditen (ketotifen) in the treatment of bronchial asthma in children aged 5 to 17 years.

One hundred thirty-eight children with chronic asthma, requiring daily treatment with bronchodilators, took part in a 7-month, double-blind, multicenter clinical study. Patients were randomized into two groups, and after a 1-month baseline, were administered Zaditen (ketotifen), 1.0 mg twice daily, or an identical placebo for a period of 6 months. After 10 weeks of receiving the study medication, bronchodilator use was reduced or stopped. In the Zaditen-treated group, 60% of the children taking theophylline were able to stop its use completely, compared to 34% of the patients taking placebo (p less than 0.05). Of the patients who were unable to stop taking theophylline, the Zaditen-and placebo-treated groups recorded average dosage reductions of 62% and 26%, respectively. These differences were statistically significant (p less than 0.05). Thus, a high percentage of patients in the placebo-treated group maintained asthma symptom control with theophylline, whereas most of the Zaditen-treated patients could stop using this medication. Although pulmonary function readings improved in both groups, those patients taking Zaditen demonstrated earlier improvement and greater changes from baseline. Significant differences (p less than 0.05) in favor of Zaditen were found for reduction of concomitant medications, patient's global evaluation, physician's clinical evaluations, incidence of emergency room visits for asthma, and upper respiratory tract infections. No unexpected side effects were observed. It is concluded that Zaditen is an effective medication for long-term control of asthma in children.

Adolescent↗
PubMed1989

Clinical significance of mildly elevated thyrotropin levels with normal thyroxine levels.

The meaning of minor elevations in the thyrotropin level (less than 10 mIU/ml) in association with a normal thyroxine level has been questioned. Although such findings are presumed to be indicative of subclinical hypothyroidism, consideration of other causes can pose problems with diagnosis. We investigated the clinical significance of equivocal elevation of thyrotropin values with a normal thyroxine level and free thyroxine index in 31 patients evaluated with a thyrotropin releasing hormone (TRH) stimulation test and antithyroid antibody determinations. Patients were categorized as euthyroid or hypothyroid on the basis of TRH responsiveness. Of the 31 patients, 23 (74%) were hypothyroid, resulting in a positive predictive value as high as 81%. Eight of 21 hypothyroid patients (38%) had antimicrosomal antibodies, and only one euthyroid patient had antimicrosomal antibodies. We find that equivocally elevated thyrotropin values indicate primary hypothyroidism about 80% of the time. The combination of a mildly elevated thyrotropin level and antimicrosomal antibodies is seen almost exclusively in patients with thyroid failure.

Adult↗