Biomedical subjects
M L Thomas
Publications and source records attributed to M L Thomas.
1,25-dihydroxyvitamin D3 and 24,25-dihydroxyvitamin D3 production by isolated renal slices is modulated by diabetes and insulin in the rat.
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Binding of C3b proceeds by a transesterification reaction at the thiolester site.
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Maintenance of normocalcemia by continuous infusion of the synthetic bovine parathyroid hormone (1-34) in parathyroidectomized rats.
This work was conducted to estimate the replacement dose of the synthetic bovine parathyroid hormone [PTH(1-34)] that is required for maintenance of serum calcium (Ca) in parathyroidectomized (PTX) rats. Male rats were PTX and used in this study only if serum Ca was reduced to at least 7 mg/dl. We found that a solution of 2% cysteine, 150 mM NaCl, and 1 mM HCL was superior to 20 mM acetic acid for maintenance of biological activity of PTH (1-34) in situ during the period of hormone infusion studied. The PTH dose-calcemic response relationship was investigated using PTH in doses of 0.6, 1, and 3 U/h. The infusion of 1 U PTH per hour raised Ca to the normal level, whereas rats infused with 0.6 U/h were hypocalcemic and 3 U/h resulted in marked hypercalcemia. To extend this observation we carried out an infusion of 1 U PTH per hour for 14 days. We found that this infusion rate of bovine PTH (1-34) provided a relatively stable level of serum calcium with modest fluctuation from normocalcemic to somewhat hypercalcemic levels for the entire 14-day period of PTH infusion. Serum calcitonin was also elevated during the infusion period and then returned to the initial level when PTH treatment was stopped. After the minipumps containing PTH were removed, the serum Ca dropped rapidly to 5 mg/dl, which was significantly lower than the control (vehicle-infused) or initial values of serum Ca (7 mg/dl). Infusion of PTH at 3 U/h for 4 days did not produce this rebound hypocalcemia after the pumps were removed. Serum Ca in those experiments returned to the initial level after hormone treatment was discontinued.
Biologic activity of 8,18-norleucine 34-tyrosine parathyroid hormone (1-34) amide in chicken kidney and bone.
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Third component of human complement: localization of the internal thiolester bond.
Human complement protein C3 was inactivated by using methylamine and thereby generating a SH group from the internal thiol ester. The protein was coupled via this SH group to activated thiol-Sepharose and digested with elastase. Fragment C3d remained attached to the thiol-Sepharose and was subsequently eluted with L-cysteine. Concomitantly, the original SH group was regenerated, and it was then labeled with iodo[2-(3)H]acetic acid. Partial sequence analysis of the radiolabeled C3d fragment showed that both components of the thiol ester are located close to the amino terminus (residues 23 and 26). Specific chemical cleavage of the alpha-chain was achieved after S-cyanylation of the thiol. The two fragments obtained corresponded to the amino-terminal section (M(r) approximately 46,000) and the carboxy-terminal section (M(r) approximately 70,000). These results together indicate that fragment C3d occupies approximately positions 345-610 of the alpha-chain. The partial sequence of C3d was extended by completion of the sequence of a previously described tryptic peptide. Comparison of residues 1-49 of C3d with a peptide from alpha(2)-macroglobulin [Swenson, R. P. & Howard, J. B. (1980) J. Biol. Chem. 255, 8087-8091] shows a previously recognized identity of seven residues around the thiol ester site and a second region of identity around a known glycosylation site of alpha(2)-macroglobulin. The relationships among these proteins and protein C4 are discussed. An overall outline of the structure of C3 is presented, showing the locations of various fragments and cleavage sites. The thiol ester group places constraints on the local folding of the peptide chain; a possible conformation is suggested and discussed in relation to the mechanism of activation.
A double-blind comparative study of the tolerance of sodium and meglumine ioxaglate (Hexabrix) with meglumine iothalamate (Conray) in ascending phlebography of the leg.
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Pharmacokinetics of cefotaxime in newborn infants.
The pharmacokinetics of cefotaxime were determined in newborn infants who were 1 to 7 days of age. Mean peak serum concentrations of 116 and 132 micrograms/ml were observed at completion of a 10-min intravenous infusion of 50 mg of cefotaxime per kg in low and average birth weight infants, respectively. The mean elimination half-lives were 4.6 and 3.4 h and rates of clearance from serum were 23 and 44 ml/min per 1.73 m2, respectively. A dosage schedule for cefotaxime in newborn infants is presented.
Renal parathyroid hormone receptors in the chick: downregulation in secondary hyperparathyroid animal models.
We characterized the binding of 125I-[Nle8, Nle18, Tyr34]parathyroid hormone-(1-34) amide [125I-nlPTH-(1-34)] to renal plasma membranes prepared from chicks to determine the effects of secondary hyperparathyroid states on renal PTH receptors. This radioligand exhibited specific binding to membranes with high affinity (Kd, 2-3 X 10(-9) M). Agonists or competitive antagonists of PTH were effective in competing for binding sites labeled with 125I-nlPTH-(1-34), whereas an inactive fragment of PTH, salmon calcitonin, and bovine growth hormone did not compete with the radioligand for renal PTH receptors. Newly hatched chicks raised on control diet with adequate vitamin D and calcium or diets deficient in either vitamin D or calcium were used to study the regulation of renal PTH receptors in experimental models of secondary hyperparathyroidism. We found that both experimental diets resulted in marked hypocalcemia and progressive loss of renal cyclic AMP responsiveness to PTH in vitro. Associated with this refractoriness to the hormone was a marked reduction in PTH receptors in membranes from both vitamin D-deficient and calcium-deficient chick kidney. No change in the affinity of the PTH receptors was found. Vitamin D3, in a single dose of 250 micrograms, partially restored serum calcium of vitamin D-deficient birds toward normal by 72 h and also partly restored renal cyclic AMP responsiveness to PTH and the PTH receptor number toward control values. We conclude that renal refractoriness to PTH observed in experimentally hyperparathyroid animals models is due to a marked loss of plasma membrane receptor sites for PTH without an apparent change in the affinity of the receptors for the hormone.
Serum calcium and parathyroid hormone during the reproductive cycle in normal and vitamin D-deficient rats.
This study was designed to investigate the ability of the vitamin D-deficient (-D) rat to maintain calcium (Ca) homeostasis during pregnancy. Serum Ca and immunoreactive parathyroid hormone (iPTH) were measured before and during pregnancy and after lactation in normal (+D) and -D rats. Serum Ca increased from 9.4 +/- 0.3 to 10.2 +/- 0.2 mg/dl during the first 3 days of pregnancy in +D animals and then declined throughout the remainder of gestation to 9.7 mg/dl at 17 days of gestation. In contrast, serum Ca rose progressively during the first 17 days of pregnancy in -D rats from 5.5 +/- 0.2 to 6.7 +/- 0.4 mg/dl. As expected, the -D rats had markedly elevated serum iPTH, but there were no changes in circulating iPTH during pregnancy in either animal model, even though serum Ca increased significantly during pregnancy in -D animals and Ca decreased in the +D rats. After lactation, serum Ca of -D rats increased 2 mg/dl before returning to prepregnancy levels. These results suggest that there are physiological mechanisms which appear to be independent of vitamin D and are responsible for elevating serum Ca during pregnancy and lactation.
Comparison of tri-iodoisophthaldiamide with meglumine lothalamate in phlebography of the leg.
One hundred patients were examined by ascending phlebography of both legs in a prospective, double-blind, within-patient study. Each leg was randomly allocated to the examination using either lopamidol 61% as the contrast medium. Immediate side effects were recorded in all patients, and delayed effects in 46 patients. Statistical analysis using the chi-square test showed that lopamidol produced significantly less immediate and delayed pain in the foot and the leg than Conray. Iopamidol produced significantly less nausea and vomiting during the injection than Conray. There was no significant difference in the quality of the phlebograms with either of contrast medium.
NH2-terminal structure and cleavage of guinea pig pro-C3, the precursor of the third complement component.
The NH2-terminal structures of the intracellular precursor of the third component of guinea pig complement (pro-C3), synthesized in macrophage cultures, and beta chain of C3 from guinea pig plasma were determined. Six of the first 16 residues of pro-C3 were identified by a microradiosequencing method. All six are nonpolar and are identical with the residues in beta chain of native plasma C3. This establishes beta chain as the NH2-terminal subunit in pro-C3. A comparison of primary structures of guinea pig and human C3 beta chains revealed identity of at least 8 residues within the NH2-terminal decapeptide. Incubation of plasmin with radiolabeled pro-C3 in macrophage lysate resulted in loss of pro-C3 and the generation of a two-chain molecule electrophoretically indistinguishable from native C3. These data indicate similarities between pro-C3 and the precursor of the fourth complement component, pro-C4, with respect to subunit organization, presence of phylogenetically conserved NH2-terminal regions, and the probable mechanism for generation of their respective native proteins.
The relationship between the number of capillaries in the skin of the venous ulcer-bearing area of the lower leg and the fall in foot vein pressure during exercise.
The changes in foot vein pressure during exercise have been measured in 30 normal legs and 109 legs with varicose veins or postphlebitic changes and correlated with the number of capillaries visible in a histological section of skin from the ulcer-bearing area. There was a significant correlation between the inability of the calf pump to reduce foot vein pressure during exercise and the number of capillaries in the skin. It is suggested that the increased number of capillaries secondary to venous hypertension during exercise may be the prime cause of the nutritional abnormalities that eventually cause a venous ulcer.
Clinical evaluation of a new broad-spectrum oxa-beta-lactam antibiotic, moxalactam, in neonates and infants.
Moxalactam, a new parenteral 1-oxa-beta-lactam antibiotics, is highly effective in vitro against gram-negative enteric bacilli, including isolated from neonates with meningitis. Studies with moxalactam in experimental coliform meningitis demonstrated favorable penetration, bioavailability, and antibacterial activity in CSF. The potential value of moxalactam for therapy of gram-negative enteric meningitis of infancy prompted this study. Pharmacokinetics of moxalactam were determined in 74 infants and serum concentration-time curves were characterized bay the two-compartment open-system kinetic model. The mean peak serum concentration at the end of 50 mg/kg, ten-minute infusions was approximately 125 micrograms/ml. Elimination half-life values correlated inversely with gestational and chronologic age. The mean half-lives were 6.2 hours in neonates less than one week of age, 4.4 hours in those one to 4 weeks, and 1.6 hours in infants one to 24 months of age. A mean CSF penetration of 30% was demonstrated after repeated doses of moxalactam in 11 infants with coliform meningitis. Thirteen neonates and two infants with gram-negative enteric bacillary infections were successfully treated with this agent. the drug was well tolerated and adverse effects were not observed. Moxalactam will be evaluated in a prospective, controlled study of gram-negative enteric meningitis by the Neonatal Meningitis Cooperative Study Group.
Sequence determination of the thiolester site of the fourth component of human complement.
The fourth component of complement (C4) is inactivated by treatment with methylamine. This property is shared wit the third component (C3) and with alpha 2-macroglobulin. In each instance, the reaction with methylamine is stoichiometric, covalent, and accompanied by the appearance of a thiol group. These data are consistent with the presence of an internal thiolester bond. Incubation of C4 with [14C] methylamine in the presence of activated thiol-Sepharose resulted in immobilization of the protein via its active-site thiol. Analysis of bound C4 indicated incorporation of 1.12 mol of [14C]methylamine per mol of protein. Digestion of the immobilized protein with porcine elastase resulted in the release of C4 beta- and gamma-chains and lower molecular weight fragments. The 14C label, however, was retained on the Sepharose beads. Subsequent release of bound material with L-cysteine indicated that the radiolabel was associated with two polypeptides of Mr 25,000 [C4d(ela25)]. The released material was dialyzed and the active-site thiol was radioalkylated with iodo[2-3H]acetic acid. C4d(ela25) was further purified by chromatography on Sephadex G-100 and, after reduction and alkylation, on Sepharose CL-6B in 0.2% NaDodSO4. The C4d(ela25) pool, containing 0.83 mol of [14C]methylamine per mol of iodo[2-3H]acetic acid, was subjected to automated sequence analysis. S-carboxy-[3H]methylcysteine was released at step 21 and gamma-glutamyl-[14C]methylamide was released at step 24. The recovery of radiolabel at positions 21 and 24 confirmed the originally calculated 14C/3H incorporation ratio and further indicated that the radiolabels were present at single sites in the C4 molecule. Comparison of the derived primary structure for the thiolester site in C4 with those for the corresponding regions in C3 and alpha 2-macroglobulin has shown sequence identity. Further comparisons among these three proteins have indicated additional homologies on both the NH2- and COOH-terminal sides of the thiolester site.
Pharmacokinetics and bacteriologic efficacy of moxalactam, cefotaxime, cefoperazone, and rocephin in experimental bacterial meningitis.
The pharmacokinetics and bacteriologic efficacy of four beta-lactam antibiotics were studied in the serum and cerebrospinal fluid (CSF) of rabbits using two test strains, Escherichia coli type K1 and group B Streptococcus type III, and 24 gram-positive isolates. Although moxalactam, cefotaxime, cefoperazone, and rocephin are active in vitro against gram-negative bacilli, the gram-positive bacteria Listeria monocytogenes and Streptococcus faecalis were resistant to all four drugs; group B streptococci were resistant to moxalactam. In rabbit CSF, moxalactam had the greatest concentration and penetration, but rocephin had the longest half-life and duration of bactericidal activity. These two drugs were most effective in the CSF of E. coli K1-infected rabbits. Except for moxalatam, the four drugs were comparable to ampicillin in reducing counts of group B Streptococcus type III in CSF. Drug accumulation in CSF and appreciable bacterial killing were observed in E. coli K1-infected animals give moxalactam either periodically or by constant infusion.
The diagnosis and management of abdominal aortic aneurysms: a comparison of computed tomography, ultrasound and aortography.
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Computed tomography in the evaluation of a femoral aneurysm.
Computed tomography was used to delineate the extent of a distal femoral aneurysm associated with arteriomegaly.