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Biomedical subjects

L J Smith

Publications and source records attributed to L J Smith.

At least 145 records · Page 8Linked to original sources
PubMed1991

Secondary structure and topology of human interleukin 4 in solution.

Human interleukin 4 (IL-4) has been studied by 2D and 3D NMR techniques using uniformly 15N-labeled recombinant protein. Assignment of resonances for all but 3 of the 130 residues of the recombinant protein has been achieved, enabling the secondary structure of the protein to be defined. This consists of four major alpha-helical regions and one short section of double-stranded antiparallel beta-sheet. Analysis of distance and angle restraints derived from NMR experiments has enabled the overall molecular topology to be determined. This is related to that found for other four-helix proteins but has several distinctive features including cross-linking of helices by means of three disulfide bonds and a short section of beta-sheet. The structural analysis gives support to the hypothesis that many helical cytokines have a common fold and provides a basis for understanding the biological function of IL-4.

Amino Acid Sequence↗
PubMed1991

Analysis of phi and chi 1 torsion angles for hen lysozyme in solution from 1H NMR spin-spin coupling constants.

Three-bond 3JHN alpha coupling constants have been determined for 106 residues and 3J alpha beta coupling constants have been measured for 57 residues of the 129-residue protein hen egg white lysozyme. These NMR data have been compared with torsion angles defined in the tetragonal and the triclinic crystal forms of the protein. For most residues the measured 3JHN alpha values were consistent with the phi torsion angles found in both crystal forms; the RMS difference between the coupling constants calculated by using the tetragonal crystal structure phi angles and the experimental 3JHN alpha values is 0.88 Hz. Thus there appears to be no significant averaging of the phi torsion angle either in the interior or at the surface of the protein. For 41 of the residues where 3J alpha beta coupling constants have been determined, the values are consistent with a single staggered conformation about the chi 1 torsion angle and there is complete agreement between the NMR data in solution and the torsion angles defined in the crystalline state. In contrast, for the other 16 residues where 3J alpha beta coupling constant values have been measured, the data indicate extensive motional averaging about the chi 1 torsion angle. These residues occur largely on the surface of the protein and examination of the crystal structures shows that many of these residues adopt a different conformation in the triclinic and tetragonal crystal forms and have high crystallographic temperature factors. It appears, however, that in solution conformational flexibility of the side chains of surface residues is significantly more pronounced than in individual crystal structures.

Amino Acids↗
PubMed1991

Taurine decreases fecal fatty acid and sterol excretion in cystic fibrosis. A randomized double-blind trial.

Patients with cystic fibrosis may still have a significant degree of steatorrhea despite adequate pancreatic enzyme supplementation. Taurine is a conditionally essential amino acid that possibly improves the micellar phase of fat digestion. Thirteen children with cystic fibrosis and a significant degree of steatorrhea (> 13 g/d) were enrolled in a randomized double-blind crossover study of taurine (30 mg/kg per day) in contrast to placebo for two successive 4-month periods. No difference was noted in height and weight velocity, lung function, vitamin A level, and essential fatty acid status. Twelve of the 13 patients showed a decrease in fecal fatty acid excretion (26.5 +/- 2.6 g/24 h vs 15.4 +/- 2.5 g/24 h), affecting mainly saturates and monounsaturates, and a decrease in total sterol excretion (1492.6 +/- 303 mg/24 h vs 1211.7 +/- 213.8 mg/24 h) while ingesting taurine. Taurine may be a useful adjunct in patients with cystic fibrosis and severe steatorrhea.

Adolescent↗
PubMed1991

Monoclonal antibodies raised against the idiotype of the murine B cell lymphoma, BCL1 act primarily with heavy chain determinants.

Anti-idiotypic antibodies can be used as probes to distinguish neoplastic cells from their normal counterparts. In addition they have been used in the passive therapy of B cell tumors. In this report we describe a panel of 7 rat monoclonal antibodies raised against idiotypic determinants carried by the IgM molecule of the BCL1 lymphoma. The majority (6/7) of these antibodies recognize private idiotypic determinants that are carried on the isolated mu heavy chain of the molecule, and do not require the lambda chain for reactivity. This is unusual for antibodies raised against the idiotype of the whole immunoglobulin molecule, which normally require both chains for reactivity. The antibodies do not, however, bind peptides corresponding to the complementarity determining regions of the mu heavy chain of BCL1. The antibodies perform well in complement mediated cytotoxicity, and, in at least one case, are effective in the passive immunotherapy of BCL1 lymphoma.

Animals↗
PubMed1991

Gene rearrangements in the diagnosis of lymphoma/leukemia. Guidelines for use based on a multiinstitutional study.

The demonstration of immunoglobulin or T-cell receptor gene rearrangements in human lymphoproliferative processes with the use of DNA hybridization has gained great popularity as a sensitive laboratory adjunct to diagnostic hematopathology. The fact that nearly all B- or T-cell malignant lymphomas and leukemias have one or more rearranged antigen receptor genes provides a biologic basis for a diagnostic test. To formally analyze the sensitivity, specificity, and reproducibility of gene rearrangements in the diagnosis of human lymphoproliferative disease, the authors conducted a large, multiinstitutional study. Through a blinded, controlled approach, gene rearrangement analysis of 275 cases was shown to carry a high correlation with conventional phenotyping and histologic diagnosis, with only minor false-positive and false-negative rates. Significantly, no rearrangements were detected in normal lymphoid tissues or carcinomas, sarcomas, or melanomas. In a randomized study of 50 cases, laboratory results showed a high rate of interlaboratory agreement, regardless of the level of previous experience. Furthermore, the reproducibility of interpretation of data (Southern blot autoradiograms) of 192 cases showed high concordance among 11 observers from multiple laboratories. Based on these findings, the authors propose a set of guidelines for interpretation of gene rearrangement analysis that, if carefully followed, renders this a highly reproducible, safe, and accurate addition to the diagnostic regimen for human lymphoproliferative processes.

B-Lymphocytes↗
PubMed1991

A new form of autosomal dominant arthrogryposis.

We report a man and his son with congenital limb contractures, limitation of ocular movements, and an electroretinal abnormality. They appear to have an autosomal dominant form of arthrogryposis, distinguishable from other previously classified forms of this disorder.

Adult↗
PubMed1991

Insulin and glucagon in prevention of hypoglycemia during exercise in humans.

To assess the roles of decrements in insulin and increments in glucagon in the prevention of hypoglycemia during moderate exercise (approximately 60% peak O2 consumption for 60 min), normal young men were studied during somatostatin infusions with insulin and glucagon infused to 1) hold insulin and glucagon levels constant, 2) decrease insulin, 3) increase glucagon, and 4) decrease insulin and increase glucagon during exercise. In contrast to a comparison study (saline infusion), when insulin and glucagon were held constant, glucose production did not increase and plasma glucose decreased from 5.5 +/- 0.2 to 3.4 +/- 0.2 mmol/l (P less than 0.001) initially during exercise. Notably, plasma glucose then plateaued and was 3.3 +/- 0.2 mmol/l at the end of exercise. This decrease was at most only delayed when either insulin was decreased or glucagon was increased independently. However, when insulin was decreased and glucagon was increased simultaneously, there was an initial increase in glucose production, and the glucose level was 4.5 +/- 0.2 mmol/l at 60 min, a value not different from that in the comparison study. Thus we conclude that both decrements in insulin and increments in glucagon play important roles in the prevention of hypoglycemia during exercise and do so by signaling increments in glucose production. However, since hypoglycemia did not develop during exercise when changes in insulin and glucagon were prevented, an additional counterregulatory factor, such as epinephrine, must be involved in the prevention of hypoglycemia during exercise, at least when the primary factors, insulin and glucagon, are inoperative.

3-Hydroxybutyric Acid↗
PubMed1991

Catecholamines in prevention of hypoglycemia during exercise in humans.

To assess the role of catecholamines in the prevention of hypoglycemia during moderate exercise (approximately 60% peak O2 consumption for 60 min), normal humans were studied with combined alpha- and beta-adrenergic blockade and with adrenergic blockade while changes in insulin and glucagon were prevented with the islet clamp technique (somatostatin infusion with insulin and glucagon infused at fixed rates). The results were compared with those from an islet clamp alone study. In contrast to a comparison study (saline infusion), adrenergic blockade resulted in a small initial decrease in plasma glucose during exercise, from 5.0 +/- 0.2 to 4.4 +/- 0.2 mmol/l (P less than 0.01), but the level then plateaued. There was a substantial exercise-associated decrement in plasma glucose when insulin and glucagon were held constant, i.e., from 5.5 +/- 0.2 to 3.4 +/- 0.2 mmol/l (P less than 0.0001), but the level again plateaued. However, when insulin and glucagon were held constant and catecholamine actions were blocked simultaneously, progressive hypoglycemia, to 2.6 +/- 0.6 mmol/l (P less than 0.001), developed during exercise. Hypoglycemia was the result of an absent increase in glucose production and an exaggerated initial increase in glucose utilization. Thus we conclude that sympathochromaffin activation plays a minor role when insulin and glucagon are operative, but a catecholamine, probably epinephrine, becomes critical to the prevention of hypoglycemia during exercise when changes in insulin and glucagon do not occur.

3-Hydroxybutyric Acid↗
PubMed1991

The role of platelet-activating factor in asthma.

There is a large body of in vitro, animal, and now human data that provide strong support for PAF as being an important mediator of asthma and airway hyperreactivity. Unfortunately, there is little direct, unequivocal evidence that this is so. Direct evidence will come from studies that test the effectiveness of potent, nontoxic, PAF receptor antagonists in patients with asthma. Another issue that needs to be addressed is the mechanism by which PAF produces bronchoconstriction and, in particular, airway hyperreactivity. Studies exploring the effect of PAF on inflammatory cell populations and functions in the lung, on other mediators (i.e., leukotrienes), and on the nonadrenergic, noncholinergic nervous system in human subjects are needed. Finally, identification of the basis for the variable response to PAF in normal subjects and in patients with asthma should provide further insight into PAF's mechanism of action and the pathogenesis of asthma and airway hyperreactivity.

Animals↗
PubMed1991

A care plan for self-administration of epoetin alfa.

A care plan was developed to assist nephrology nurses managing the care of patients self-administering epoetin alfa. This is a generic care plan intended to serve as a basis for communication and should be adapted for appropriateness to individual facilities.

Erythropoietin↗
PubMed1990

Effect of fasting on hyperoxic lung injury in mice. The role of glutathione.

Fasted mice exposed to 100% oxygen have more lung damage and die sooner than do fed mice. The mechanism responsible for this phenomenon has not been identified. We performed the following experiments to test the hypothesis that reduced glutathione content in lung tissue of fasted mice contributes to the increased susceptibility to hyperoxic lung damage. First, air-exposed mice were fasted for as long as 3 days. They had little change in lung levels of superoxide dismutase (SOD) or catalase, but they had a 41% decrease in glutathione by Day 3 (p less than 0.001). Second, fed mice and fasted mice were exposed to 100% oxygen for as long as 4 days. Both groups had nearly identical values of lung SOD and catalase, but the fasted mice had lower levels of glutathione (p less than 0.001). Third, fed mice received the glutathione synthesis inhibitor buthionine sulfoximine (BSO; 20 mM) in their drinking water for 2 wk and were then exposed to either air or 100% oxygen. Air-exposed mice receiving BSO for 14 days had no change in lung SOD content, a 43% increase in catalase (p less than 0.001), and a 41% decrease in glutathione (p less than 0.01). Oxygen-exposed, BSO-treated mice had no change in SOD and an increase in catalase, but lower glutathione levels, more deaths, and increased lung damage on Day 3 (BAL protein: 1.72 +/- 0.21 versus 0.94 +/- 0.08 mg/ml; p less than 0.01) than did diluent-treated mice. Fourth, fasted mice were given liposomes containing glutathione intratracheally.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Inhibition of leukotriene D4-induced bronchoconstriction in normal subjects by the oral LTD4 receptor antagonist ICI 204,219.

The sulfidopeptide leukotrienes may play a role in the pathogenesis of asthma. Previous clinical trials with leukotriene antagonists have shown only minimal protection from subsequent challenge with inhaled LTD4. Using a double-blind, placebo-controlled crossover design, we tested the hypothesis that the LTD4 receptor antagonist, ICI 204,219, could inhibit LTD4-induced bronchoconstriction in normal subjects. On separate days, 3 to 7 days apart, a single oral 40-mg dose of ICI 204,219 or placebo was ingested. At 2 h (Group I), 12 h (Group II), or 24 h (Group III) after the dose, six subjects in each group underwent bronchoprovocation testing with aerosolized LTD4. The airway response was assessed by measuring specific airway conductance (SGaw) and the FEV1. ICI 204,219 had no effect on baseline pulmonary function. When given 2 h before the LTD4 challenge, ICI 204,219 increased by 117-fold the concentration of LTD4 required to reduce SGaw 35%: 34 +/- 10 versus 3,965 +/- 894 micrograms/ml (placebo versus ICI 204,219; p less than 0.05). When given 12 h before the LTD4 challenge, ICI 204,219 increased by ninefold the concentration of LTD4 required to reduce SGaw 35%: 33 +/- 11 versus 304 +/- 125 micrograms/ml (p less than 0.05). When given 24 h before the LTD4 challenge, a smaller effect was found: 12 +/- 3 versus 60 +/- 24 micrograms/ml (p less than 0.05). Plasma levels of ICI 204,219 correlated with efficacy across groups (r = 0.83, p less than 0.001), but imperfectly within groups. No adverse effects (symptoms or abnormal laboratory test results) were noted after ingesting the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1990

Effects of inhaled leukotriene D4 and platelet-activating factor on airway reactivity in normal subjects.

Inflammatory mediators such as platelet-activating factor (PAF) and the sulfidopeptide leukotrienes (LT) may contribute to airway hyperreactivity and asthma. PAF has been reported to produce bronchoconstriction and a sustained increase in airway reactivity when inhaled by normal subjects. Leukotrienes produce bronchoconstriction in both normal and asthmatic subjects, but whether they increase airway reactivity is unclear. Before initiating studies to determine how these bioactive mediators influence airway function, we sought to confirm that PAF increases airway reactivity and identify whether one of the sulfidopeptide leukotrienes, LTD4, has a similar effect. Eight normal male subjects inhaled saline and increasing concentrations of either histamine (0.1 to 50 mg/ml), PAF (1 to 1,000 micrograms/ml), or LTD4 (1 to 500 micrograms/ml) on separate days, at least 1 wk apart, until specific airway conductance (SGaw) decreased 50% or the maximal concentration was reached. After inhaling the test substance, methacholine (MCh) challenges were performed at 6 h, at 1, 3, and 7 days, and weekly thereafter until airway reactivity (measured as the MCh concentration that decreased SGaw 35% [PC35SGaw]) normalized. The four postsaline MCh challenges (6 h to 7 days) were used to determine the 95% confidence interval for PC35SGaw (in each subject) and identify significant changes in airway reactivity after inhaling each test substance. Airway reactivity did not change after inhaling histamine. After inhaling PAF, six of eight subjects developed increased airway reactivity, which was maximal at 1 day and persisted for 14 days in three. After inhaling LTD4, six of eight subjects also developed increased airway reactivity, which was maximal at 7 days and persisted for 14 days in two.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1990

Failure of nocturnal hypoglycemia to cause daytime hyperglycemia in patients with IDDM.

To test the hypothesis that nocturnal hypoglycemia causes postprandial hyperglycemia the next day (the Somogyi phenomenon) in patients with insulin-dependent diabetes mellitus (IDDM), we studied 10 moderately well controlled patients, who were on their usual therapeutic regimens, from 2000 to 2000 on three occasions. On a control day, samples were obtained without intervention. On another day, nocturnal hypoglycemia was prevented (by intravenous infusion of glucose, if necessary, from 2200 to 0400 to keep plasma glucose levels at greater than 5.6 mM). On another day, nocturnal hypoglycemia was induced (by stepped intravenous insulin infusions between 2200 and 0200 to reduce plasma glucose levels to less than 2.8 mM). After nocturnal hypoglycemia (1.9 +/- 0.2 mM), fasting (0800), morning (0800-1100), afternoon (1200-1500), evening (1600-2000), and entire-day (0800-2000) plasma glucose concentrations were no higher than those after prevention of nocturnal hypoglycemia or sampling only. On the control day, fasting and daytime plasma glucose levels were directly related to the preceding 2200 (r = 0.723, P less than 0.02, and r = 0.762, P = 0.01, respectively) and nocturnal nadir (r = 0.714, P less than 0.02, and r = 0.728, P less than 0.02) plasma glucose concentrations. Daytime plasma glucose levels were unrelated to peak nocturnal plasma glucagon, epinephrine, norepinephrine, growth hormone, or cortisol concentrations. We conclude that nocturnal hypoglycemia does not appear to cause clinically important daytime hyperglycemia in patients representative of most patients with IDDM.

3-Hydroxybutyric Acid↗