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Biomedical subjects

V P Butler

Publications and source records attributed to V P Butler.

At least 19 recordsLinked to original sources
PubMed1991

Human gamma delta T cells amplify IgE production by Epstein-Barr virus-activated B cells.

In summary, these data document that gamma delta T cells regulate B cell differentiation, antibody synthesis, and IgE secretion in EBV-activated B cells. The classical "helper" subset of CD4+ alpha beta T cells, although potent inducers of other Ig isotypes, are not as efficient in augmenting IgE synthesis. However, interactions between alpha beta and gamma delta cells enhance the IgE response further. The precise mechanism by which gamma delta T cells function to augment IgE secretion is under study. It will be important, for example, to determine whether gamma delta T cells, or products of these cells, directly regulate class switching or mediate the clonal expansion of IgE-expressing B cells. In this regard, we ruled out the possibility that IL-4 release alone could replace gamma delta cells in increasing IgE secretion. Finally, we think it is of potential interest that gamma delta cells migrate to skin epithelia as well as gastrointestinal and pulmonary mucosa, sites of invasion by parasitic organisms and contact with allergens. If gamma delta T cells were specifically activated, either directly or indirectly, by these foreign pathogens, then the data presented here might elucidate the cellular basis for the events leading to IgE secretion, a critical step in the immune response to both parasites and allergens.

B-Lymphocytes↗
PubMed1990

Treatment of 150 cases of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments. Final report of a multicenter study.

One hundred fifty patients with potentially life-threatening digitalis toxicity were treated with digoxin-specific antibody fragments (Fab) purified from immunoglobulin G produced in sheep. The dose of Fab fragments was equal to the amount of digoxin or digitoxin in the patient's body as estimated from medical histories or determinations of serum digoxin or digitoxin concentrations. The youngest patient received Fab fragments within several hours of birth, and the oldest patient was 94 years old. Seventy-five patients (50%) were receiving long-term digitalis therapy, 15 (10%) had taken a large overdose of digitalis accidentally, and 59 (39%) had ingested an overdose of digitalis with suicidal intent. The clinical response to Fab was unspecified in two cases, leaving 148 patients who could be evaluated. One hundred nineteen patients (80%) had resolution of all signs and symptoms of digitalis toxicity, 14 (10%) improved, and 15 (10%) showed no response. After termination of the Fab infusion, the median time to initial response was 19 minutes, and 75% of the patients had some evidence of a response by 60 minutes. There were only 14 patients with adverse events considered to possibly or probably have been caused by Fab; the most common events were rapid development of hypokalemia and exacerbation of congestive heart failure. No allergic reactions were identified in response to Fab treatment. Of patients who experienced cardiac arrest as a manifestation of digitalis toxicity, 54% survived hospitalization.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1988

Cellular electrophysiologic effects of vertebrate digitalis-like substances.

Substances structurally and functionally similar to digitalis glycosides are produced by several vertebrate species. There also is evidence for a digitalis-like substance of human origin. Standard microelectrode techniques were used to study the direct effects on the cellular electrophysiology of canine Purkinje fibers of 1) bufalin, an unconjugated cardiotonic steroid molecule that is produced by the toad Bufo marinus, and 2) an extract of human bile that showed digitalis-like immunoreactivity on radioimmunoassay. The goal of this study was to determine whether these substances have arrhythmogenic effects comparable with those seen with toxic doses of digitalis glycosides. Bufalin, 2 x 10(-8) M, significantly (p less than 0.05) reduced maximal diastolic potential, action potential amplitude and duration and maximal rate of rise of phase 0 (Vmax) within 40 min of onset of exposure. All six fibers developed delayed afterdepolarizations and two developed triggered rhythms. Ouabain was less potent, in that a 2 x 10(-7) M concentration was required to comparably reduce maximal diastolic potential, action potential amplitude and duration and Vmax within 30 min. These Purkinje fibers also developed delayed afterdepolarizations and triggered rhythms. A sample of an extract of human bile that showed digitalis-like immunoreactivity with an antibufalin serum also reduced maximal diastolic potential, action potential amplitude and duration and Vmax, and produced delayed afterdepolarizations and triggered activity. In contrast, immunologically unreactive bile extracts had no appreciable effect on the action potential. In summary, the cardiac toxicity of digitalis substances produced by lower vertebrates is comparable with that induced by the glycosides. Moreover, it appears that humans may produce digitalis-like substances that may be cardiotoxic.

Action Potentials↗
PubMed1987

Digoxin inactivation by the gut flora in infancy and childhood.

Inactivation of digoxin by reduction of the lactone ring has recently been shown to occur in one third of adults and to be mediated by anaerobic intestinal bacteria. Children from birth through adolescence were studied to determine the pattern of development of this gut flora-mediated process. None of 36 digitalized infants 8 months of age or less excreted reduced digoxin metabolites in the urine. The adult pattern of digoxin reduction product excretion by one third of patients was observed after 16 months of age; however, high levels of digoxin reduction products such as are found in 10% of adults were not encountered in children less than 9 years of age. Even though reduced metabolites were not formed in vivo early in life, stool cultures of 20 of 73 infants younger than 8 months of age contained digoxin reduction product-forming bacteria at high concentrations, in some instances as early as the second week of life. Maturation of the gut flora with respect to digoxin metabolism appears to be a protracted process. The relative digoxin resistance of infants and children is not due to bacterial inactivation.

Adolescent↗
PubMed1985

Treatment of 63 severely digitalis-toxic patients with digoxin-specific antibody fragments.

Sixty-three patients with life-threatening digitalis intoxication were treated with purified fragments of digoxin-specific antibodies (Fab) obtained from sheep. Twenty-eight patients developed toxicity as the result of digitalis ingestion in a suicide attempt, 5 ingested a large amount of digoxin accidentally and 30 developed toxicity in the course of treatment for underlying heart disease. The dosage of digoxin-specific Fab was calculated to be equimolar to the amount of cardiac glycoside in the patient's body. Digitalis toxicity was completely reversed in most cases, with onset of effect usually within 30 minutes of administration of Fab fragments. Unbound and, therefore, active digoxin serum concentrations decreased to undetectable levels within minutes after administration of the fragments. In all patients who had elevated serum potassium concentrations caused by massive digitalis toxicity, treatment with the Fab fragments reversed the hyperkalemia. There were no obvious adverse reactions to treatment. Potentially life-threatening digitalis intoxication can be rapidly and safely reversed by treatment with purified digoxin-specific Fab fragments.

Adolescent↗
PubMed1985

Studies on human low serum IgD phenotype and Gm markers.

The human "low serum IgD phenotype" was studied by simultaneous Gm typing and IgD immunoassay of several populations. An association between Gm (f+b+) haplotype and low human IgD was confirmed and extended to the "low serum IgD phenotype"--as defined from population distribution and genetic studies by Dunnette et al. 1978. Further, it was shown that Black American sera determined by Gm haplotype, had a similar percentage of "low serum IgD phenotype" samples (16%) although they lacked the "associated" Gm(f+b+) haplotype of White American samples. Sardinian sera showed a low incidence of the "low serum IgD phenotype" which was not correlated with Gm haplotype distribution. Familial aggregation of the "low serum IgD phenotype" was observed. No association was found between "low serum IgD phenotype" and serum IgE values. Age related abiotrophy of IgD could not be attributed to selective survival of "low serum IgD phenotype" persons.

Adult↗
PubMed1982

Immunochemical studies of antisera to human fibrinopeptide-B.

The immunochemical specificity of rabbit antisera to human fibrinopeptide-B (FPB) has been studied by comparing the relative abilities of FPB and of various proteins and peptides containing the NH2-terminal segment of the B beta-chain of human fibrinogen to inhibit the binding of a radioiodinated FPB derivative by each of seven anti-FPB sera. Anti-FBP sera varied in the extent to which they cross-reacted with fibrinogen, the NH2-terminal disulfide knot of fibrinogen (N-DSK), B beta 1(Pyr)-118(Met), B beta 1(Pyr)-42(Arg), and desarginyl-FPB. Anti-FPB sera have been identified that discriminate effectively between FPB and larger FBP-containing peptides; such antisera can be used to measure FPB in the absence of the larger peptides or to demonstrate the presence of larger peptides such as B beta 1(Pyr)-42(Arg) in extracts of clinical plasma samples by means of an increase in FPB immunoreactivity following thrombin treatment. One anti-FPB serum has been identified that is capable of detecting desarginyl-FPB, and this antiserum has been used in the development of a radioimmunoassay for desarginyl-FPB. Thus, by precisely defining the specificity of anti-FPB sera, it has been possible to identify antisera that are useful, not only in the measurement of FPB, but also in the detection of other important related molecules, such as B beta 1(Pyr)-42(Arg) and desarginyl-FPB. The immunochemical detection of these FPB-related peptides should provide useful information concerning the action of proteolytic enzymes, such as plasmin on the NH2-terminal segment of the B beta-chain of fibrinogen, and of carboxypeptidase-B on free FPB, in human plasma.

Cross Reactions↗
PubMed1977

Effects of sheep digoxin-specific antibodies and their Fab fragments on digoxin pharmacokinetics in dogs.

Intact sheep antidigoxin antibodies and their Fab fragments have both been found to exert profound effects on digoxin pharmacokinetics in [3H] digoxin-treated dogs. Both classes of molecule remove digoxin from the extravascular space and sequester it in the circulation in protein-bound form, a form in which the digoxin is presumably inactive. These two classes of molecule differ, however, in that the intact antibody molecules interfere with digoxin excretion, thereby promoting the retention of the glycoside; this retained digoxin is eventually released in free, active form when the administered antibody is metabolically degraded. In contrast, urinary excretion of digoxin continues in Fab-treated dogs, with significant quantities of digoxin being excreted promptly in the urine in complex with Fab fragments. These differences in urinary excretion, together with the probable decreased immunogenicity of sheep antidigoxin Fab fragments, suggest that such fragments possess potential advantages over intact antibody molecules for use in the therapy of life-threatening digoxin intoxication in man.

Animals↗
PubMed1976

Reversal of advanced digoxin intoxication with Fab fragments of digoxin-specific antibodies.

Purified Fab fragments of ovine digoxin-specific antibodies reversed severe digoxin intoxication in a patient who had taken 22.5 mg of the drug with suicidal intent. Atrioventricular block with extreme bradycardia was temporarily managed by pacing, but progressive, intractable hyperkalemia (serum potassium of 8.7 meq per liter) with increasing pacing threshold and progressive intraventricular conduction delay was controlled only after infusion of 1100 mg of Fab. Sinus rhythm returned 10 minutes after completion of Fab infusion. Within five hours, the serum potassium concentration fell to 4.0 meq per liter. Free digoxin concentrations in serum fell sharply to undetectable levels, whereas total serum digoxin concentration concomitantly increased 12-fold. Renal excretion of digoxin bound to Fab was documented. Reversal of toxicity was not accompanied by hemodynamic instability, and antibodies to sheep Fab fragments were not detected in the patient's serum after treatment. Thus, purified digoxin-specific Fab fragments are capable of rapid reversal of advanced digoxin toxicity.

Adult↗
PubMed1976

Reactivity of fibrinogen and fibrinopeptide A containing fibrinogen fragments with antisera to fibrinopeptide A.

Two antisera used in the radioimmunoassay for human fibrinopeptide A (FPA) which appear to have different immunochemical specificities have been tested for cross-reactivity with fibrinogen and with three fragments of fibrinogen which contain the FPA sequence. These fragments were the three-chain, NH2-terminal disulfide knot (N-DSK) produced by CNBr cleavage of fibrinogen, the reduced, carboxymethyl Aalpha chain portion of the N-DSK, and fragment E produced by plasmin digestion of fibrinogen. One antiserum (R-2) showed high specificity for free FPA and less than 2% cross-reactivity with fibrinogen or the FPA-containing fragments. The other antiserum (R-33) possessed a much higher degree of cross-reactivity with the FPA-containing fragments. Synthetic and native fibrinopeptides were found to be indistinguishable in the assay system with either antiserum. As a result of these studies, an hypothesis has been developed concerning the nature of the antigenic determinants on FPA which favor measurement of free FPA and limit cross-reactivity with larger, FPA-containing peptides.

Amino Acid Sequence↗
PubMed1976

Immunochemical studies of human fibrinopeptide A using synthetic peptide homologues.

Previous studies have indicated that rabbit antisera R2 and R33 to human fibrinopeptide A differ markedly in terms of cross-reactivity with fibrinogen and fibrinopeptide A-containing fragments of the fibrinogen molecule. Antiserum specificity was characterized by comparison of inhibition of binding to radiolabeled tyrosyl fibrinopeptide A produced by synthetic fragments and enzymatic digests of the fibrinopeptide A molecule vs. the complete fibrinopeptide sequence (Aalpha 1-16). Synthetic COOH-terminal homologues through the dodecapeptide (Aalpha 5-16) exhibited less than 16% immunoreactivity with R33 antiserum, which cross-reacts extensively with fibrinogen and fibrinopeptide A-containing fibrinogen fragments. In contrast, the synthetic COOH-terminal decapeptide (Aalpha 7-16) gave 100% immunoreactivity with R2 antiserum, which cross-reacts minimally with fibrinogen and fibrinopeptide A-containing fibrinogen fragments. Synthetic homologues smaller than Aalpha 7-16, such as Aalpha9-16 and Aalpha 7-11, reacted only minimally with R2 antiserum. Carboxypeptidase B digests of fibrinopeptide A retained less than 25% of their initial immunoreactivity with R2 antiserum. It is concluded that the antigenic determinants of R2 immunoreactivity reside entirely within the COOH-terminal ten-residue sequence of fibrinopeptide A, and that Phe-8, Asp-7, and Arg-16 contribute significantly to R2 immunoreactivity. The R2 antigenic determinants appear to be significantly less accessible to reaction with antibody than the R33 determinants when the fibrinopeptide is attached to its parent alpha chain (Canfield et al., 1976). A possible mechanism for the sequestration is discussed.

Amino Acid Sequence↗