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Biomedical subjects

D J McCormick

Publications and source records attributed to D J McCormick.

108 records · Page 6Linked to original sources
PubMed1987

Rapid degradation of neurotensin by intact murine neuroblastoma cells (clone N1E-115).

Murine neuroblastoma clone N1E-115, which possesses receptors for neurotensin mediating the formation of intracellular cyclic GMP and the stimulation of inositol phospholipid hydrolysis, exhibited only partial desensitization to neurotensin. This result led to the observation that neurotensin was very rapidly degraded by intact N1E-115 cells. In experiments measuring the time course of [3H]neurotensin degradation, a minimum of six major tritiated products were found, with the breakdown peptides formed and the degree of proteolysis of [3H]neurotensin being dependent upon the length of incubation and the concentration of cells. Clone N1E-115 degraded [3H]neurotensin in an apparently sequential fashion; the primary initial cleavage of intact neurotensin was at the peptide bond between residues Arg8 and Arg9. Initial degradation peptides from the active carboxyl-terminal portion of neurotensin were more rapidly degraded, after formation, than were the peptides from the inactive amino-terminal half of neurotensin. The final two degradation products found were tyrosine, from the carboxyl-terminal portion of neurotensin, and an as yet unidentified peptide from the amino-terminal half of neurotensin. [3H]Neurotensin(8-13) was more rapidly hydrolyzed under identical conditions than was [3H]neurotensin itself. A combination of the protease inhibitors 1,10-phenanthroline and Z-Pro-Prolinal was able to inhibit almost completely the degradation of neurotensin by clone N1E-115.

Animals↗
PubMed1987

Intermittent pacemaker syndrome: revision of VVI pacemaker to a new cardiac pacing mode for tachy-brady syndrome.

A patient with tachy-brady syndrome manifested by paroxysmal atrial fibrillation and symptomatic sinus bradycardia and treated by VVI pacing developed pacemaker syndrome during episodes of ventricular pacing. His cardiac pacemaker was revised to a dual chamber system utilizing the new AV sequential DDI pacing mode which eliminated pacemaker-related tachycardias and totally abolished the pacemaker syndrome symptoms. There have been no further episodes of atrial fibrillation, possibly due to elimination of temporal dispersion of refractory periods during bradycardia. The propensity for atrial fibrillation has also been minimized by excluding competitive atrial stimulation during DVI pacing. The DDI mode provides the clinician increased utility and flexibility in the use of AV sequential pacing therapy.

Arrhythmia, Sinus↗
PubMed1987

Definition of myasthenogenic sites of the human acetylcholine receptor using synthetic peptides.

Experimental autoimmune myasthenia gravis (EAMG) and antibodies that modulate AChRs from cultured human muscle are induced by a disulfide-looped peptide comprising the human acetylcholine receptor (AChR) alpha-subunit residues 125-147 (H alpha 125-147). To delineate the essential antigenic requirements for induction of EAMG by this peptide, a series of peptides was synthesized: (a) a nonlooped analog (Cys 128 replaced by Ser) stimulated modulating autoantibodies, induced EAMG, and bound antibodies induced by native AChR; (b) H alpha 131-147, a heptadecylpeptide shorter by 6 N-terminal residues, induced modulating antibodies, EAMG, and T cells that responded to H alpha 125-147, but not to H alpha 137-147; (c) H alpha 137-147, an undecapeptide shorter than H alpha 125-147 by 12 N-terminal residues, did not stimulate T cells or induce antibody production, but it bound antibodies generated by the longer peptides. Thus, when coupled to an epitope that could stimulate helper T cells, the region 137-147 was able to stimulate B cells. This study has defined a myasthenogenic region of the human AChR's alpha-subunit, 17 amino acids long, that contains several distinct epitopes, including at least one N-terminal site inducing T-cell responses (region 131-136) and two possibly overlapping sites that induce antibodies (regions 131-136 and 137-147). Further definition of antigenic sites inducing helper and suppressor T-cell responses and stimulating production of autoantibodies to AChR is essential to the goal of antigen-specific immunotherapy for myasthenia gravis.

Action Potentials↗
PubMed1985

Synthesis of an antigenic site of native acetylcholine receptor peptide 159-169 of Torpedo acetylcholine receptor alpha-chain.

A region of the alpha-subunit of the nicotinic acetylcholine receptor (AChR) of the Torpedo electric organ, containing residues 161-166, has been proposed to be a major antigenic site in the native AChR protein. We report the synthesis of a peptide corresponding to residues 159-169, which contains the proposed antigenic region. In quantitative radiometric titrations, radiolabelled anti-(native AChR) antibodies from three different species, rabbit, rat and dog, exhibited considerable binding (approx. 15% relative to native AChR) to Sepharose-immobilized peptide 159-169, but did not bind significantly to Sepharose-immobilized unrelated proteins or peptides. Specificity was further confirmed by the finding that no rabbit anti-AChR antibodies bound to the peptide after absorption with native AChR. These data indicate that the region 159-169 contains an antigenic site that is readily accessible in solubilized native Torpedo AChR.

Animals↗
PubMed1985

Region of peptide 125-147 of acetylcholine receptor alpha subunit is exposed at neuromuscular junction and induces experimental autoimmune myasthenia gravis, T-cell immunity, and modulating autoantibodies.

A major antigenic region of native nicotinic acetylcholine receptors (AcChoR) has been identified by using a synthetic disulfide-looped peptide corresponding to alpha-subunit residues 125-147 of Torpedo electric organ AcChoR: Lys-Ser-Tyr-Cys-Glu-Ile-Ile-Val-Thr-His-Phe- Pro-Phe-Asp-Gln-Gln-Asn-Cys-Thr-Met-Lys-Leu-Gly. The peptide bound 26-56% of polyclonal antibodies induced in rat, rabbit, and dog by immunization with native AcChoR. Rats inoculated with 50 micrograms of unconjugated peptide developed helper T-cell responses, delayed hypersensitivity, and antibodies to native AcChoR. Anti-peptide antibodies were more reactive with native than denatured AcChoR and bound to the alpha subunit. Some reacted exclusively with mammalian muscle AcChoR, some induced modulation of AcChoR on cultured myotubes, but none inhibited binding of alpha-bungarotoxin to solubilized or membrane-associated AcChoR. Repeated immunization induced experimental autoimmune myasthenia gravis: clinical signs in one rat and electrophysiologic and/or biochemical signs in 10 of 11 rats. Thus, at least part of the corresponding region of the mammalian AcChoR alpha subunit is extracellular at the neuromuscular junction and a potential target for pathogenic autoantibodies in patients with acquired myasthenia gravis.

Amino Acid Sequence↗
PubMed1984

Localization and synthesis of the acetylcholine-binding site in the alpha-chain of the Torpedo californica acetylcholine receptor.

The sequence of the alpha-chain of the acetylcholine receptor of T. californica has been determined by recent cloning studies. The integrity of the disulphide bond between Cys-128 and cys-142 has been shown to be important for the maintenance of the binding activity of the receptor, thus implicating the regions around the disulphide bridge in binding with acetylcholine. In the present work, a synthetic peptide containing this loop region (residues 125-147) was synthesized. Solid-phase radiometric binding assays demonstrated a high binding of 125I-labelled alpha-bungarotoxin to the synthetic peptide. It was further shown that the free peptide bound well to [3H]acetylcholine. Additional experiments demonstrated that pretreatment of peptide 125-147 with 2-mercaptoethanol destroyed its binding activity, clearly showing that the integrity of the disulphide structure was essential for binding. Unlabelled acetylcholine also inhibited the binding of labelled acetylcholine to the synthetic peptide. The region 125-147, therefore, contains essential elements of the acetylcholine binding site of the Torpedo receptor.

Acetylcholine↗
PubMed1984

Percutaneous balloon valvuloplasty of the pulmonary valve: role of right to left shunting through a patent foramen ovale.

Percutaneous balloon valvuloplasty was performed on a patient with pulmonary stenosis. Right to left shunting through a patent foramen ovale during balloon inflation was documented by contrast two-dimensional echocardiography. Right and left ventricular pressures recorded during balloon inflation showed a decrease in left ventricular end-diastolic pressure and equilibration with right ventricular end-diastolic pressure. Systemic hypotension was minimal during balloon inflation, possibly due to persistent filling of the left ventricle via the patent foramen ovale. Persistent right ventricular systolic hypertension immediately after valvuloplasty may have been due to infundibular narrowing and resolved on restudy 2 weeks later.

Adult↗
PubMed1982

The antigens of pigeon breeder's disease. VII. Isoelectric focusing studies on unfractionated pigeon dropping extract.

Isoelectric focusing (IEF) studies on pigeon dropping extracts (PDE) revealed that it is a complex mixture of components that are acidic in nature. Chromatographically purified antigens PDEB, PDE1, and PDE3 showed multiple bands in IEF, indicating a microheterogeneity of these components, with peak concentrations focusing at pH 6.1, 4.6, and 3.8, respectively. The isoelectric points are compatible with the chromatographic behavior of these antigens on DEAE-cellulose. Crossed immunoelectrofocusing (CRIF) resolved PDE into seven precipitin lines with rabbit antiserum in a pH gradient from 3.5 to 9.5, and into nine precipitable components in a pH gradient from 2.5 to 7.0. The complexity of this antigen source appears to reside in the heterogeneity of immunologically related antigens. A comparison of pigeon breeder's sera by CRIF of PDE revealed a qualitative difference in precipitation patterns obtained with symptomatic and asymptomatic individuals. Sera from all (eight out of eight) of the symptomatic breeders tested precipitated an unidentified component of PDE, whereas none (zero out of four) of the sera from asymptomatic breeders detected this antigen. These results suggest that CRIF of PDE is useful as a diagnostic tool and that some specific component of PDE may be involved in the pathogenesis of the disease.

Alveolitis, Extrinsic Allergic↗
PubMed1979

Practolol metabolism in various small animal species.

1. The metabolism of the beta-adrenergic blocking agent practolol has been studied in a variety of small animal species, using both ring- and acetyl-14C-labelled material. After oral dosing at 100 mg/kg, elimination of 14C in urine and expired air was monitored, and urinary metabolite patterns were examined by t.l.c. 2. Marmoset was unusual in extensively deacetylating practolol (c. 57% dose). Urinary elimination was low, with only 25% being recovered in 4 days; over 30% of urinary 14C was present as desacetyl practolol, whereas less than 50% was unchanged practolol. 3. Hamster was also atypical, in its extensive hydroxylation of practolol. Urine contained 60% dose; 11% of urinary radioactivity was present as 3-hydroxypractolol, much of the polar material present (48%) appeared to be a conjugate of this, and only 35% was present as practolol. 4. For the other species studied (rat, mouse, guinea-pig and rabbit, metabolism was more limited. Deacetylation was typically about 5%, but was somewhat higher in the mouse (8--14%). Urine was the major route of elimination and practolol represented 50--90% of urinary radioactivity. 5. Despite extensive toxicity studies, both in species which metabolize practolol similarly to man and in species such as the hamster and marmoset which metabolize practolol extensively, no animal model has been found for the human adverse reactions.

Animals↗
PubMed1979

Nonlethal mushroom poisoning.

The harvesting and consumption of wild mushrooms has become a popular pastime in many areas of the United States. Reports of mushroom poisonings and fatalities have been increasing since 1964. Between May 1973 and April 1978, 16 cases of mushroom poisoning were treated at our institution, including 13 within a 12-month period ending April 1978. All patients exhibited either gastrointestinal or neurologic symptoms, which responded to supportive therapy. There were no fatalities. In most cases, the clinical course can be predicted and appropriate therapy instituted if the mushroom is identified or if the interval between the ingestion and the onset of symptoms can be ascertained and certain characteristic symptoms are observed.

Adolescent↗
PubMed1976

The absorption of [G-3H]-acetylglycyrrhetate after oral administration to rats.

A tritium-labelled form of aluminium acetylglycyrrhetate has been synthesised by catalytic exchange with tritiated water. An oral dose of aluminium [3H]-acetylglycyrrhetate to rats was mainly excreted in the faeces (a mean of 73%). A mean of 4% was excreted in the urine and after five days 17% of the radioactivity was retained in the carcass. The amounts of non-volatile (drug-related radioactivity excreted in faeces and urine during five days were 65% and 3%, respectively, while 6% was retained in the carcass. The total amount of tritiated water produced was 24% of the dose. Experiments in rats with cannulated bile ducts indicated that much of the faecal radioactivity represented unabsorbed drug. 15% of an oral dose was eliminated in bile during 2 days. A minimum value for the extent of absorption of an oral dose was estimated as 21%. Plasma levels of radioactivity were very low and peak levels of drug-related radioactivity were reached at 30 min and represented about 0.2% of the dose in total plasma.

Animals↗
PubMedDate not supplied

Receptor-specific activity of heteromeric thyrotropin (TSH) analogs: development of synthetic TSH antagonists.

In an attempt to create potent and specific inhibitors of the interaction of thyrotropin (thyroid-stimulating hormone [TSH]) with its receptor, we designed a series of 18 synthetic peptides containing sequences of both alpha and beta subunits that were shown previously to interact with the TSH receptor. These "heteromeric" peptide analogs included amino acid residues from alpha 26-46, beta 31-52, beta 88-95 and beta 101-112 that were arranged variously and were separated from each other by artificial amino acid spacers. Each peptide was tested for its ability to interact with the TSH receptor in a radio-receptor assay (TSH-RRA) using porcine thyroid membranes and a bio-assay for TSH using FRTL-5 cells. Twelve of the 18 peptides showed binding activity in the TSH-RRA. None of the analogs demonstrated thyroid stimulatory activity, but five inhibited TSH bioactivity and were, thus, pure antagonists, the most potent possessing EC50 values in the 3-5 microM range. Specificity of the antagonists was tested by measuring their ability to inhibit hCG binding to ovarian membranes, hCG-stimulated progesterone production in MA-10 rat Leydig tumor cells and FSH binding to testicular membranes. Only those peptides that included the alpha-subunit sequence CFSR or CCFSR exhibited binding activity for the heterologous receptors, and that activity was 10-fold lower than in the TSH assays. None of the heteromeric peptides showed activity in the hCG bioassays, further demonstrating their specificity as TSH antagonists. These studies illustrate the utility of a synthetic peptide approach in the development of analogs of peptide hormones. Future alterations that significantly enhance the potency of these antagonists may result in substances with clinical efficacy in diseases such as Graves' disease and differentiated thyroid cancer that involve the thyrotropin receptor.

Amino Acid Sequence↗