Search PubMed⌕ Search

Biomedical subjects

S M Taylor

Publications and source records attributed to S M Taylor.

At least 55 records · Page 3Linked to original sources
PubMed1999

The role of the human Fc receptor Fc gamma RIIA in the immune clearance of platelets: a transgenic mouse model.

In humans, the Fc receptor for IgG, FcgammaRIIA, is expressed on macrophages and platelets and may play an important role in the pathophysiology of immune-mediated thrombocytopenia. Mice lack the genetic equivalent of human FcgammaRIIA. To better understand the role of FcgammaRIIA in vivo, FcgammaRIIA transgenic mice were generated and characterized. One transgenic mouse line expressed FcgammaRIIA on platelets and macrophages at levels equivalent to human cells, and cross-linking FcgammaRIIA on these platelets induced platelet aggregation. Immune-mediated thrombocytopenia in this transgenic line was studied using i.v. and i.p. administration of anti-mouse platelet Ab. In comparison with matched wild-type littermates that are negative for the FcgammaRIIA transgene, Ab-mediated thrombocytopenia was significantly more severe in the FcgammaRIIA transgenic mice. In contrast, FcR gamma-chain knockout mice that lack functional expression of the Fc receptors FcgammaRI and FcgammaRIII on splenic macrophages did not demonstrate Ab-mediated thrombocytopenia. We generated FcgammaRIIA transgenic x FcR gamma-chain knockout mice to examine the role of FcgammaRIIA in immune clearance in the absence of functional FcgammaRI and FcgammaRIII. In FcgammaRIIA transgenic x FcR gamma-chain knockout mice, severe immune thrombocytopenia mediated by FcgammaRIIA was observed. These results demonstrate that FcgammaRIIA does not require the FcR gamma-chain for expression or function in vivo. Furthermore, taken together, the data suggest that the human Fc receptor FcgammaRIIA plays a significant role in the immune clearance of platelets in vivo.

Animals↗
PubMed1999

Internal carotid artery patency following common carotid artery occlusion: management of the asymptomatic patient.

Rarely, internal carotid artery (ICA) patency is maintained above a common carotid artery occlusion (CCAO) through collateral flow of the ipsilateral external carotid artery or an aberrant ICA branch. Several small series report excellent results of ICA revascularization in relieving cerebral ischemic symptoms in these patients. The natural history of CCAO with patent ICA in the asymptomatic patient, however, is unknown. The Greenville Memorial Hospital Vascular Teaching Service registry and all carotid duplex scans done in the Greenville Hospital System vascular laboratory from January 1994 through December 1997 were reviewed. Data collection included chart review, phone interviews, and the review of angiograms and duplex scans. This study suggests that carotid duplex is more sensitive for detecting ICA flow after CCAO than routine contrast angiography. It also suggests that while rare in presentation, asymptomatic patients with CCAO and a patent ICA appear to have a benign neurologic course and can probably be observed without a high risk of stroke.

Carotid Artery, Common↗
PubMed1999

The impact of a community-wide vascular access program on the management of graft thromboses in a dialysis population of 495 patients.

BACKGROUND: The unpredictability of prosthetic vascular access thrombosis precludes the scheduling of elective graft thrombectomy. This results in inconsistent dialysis for patients, as well as logistical challenges for dialysis clinics and surgeons, and increased cost. In an effort to solve this problem a community-wide, prospective vascular access program (VAP) was established. This study evaluates the impact of the VAP by comparing the operative procedures and outcomes of vascular access surgery performed in the community before and after establishment of the program. METHODS: All 17 surgeons who perform vascular access, representing five independent practice groups in Greenville, South Carolina, formed a VAP in November 1996. Dialysis patients were pooled, and all graft thrombectomies were managed on a rotational basis by a surgeon assigned daily to a specifically designated access thrombectomy operating room. The hospital records of all patients undergoing vascular access procedures from November 1, 1995, through October 31, 1996 (pre-VAP), and November 1, 1996, through October 31, 1997 (post-VAP), were reviewed. RESULTS: Comparison of the pre-VAP and post-VAP groups showed no significant difference in the number of patients undergoing vascular access procedures (391 versus 378), number of vascular access procedures performed (1034 versus 1,048), or average number of vascular access procedures performed per patient (2.64 versus 2.79). There was no statistical difference in the number of thrombectomies and revisions (786 versus 765; P = 0.114) or thrombectomies alone (248 versus 283; P = 0.114) in the pre-VAP and post-VAP groups. There was a significant increase in the number of procedures performed on an outpatient basis in the post-VAP group (757; 73%) compared with the pre-VAP group (575; 56%); P <0.001. There was also a significant difference in the percentage of cases performed after 6:00 PM in the pre-VAP group (262; 25%) compared with the post-VAP group (48; 4.5%; P = 0.001). CONCLUSIONS: Dialysis graft thrombosis, occurring in 75% of our patients annually, represents a substantial logistical dilemma necessitating the incorporation of 1,000 additional operations into a busy elective surgery schedule. An organized VAP reduces inpatient hospitalization, minimizes expensive after hours surgery, and enhances patient and physician convenience while providing a mechanism to monitor clinical outcomes and assure timely dialysis.

Ambulatory Surgical Procedures↗
PubMed1999

Prophylactic inferior vena cava filters in trauma patients at high risk: follow-up examination and risk/benefit assessment.

PURPOSE: The efficacy of prophylactic inferior vena cava filters in selected trauma patients at high risk has come into question in relation to risk/benefit assessment. To evaluate the usefulness of prophylactic inferior vena cava filters, we reviewed our experience and overall complication rate. METHODS: From February 1991 to April 1998, the trauma registry identified 7333 admissions. One hundred eighty-seven prophylactic inferior vena cava filters were inserted. After the exclusion of 27 trauma-related deaths (none caused by thromboembolism), 160 patients were eligible for the study. The eligible patients were contacted and asked to complete a survey and return for a follow-up examination to include physical examination, Doppler scan study, vena cava duplex scanning, and fluoroscopic examination. The patients' hospital charts were reviewed in detail. The indications for prophylactic inferior vena cava filter insertion included prolonged immobilization with multiple injuries, closed head injury, pelvic fracture, spine fracture, multiple long bone fracture, and attending discretion. RESULTS: Of the 160 eligible patients, 127 were men, the mean age was 40.3 years, and the mean injury severity score was 26.1. The mean day of insertion was hospital day 6. Seventy-five patients (47%) returned for evaluation, with a mean follow-up period of 19.4 months after implantation (range, 7 to 60 months). On survey, patients had leg swelling (n = 27), lower extremity numbness (n = 14), shortness of breath (n = 9), chest pain (n = 7), and skin changes (n = 4). All the survey symptoms appeared to be attributable to patient injuries and not related to prophylactic inferior vena cava filter. Physical examination results revealed edema (n = 12) and skin changes (n = 2). Ten Doppler scan studies had results that were suggestive of venous insufficiency, nine of which had histories of deep vein thrombosis. With duplex scanning, 93% (70 of 75) of the vena cavas were visualized, and all were patent. Only 52% (39 of 75) of the prophylactic inferior vena cava filters were visualized with duplex scanning. All the prophylactic inferior vena cava filters were visualized with fluoroscopy, with no evidence of filter migration. Of the total 187 patients, 24 (12.8%) had deep vein thrombosis develop after prophylactic inferior vena cava filter insertion, including 10 of 75 (13.3%) in the follow-up group, and one patient had a nonfatal pulmonary embolism despite filter placement. Filter insertion complications occurred in 1.6% (three of 187) of patients and included one groin hematoma, one arteriovenous fistula, and one misplacement in the common iliac vein. CONCLUSION: This study's results show that prophylactic inferior vena cava filters can be placed safely with low morbidity and no attributable long-term disabilities. In this patient population with a high risk of pulmonary embolism, prophylactic inferior vena cava filters offered a 99.5% protection rate, with only one of 187 patients having a nonfatal pulmonary embolism.

Adult↗
PubMed1999

The effects of salbutamol, beclomethasone, and dexamethasone on fibronectin expression by cultured airway smooth muscle cells.

Possible mechanisms of adverse drug effects in asthma include worsening of cellular hyperplasia and stimulation of extracellular matrix deposition. In this study, salbutamol, dexamethasone and beclomethasone were investigated to ascertain their ability to induce mitogenesis and stimulate fibronectin expression in cultured canine airway smooth muscle cells. In cells maintained in serum-free media for 72 h, salbutamol (1 nM-10 microM) caused mitogenesis. The control cells had 2.57 +/- 0.34 x 10(5) cells per ml (mean +/- SEM, N = 13), while salbutamol (1 microM) caused a maximal increase in cell number to 3.57 +/- 0.23 x 10(5) cells/ml (P < 0.01). In cells stimulated to replicate by addition of either fetal bovine serum or canine serum, no additional mitogenic effect of salbutamol was seen. Salbutamol did not have a detectable quantitative effect on fibronectin matrix expression. The glucocorticoids, beclomethasone and dexamethasone, significantly altered fibronectin expression by cultured airway smooth muscle cells. Beclomethasone increased fibronectin expression, while dexamethasone decreased expression.

Albuterol↗
PubMed1999

Effects of a new C5a receptor antagonist on C5a- and endotoxin-induced neutropenia in the rat.

A new C5a receptor antagonist, the cyclic peptide Phe-[Orn-Pro-D-cyclohexylalanine-Trp-Arg], (F-[OPdChaWR]), was tested for its ability to antagonize the neutropenic effects of both C5a and endotoxin in rats. Human recombinant C5a (2 microg kg(-1) i.v.) caused rapid neutropenia, characterized by an 83% decrease in circulating polymorphonuclear leukocytes (PMNs) at 5 min. Administration of F-[OPdChaWR] (0.3-3 mg kg(-1) i.v.), did not affect the levels of circulating PMNs but, when given 10 min prior to C5a, it inhibited the C5a-induced neutropenia by up to 70%. Administration of E. Coli lipopolysaccharide (LPS, 1 mg kg(-1) i.v.) also caused neutropenia with an 88% decrease in circulating PMNs after 30 min. When rats were pretreated with F-[OPdChaWR] (0.3 - 10 mg kg(-1) i.v.) 10 min prior to LPS, there was a dose-dependent antagonism of the neutropenia caused by LPS, with up to 69% reversal of neutropenia observed 30 min after LPS administration. These findings suggest that C5a receptor antagonists may have therapeutic potential in the many diseases known to involve either endotoxin or C5a.

Animals↗
PubMed1999

Response-selective C5a agonists: differential effects on neutropenia and hypotension in the rat.

Some in vivo activities of two complement C5a agonist analogues have been evaluated by measuring changes in blood pressure and neutropenia in the rat and comparing the results with their receptor affinities in peritoneal macrophages and polymorphonuclear leucocytes (PMNs). In vitro C5a receptor (C5aR) binding experiments showed that YSFKPMPLaR and YSFKD(NMeNle)PlaR had similar affinities for the macrophage C5aR (IC50 0.2, 0.1 microM respectively). In PMNs, the affinity of YSFKPMPLaR (IC50 0.1 microM) was similar to that in macrophages, whereas the affinity of YSFKD(NMeNle)PLaR for the PMN C5aR was >100 microM. Given i.v., YSFKD(NMeNle)PLaR had similar activity to YSFKPMPLaR on blood pressure but did not cause neutropenia. These results demonstrate selectivity of a new C5a agonist in vitro, which is paralleled in vivo. The results suggest the possibility of developing selective agonists of C5a for in vivo use in humans.

Amino Acid Sequence↗
PubMed1999

Pharmacological characterization of antagonists of the C5a receptor.

1. Potent and highly selective small molecule antagonists have recently been developed by us for C5a receptors (C5aR) on human polymorphonuclear leukocytes (PMN). In this study we compared a new cyclic antagonist, F-[OPdChaWR], with an acyclic derivative, MeFKPdChaWr, for their capacities to bind to C5aR on human PMN and human umbilical artery membranes. We also compared their inhibition of myeloperoxidase (MPO) secretion from human PMNs and their inhibition of human umbilical artery contraction induced by human recombinant C5a. 2. In both PMNs and umbilical artery, the cyclic and acyclic C5a antagonists displayed insurmountable antagonism against C5a. There were differences in selectivities for the C5aR with F-[OPdChaWR] (pKb 8.64+/-0.21) being 30 times more potent than MeFKPdChaWr (pKb 7.16+/-0.11, P<0.05) in PMNs, but of similar potency (pKb 8.19+/-0.38 vs pKb 8.28+/-0.29, respectively) in umbilical artery. This trend was also reflected in their relative binding affinities, both antagonists having similar affinities (-logIC50 values) for C5aR in umbilical artery membranes (F-[OPdChaWR], 7.00+/-0.46; MeFKPdChaWr, 7.23+/-0.17), whereas in PMN membranes the C5aR affinity of the cycle F-[OPdChaWR] (7.05+/-0. 06) was four times higher than that of acyclic MeFKPdChaWr (6.43+/-0. 24, P<0.05). 3. In summary, the results reveal that these antagonists are insurmountable in nature against C5a for C5aR on at least two human cell types, and the differences in relative receptor binding affinities and antagonistic potencies against C5a are consistent with differences in receptors within these cell types. The nature of these differences is yet to be elucidated.

Antigens, CD↗
PubMed1999

The influence of Lys68 in decepeptide agonists of C5a on C5a receptor binding, activation and selectivity.

The potent, conformationally biased C5a agonist peptide YSFKPMPLaR (C5a65-74, Y65, F67, P69, P71, D-Ala73) was used as a template to gain insight into the nature and importance of lysine at position 68 in the peptide-receptor interaction. A panel of YSFKPMPLaR analogs with systematic substitutions for Lys68 was evaluated for C5a receptor (C5aR) binding affinity and activation in two well-characterized assay systems: human polymorphonuclear leukocytes (PMNs) and human fetal artery. In addition, we determined the activity of these new analogs in transfected rat basophilic leukemia (RBL) cells in which the Glu at position 199 of the C5aR (wtGlu199) was replaced by a Gln (C5aR-Gln199) or a Lys (C5aR-Lys199). Our results indicated that Lys68 in YSFKPMPLaR plays an important role in binding the C5aR expressed on PMNs and RBL cells. Furthermore, the data indicated that Lys68 interacted with Glu199 of the C5aR in PMNs and RBL cells. In human fetal artery, however, Lys68 substitutions had little or no effect on activity, which suggested that the receptor conformation may be different in this tissue. Thus, the interaction between Lys68 of the decapeptide agonist and Glu199 of the C5aR may be cell type-specific and may form the molecular basis for tissue-specific responses to C5a agonists.

Antigens, CD↗
PubMed1999

Arterially perfused eye model of uveitis.

OBJECTIVE: To develop an in vitro model of uveitis based on an ex situ perfused eye to evaluate the anti-inflammatory activity of new pharmacological products. PROCEDURE: Eyes were removed from more than 60 dogs and 9 horses immediately after euthanasia and perfused with nutrient medium through the lateral long ciliary artery. Perfused eyes produced aqueous humour, and perfusion pressure was adjusted to obtain an intraocular pressure in the physiological range. When the eyes were treated with histamine, a complement C5a analogue peptide and hydrogen peroxide, typical signs of uveitis were produced. These included miosis, vascular leakage, reduced intraocular pressure, reduced flow of perfusate and, in some eyes, conjunctival oedema. RESULTS: Canine eyes showed a decrease in intraocular pressure and a decrease in perfusate flow rate when challenged with 100 mumol/L hydrogen peroxide. Flunixin meglumine (5 mumol/L), ketoprofen (5 mumol/L), indomethacin (5 mumol/L) as well as a new drug pirfenidone (10 mumol/L) prevented changes in intraocular pressure induced by hydrogen peroxide, but did not significantly moderate the mediator-induced changes in perfusate flow. CONCLUSIONS: This model is suitable for evaluating potential anti-inflammatory activity of drugs without having to induce uveitis in an experimental animal. The technique is suitable for species that range in size from cats to horses.

Animals↗
PubMed1999

An analysis of limb-threatening lower extremity wound complications after 1090 consecutive coronary artery bypass procedures.

The objective of this study was to examine and characterize limb-threatening lower extremity wound or soft tissue complications after coronary artery bypass (CABG) and determine risk factors for their cause. While minor wound problems of the leg after CABG are not uncommon, serious limb-threatening complications, though less frequent, do occur and are often de-emphasized in the surgical literature. A review of 1090 consecutive CABG procedures performed from January 1, 1995 through December 31, 1995 was instituted, which screened for limb-threatening lower extremity wound or soft tissue complications defined as wounds that: required additional surgery for treatment; prolonged the length of stay; or which required lengthy home health nursing for treatment. Minor lymph leaks, leg swelling, infections or wound problems treated as an outpatient were excluded. Of 1090 patients, 54 (5.0%) experienced a limb-threatening lower extremity complication. Complications were categorized as vein harvest incision non-healing (n = 36, 66.7%), decubitus ulceration (n = 11, 20.4%), forefoot ischemia/embolization (n = 10, 18.5%), groin hematoma/abscess (n = 6, 11.1%), severe cellulitis (n = 3, 5.6%), or a combination (n = 12, 22.2%). Statistically significant risk factors by univariate and bivariate analysis for a complication included older age (68 years vs 62 years, p = 0.007), female sex (57% vs 28%, p < 0.001), diabetes (57% vs 33%, p = 0.005) and longer pump time (129 min vs 114 min, p = 0.009). These complications necessitated five major lower extremity amputations and nine revascularization procedures. Chronic lower extremity ischemia from peripheral vascular disease (PVD) was a major contributing factor for the development of wounds in at least 23 (42.6%) of these patients, though suspected in only 10 (43.5%) preoperatively. A non-healing vein harvest incision below the knee of a patient retrospectively found to have inadequate distal circulation for healing occurred in 17 (31.5%) of the total 54 cases. It was concluded that non-healing vein incisions, decubitus ulcers and forefoot ischemic lesions frequently occurring in older diabetic females with undetected pre-existing PVD, comprise the majority of limb-threatening leg complications after CABG. Nearly one-third of the complications may have been avoided had the vein harvest incision not been made at the ankle of a patient with unappreciated PVD.

Age Distribution↗
PubMed1999

Nonendarterectomy procedures of the carotid artery: a five-year review.

Although the efficacy of carotid endarterectomy has been well established, nonendarterectomy procedures of the carotid bifurcation have only sporadically been reported. Of 334 consecutive nontraumatic carotid procedures performed on 321 patients from July 1992 until May 1997, 306 (91.6%) were carotid endarterectomies, 14 (4.2%) were carotid-subclavian bypasses/transpositions, and 14 (4.2%) were nonendarterectomy procedures of the carotid artery. These latter 14 cases (nine females and five males; mean age, 63 years) were all symptomatic (neurological or painful mass) and included carotid kink/coil resection (n = 3; 0.9%), endarterectomy and vertebral transposition (n = 2; 0.6%), carotid aneurysm resection (n = 2; 0.6%), carotid body tumor resection (n = 2; 0.6%), carotid stump ligation/external endarterectomy (n = 1; 0.3%), infected/bleeding carotid patch removal with vein graft replacement (n = 1; 0.3%), saphenous vein graft replacement (n = 1; 0.3%), carotid dilatation for fibromuscular dysplasia (n = 1; 0.3%), and descending aorta to carotid bypass (n = 1; 0.3%). With 30 day follow-up complete for all 334 carotid operations, 10 perioperative strokes (2.9%) and five deaths (1.5%) occurred for a combined stroke/death rate of 3.3 per cent. Of the 14 nonendarterectomy carotid artery operations, there were no strokes or deaths; with mean follow-up of 13 months, 13 patients (92.9%) are asymptomatic, patent, and disease-free. Three severe transient cranial nerve (CN) neuropraxias (21.4%), one myocardial infarction (7.1%), and one late death (mesenteric ischemia at 2 months), however, occurred. Although no statistical differences in stroke, death, and stroke/death occurred between the endarterectomy versus the nonendarterectomy group, transient CN injury was more common in the nonendarterectomy group (21.4% versus 4.1%; P = 0.027). Although nonendarterectomy procedures of the carotid bifurcation are infrequently needed, they seem safe, effective, and indicated in selected patients, despite a higher incidence of transient CN injury.

Aneurysm↗
PubMed1999

The pitfalls of establishing a statewide vascular registry: the South Carolina experience.

Concerned about the inadequacy of a centralized database and the importance of low morbidity and mortality on carotid endarterectomy efficacy, the South Carolina Vascular Surgical Society prospectively instituted a computer registry for carotid procedures performed by its members, to establish a statewide standard of practice. From January 1994 through December 1997, 23 of the 30 physician members voluntarily registered data on 1652 carotid operations at 14 hospitals into a central database. Blinded results were reviewed biannually. Complete data (1995-1997) were available for 1199 cases. The patients tended to be >64 years old (72%), male (62%), and white (93%). Carotid endarterectomy was the most frequently performed operation (90%). Perioperative complications (< or = 30 days) occurred in 173 patients (14.4%), including stroke (n = 19; 1.6%), death (n = 8; 0.7%), and stroke/death (n = 25; 2.0%). Although 23 surgeons (77% of the society) contributed some data, only 10 surgeons (33%) contributed complete data on >10 patients/year. Despite biannual efforts to boost participation, case entry remained stable (1994, 358; 1995, 347; 1996, 425; and 1997, 427), representing about one-third of the estimated carotid procedures performed in the state during that period. The cost of the registry was approximately $11,500. Audit of 8 surgeons revealed a >95 per cent match against the statewide discharge database and low error rate versus independent medical record review. This experience confirms that excellent outcomes after carotid endarterectomy are not limited to a few select centers and can be accomplished by adequately trained surgeons in a variety of institutional settings. Incomplete physician participation, however, inevitably raises questions about the utility of such efforts. Until volunteer registries induce full participation by heightening perceived physician benefit, their role will remain limited for future outcomes research.

Carotid Artery Diseases↗
PubMed1999

Development of C5a receptor antagonists.

During host defense, the human complement system of plasma proteins initiates inflammatory and cellular immune responses to stimuli such as infectious organisms, chemical and physical injury, radiation and neoplasia. Elevated levels of one of these plasma proteins C5a, a 74 amino acid peptidic anaphylatoxin which is one of the most potent pro-inflammatory agents, correlate with the initiation and development of many inflammatory diseases. New agents which prevent binding of C5a to its G-protein-coupled receptors can inhibit the pro-inflammatory actions of C5a and thus be potentially used to treat chronic inflammatory disorders driven by complement activation and C5a production. In recent years significant progress has been made towards the development of potent antagonists of human C5a receptors and clinically useful compounds can reasonably be expected within the next few years.

Journal Article↗
PubMed1998

Mutations in the reduced folate carrier gene which confer dominant resistance to 5,10-dideazatetrahydrofolate.

L1210/D3 mouse leukemia cells are resistant to 5, 10-dideazatetrahydrofolate due to expansion of cellular folate pools which block polyglutamation of the drug (Tse, A., and Moran, R. G. (1998) J. Biol. Chem. 273, 25944-25952). These cells were found to have two point mutations in the reduced folate carrier (RFC), resulting in a replacement of isoleucine 48 by phenylalanine and of tryptophan 105 by glycine. Each mutation contributes to the resistance phenotype. Genomic DNA from resistant cells contained both the wild-type and mutant alleles, but wild-type message was not detected. Folic acid was a much better substrate, and 5-formyltetrahydrofolate was a poorer substrate for transport in L1210/D3 cells relative to L1210 cells. Enhanced transport of folic acid was due to a marked, approximately 20-fold, decrease in the influx Km. Influx of methotrexate and 5,10-dideazatetrahydrofolate were minimally altered. Transfection of mutated rfc cDNA into RFC-null L1210/A cells produced the substrate specificity and 5, 10-dideazatetrahydrofolate resistance observed in the L1210/D3 line. Transfection of the mutant cDNA into wild-type cells also conferred resistance to 5,10-dideazatetrahydrofolate. We conclude that the I48F and W105G mutations in RFC caused resistance to 5, 10-dideazatetrahydrofolate, that the region of the RFC protein near these two positions defines the substrate-binding site, that the wild-type allele was silenced during the multistep development of resistance, and that this mutant phenotype represents a genetically dominant trait.

Animals↗
PubMed1998

Small molecular probes for G-protein-coupled C5a receptors: conformationally constrained antagonists derived from the C terminus of the human plasma protein C5a.

Activation of the human complement system of plasma proteins in response to infection or injury produces a 4-helix bundle glycoprotein (74 amino acids) known as C5a. C5a binds to G-protein-coupled receptors on cell surfaces triggering receptor-ligand internalization, signal transduction, and powerful inflammatory responses. Since excessive levels of C5a are associated with autoimmune and chronic inflammatory disorders, inhibitors of receptor activation may have therapeutic potential. We now report solution structures and receptor-binding and antagonist activities for some of the first small molecule antagonists of C5a derived from its hexapeptide C terminus. The antagonist NMe-Phe-Lys-Pro-D-Cha-Trp-D-Arg-CO2H (1) surprisingly shows an unusually well-defined solution structure as determined by 1H NMR spectroscopy. This is one of the smallest acyclic peptides found to possess a defined solution conformation, which can be explained by the constraining role of intramolecular hydrogen bonding. NOE and coupling constant data, slow deuterium exchange, and a low dependence on temperature for the chemical shift of the D-Cha-NH strongly indicate an inverse gamma turn stabilized by a D-Cha-NH. OC-Lys hydrogen bond. Smaller conformational populations are associated with a hydrogen bond between Trp-NH.OC-Lys, defining a type II beta turn distorted by the inverse gamma turn incorporated within it. An excellent correlation between receptor-affinity and antagonist activity is indicated for a limited set of synthetic peptides. Conversion of the C-terminal carboxylate of 1 to an amide decreases antagonist potency 5-fold, but potency is increased up to 10-fold over 1 if the amide bond is made between the C-terminal carboxylate and a Lys/Orn side chain to form a cyclic analogue. The solution structure of cycle 6 also shows gamma and beta turns; however, the latter occurs in a different position, and there are clear conformational changes in 6 vs 1 that result in enhanced activity. These results indicate that potent C5a antagonists can be developed by targeting site 2 alone of the C5a receptor and define a novel pharmacophore for developing powerful receptor probes or drug candidates.

Antigens, CD↗
PubMed1998

A naturally occurring mutation in Fc gamma RIIA: a Q to K127 change confers unique IgG binding properties to the R131 allelic form of the receptor.

Fc gamma RIIa is widely expressed on hematopoietic cells. There are two known allelic polymorphic forms of Fc gamma RIIa, Fc gamma RIIa-R131 and Fc gamma RIIa-H131, which differ in the amino acid at position 131 in the second lg-like domain. In contrast to Fc gamma RIIa-R131, Fc gamma RIIa-H131 binds hlgG2 but not mIgG1, and this differential binding has clinical implications for host defense, autoimmune disease, immunohematologic disease, and response to therapeutic monoclonal antibodies. We identified a novel Fc gamma RIIA genotype in a healthy individual homozygous for Fc gamma RIIA R/R131 in whom a C to A substitution at codon 127 changes glutamine (Q) to lysine (K) in one of the two Fc gamma RIIA genes. This individual's homozygosity for Fc gamma RIIA-R/R131 leads to the prediction that the receptors on her cells would not bind hIgG2. Monocyte and neutrophil phagocytosis of hIgG2-opsonized erythrocytes was significantly higher (P < .05) for cells from this K/Q127, R/R131 individual than for Q/Q127, R/R131 donors. Platelet aggregation stimulated by an mIgG1 anti-CD9 antibody in this individual was significantly different (P < .05) from Q/Q127, H/R131 and Q/Q127, H/H131 donors and similar to Q/Q127, R/R131. Our data show that the K127/R131 receptors have a unique phenotype, binding both hIgG2 and mIgG1. Further functionally significant mutations in human Fc gamma receptors and possible novel mechanisms for inherited differences in disease susceptibility should be sought with unbiased screening methods.

Alleles↗