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Biomedical subjects

B Cunningham

Publications and source records attributed to B Cunningham.

At least 37 records · Page 2Linked to original sources
PubMed1996

Novel analog of atrial natriuretic peptide selective for receptor-A produces increased diuresis and natriuresis in rats.

Atrial natriuretic peptide (ANP) binds to natriuretic peptide receptor-A (NPR-A), a membrane guanylyl cyclase, and to natriuretic peptide receptor-C (NPR-C), which plays a role in peptide clearance. Rat ANP (rANP) mutants that bind rat NPR-A selectively over rat NPR-C were isolated from randomized libraries of rANP-display phage by differential panning. One variant was identified with reduced NPR-C binding; rANP (G16R, A17E, Q18A) [rANP(REA18)]. Synthetic rANP(REA18) was equipotent with rANP in stimulating cGMP production from cloned rat NPR-A (ED50 = 1.8 nM) and was reduced in NPR-C binding by approximately 200-fold. When infused into conscious rats at 0.325 microg/min for 30 min rANP elicited an identical decrease in blood pressure compared with 0.25 microg/min of rANP(REA18), however the natriuretic (P < 0.05) and diuretic (P = 0.07) responses to rANP(REA18) were greater. These data are consistent with a role for NPR-C as a local decoy receptor attenuating NPR-A effects in the kidney, where these receptors are coexpressed. Improved NPR-A specificity could provide more effective natriuretic peptides for treatment of acute renal failure or heart failure.

Amino Acid Sequence↗
PubMed1995

Stability of reamed and unreamed intramedullary tibial nails: a biomechanical study.

We examined the correlation of bone mineral density and bone strength in the cadaver tibia, and looked in vitro at the relative stability of tibial fractures fixed with either reamed or unreamed tibial nails. Bone-mineral density correlated well with bone strength (r = 0.946), but paired tibias did not correlate closely. The unreamed nail-bone construct was less stable than the reamed construct in each pair tested (P < 0.05), and a comparison of all bones showed it to be less stable at all levels of our testing regimen, including failure (P < 0.01). Bending and breakage was seen in four of the smaller unreamed interlocking screws (4 mm).

Biomechanical Phenomena↗
PubMed1995

The use of capillary electrophoresis to monitor the stability of a dual-action cephalosporin in solution.

Ro 23-9424 is a broad-spectrum antibacterial agent consisting of a cephalosporin and a quinolone moiety which are held together by an ester linkage. This compound has limited solubility in water but is more soluble at alkaline pH. Such high pH values, however, lead to stability problems due to the lability of the ester linkage, and result in the formation of the free quinolone and cephalosporin moieties. The balance between solubility and stability presents a challenge in formulation development for this compound. Thus, it is important to effectively monitor the stability of Ro 23-9424 after it has been reconstituted in different solvent systems. In this manner, a diluent which does not lead to degradation of the drug can be identified. A capillary electrophoresis method was developed and validated to monitor the stability of Ro 23-9424. The method was found to meet acceptable criteria for method precision, system precision, linearity and limits of detection and quantitation. The method was used to monitor the stability and measure the half-life of Ro 23-9424 in water and in an L-arginine-sodium benzoate-saline diluent designed to mimic the drug delivery system. This work shows that capillary electrophoresis can be used to compare the stability of a drug in different solutions as an aid in formulation development.

Anti-Infective Agents↗
PubMed1994

Diagnosis of breast implant rupture: imaging findings and relative efficacies of imaging techniques.

OBJECTIVE: The purpose of this study was to compare the efficacies of mammography, sonography, CT, and MR imaging in the detection of breast implant rupture and to analyze the imaging findings. SUBJECTS AND METHODS: Thirty-two women with 63 silicone breast implants participated in the study. All but one had signs and symptoms suggestive of rupture, and all had requested that their implants be removed before they were enrolled in this imaging study. All patients had film-screen mammography, sonography, CT, and MR imaging. Twenty-two ruptures were found at surgery; 21 were intracapsular and one was extracapsular. The relative efficacies of the imaging studies were determined, and the imaging findings were compared with the surgical results. RESULTS: Of the 32 women with 63 implants, mammographic sensitivity for detecting implant rupture was only 23% but the specificity was 98%. Sonography had a higher sensitivity (59%), but its specificity was significantly lower (79%). CT had a sensitivity of 82% and a specificity of 88%. MR was the only imaging technique that consistently provided evidence that enabled the evaluation of intracapsular and extracapsular ruptures. The sensitivity and specificity of MR imaging were 95% and 93%, respectively. CONCLUSION: Our results show that MR imaging is more sensitive and specific for the detection of breast implant rupture than is mammography, CT, or sonography.

Adult↗
PubMed1993

Recognition by HLA-A2-restricted cytotoxic T lymphocytes of endogenously generated and exogenously provided synthetic peptide analogues of the influenza A virus matrix protein.

Experiments were carried out to determine whether complexes between MHC class I molecules and synthetic peptides are representative of those formed under more physiologically relevant conditions, with peptides derived intracellularly from processed antigens. Lysis of cells sensitized with exogenously provided and endogenously generated peptide analogues of the optimal nonameric peptide 58-66 (GILGFVFTL; derived from the influenza virus matrix protein) was compared. Endogenous loading was accomplished by expressing minigene DNA coding for alanine-substituted analogues of peptide 58-66 in HLA-A2-positive cells. Susceptibility to lysis by HLA-A2-restricted, peptide-specific cytotoxic lymphocytes was compared with lysis of cells sensitized with the same synthetic peptides. Although results were quite comparable, differences were observed. The endogenously presented analogues 58-66L60A, G61A, T65A, and L66A were recognized more efficiently than the corresponding exogenously presented analogues. This difference in recognition was most striking for peptide 58-66G61A. These results indicate the need for caution in using synthetic peptides in defining peptide binding motifs. Additional experiments with endogenously expressed analogues of 58-66 with substitutions other than alanine were carried out to define the interaction between this peptide and HLA-A2. Results are compatible with the interpretation that residues 58, 59, and 60 interact with pockets A, B, and D, respectively, in the HLA-A2 binding groove and that these interactions contribute to peptide binding.

Amino Acid Sequence↗
PubMed1992

Sequence motifs important for peptide binding to the human MHC class I molecule, HLA-A2.

Previous studies have indicated that most HLA-A2-binding peptides are 9 amino acid (aa) residues long, with a Leu at position 2 (P2), and a Val or Leu at P9. We compared the binding properties of different peptides by measuring the rate of dissociation of beta 2-microglobulin from peptide-specific HLA-A2 complexes. The simplest peptide that we identified that could form HLA-A2 complexes had the sequence (in single letter aa code) GLFGGGGGV, indicating that three nonglycine aa are sufficient for binding to HLA-A2. To determine whether most nonapeptides that contained Leu at P2 and Val or Leu at P9 could bind to HLA-A2, we tested the binding of nonapeptides selected from published HIV and melanoma protein sequences, and found that six of seven tested formed stable HLA-A2 complexes. We identified an optimal antigenic undecapeptide from the cytomegalovirus gB protein that could form stable HLA-A2 complexes that contained apparent anchor residues at P2 and P11 (sequence FIAGN-SAYEYV), indicating that the spacing between anchor residues can be somewhat variable. Finally, we tested the importance of every aa in the influenza A matrix peptide 58-66 (sequence GILGFVFTL) for binding to HLA-A2, by using Ala-substituted and Lys-substituted peptides. We found that multiple positions were important for stable binding, including P2, P3, P5-P7, and P9. We conclude that the P2 and P9 anchor residues are of prime importance for peptide binding to HLA-A2. However, other peptide side chains (especially at P3) contribute to the stability of the interaction. In certain cases, the optimal length for peptide binding can be longer than 9 residues.

Amino Acid Sequence↗
PubMed1988

Structure-activity relationships of pyrimidines as dihydroorotate dehydrogenase inhibitors.

The activity of dihydroorotate dehydrogenase (DHO-dehase) has been reported to decrease both in vitro and in vivo in hepatocellular carcinomas. DHO-dehase, the fourth enzyme of the de novo pyrimidine biosynthetic pathway, is a mitochondrial enzyme which is both a potential rate-limiting reaction in the de novo pyrimidine biosynthetic pathway and a potential therapeutic target for tumor inhibitors. This paper reports results on a series of pyrimidine analogs of dihydroorotate (DHO) and orotic acid (OA) as inhibitors of DHO-dehase. The enzyme test results established that the intact amide and imide groups of the pyrimidine ring and the 6-carboxylic acid are required for significant enzyme inhibition. The testing of several functional groups similar in characteristics to that of the carboxylic acid, such as sulfonamide, tetrazole and phosphate, indicated that the carboxylic acid group is preferred by the enzyme. Using various 5-substituted OA and DHO derivatives, it was shown that there is a steric limitation of a methyl group at this position. The compound D,L-5-trans-methyl DHO (7) (Ki of 45 microM) was both an inhibitor and a weak substrate for the enzyme, demonstrating that mechanism-based enzyme inhibitors should be effective. The testing results further suggest that a negatively charged enzyme substituent may be present near the 5-position of the pyrimidine ring and that there may be an enzyme-substrate metal coordination site near the N-1 and carboxylic acid positions of the pyrimidine ring. The combined testing results were then used to define both conformational and steric substrate enzyme binding requirements from which a model was proposed for the binding of DHO and OA to the DHO-dehase active site.

Dihydroorotate Oxidase↗
PubMed1983

Paracetamol absorption from Paramax, Panadol and Solpadeine.

Plasma paracetamol concentrations were measured after oral administration of three pharmaceutical preparations to four healthy volunteers. The formulations were Paramax (paracetamol with metoclopramide), Solpadeine (paracetamol with codeine and caffeine) and Panadol (paracetamol alone). After Solpadeine, concentrations at 15 min were significantly higher than after Panadol. Absorption of paracetamol from Paramax tablets did not differ significantly from Solpadeine or Panadol.

Acetaminophen↗
PubMed1980

Immunological characteristics in cattle of allergens derived from smooth Brucella abortus S99.

Allergens prepared from a smooth strain of Brucella abortus (S99) were used in an intradermal test for the diagnosis of brucellosis in cattle. The development and testing of the allergen from the initial less purified stages is described. The removal of serological activity noted in some of the earlier preparations can be related to the elimination of molecules of high molecular weight. The final allergen is of a high order of sensitivity and specificity and does not cause production of complement fixing or agglutinating antibodies. Intradermal testing with such an allergen could be a most useful addition to present serological procedures as it could be carried out at the same time as tuberculin testing. As a routine surveillance test, particularly in low prevalence areas, it would eliminate the necessity for extensive blood sampling and in many cases detect the infected herd before serological tests would have become positive.

Agglutination Tests↗
PubMed1980

Plasmapheresis as immunotherapeutic modality in the treatment of the canine venereal tumor.

Plasmapheresis was evaluated as a treatment modality for the transmissible venereal tumor (TVT) of the dog. The TVT is a unique tumor because of its capability for transplantation as a homograft between untreated randomly bred dogs and is characterized by the presence of dog leukocyte antigen (DLA) determinants on its tumor cells and reactivity in the mixed leukocyte tumor cell culture (MLTC). In the progressing phase, high titers of blocking antibodies measurable in the MLTC were noted. The purpose of this study was to evaluate the influence of plasmapheresis on the growth of established TVT and to correlate tumor response with the removal of blocking factors. Six pairs of DLA-identical dogs were used as experimental and control animals. Plasmapheresis was performed by discontinuous centrifugation using the Hemonetics model 30. An average of 1100 +/- 120 ml of plasma was exchanged on consecutive days during the third week after tumor injection. Consistently lower growth rates were observed in 2 experimental dogs, but there was no early rejection. Sera taken at day 14 of tumor growth contained significant blocking activity in all 12 dogs. Sera obtained post-plasmapheresis showed a decrease of blocking activity in all 6 experimental dogs, P less than 0.001. The TVT appears to be a suitable model for preclinical studies of plasmapheresis alone and in combination with other modalities.

Animals↗
PubMed1978

The half-life of bovine (incomplete) antibodies to Brucella abortus.

The half-life of bovine immunoglobulins was established in a group of 60 calves suckled on non-infected dams immunised with antigens to Brucella abortus. The half-life of the "incomplete antibody" as determined by the anti-bovine globulin test was 20.9 days. Up to 45 days, the mean half-life of antibodies in the calves was 17.1 days; from 46 to 99 days it was 21.1 days and for periods exceeding 100 days it was 24.4 days. In 39 calves born of and suckled on infected dams the mean half-life of antibodies was 22.4 days. Up to 100 days the figure was 19.5 days; over 100 days it was 22.8 days. There was no significant difference in the mean half-life of antibody between calves from infected and non-infected dams. In both cases the antibodies appear to be catabolised at a progressively slower rate.

Animals↗
PubMed1978

A study of the macro and micro immunoglobulins to Brucella abortus and their transfer from cow to calf via the colostrum.

Samples of adult bovine serum, colostrum, the serum of unsuckled and suckled calves were subjected to gel filtration through Sephadex G 200. All samples (except those of unsuckled calves) contained antibodies to Brucella abortus. Four phases were recorded in normal adult serum corresponding to IgM, IgG, Albumin and a fourth phase of smaller nitrogen-containing molecules. In colostrum phase 2 was relatively large and phase 3 was absent indicating absence of albumin. In the serum of the unsuckled calves phase 2 was absent, indicating a virtual absence of IgG. Agglutinins and Complement fixing antibodies were found in the fractions of both phase 1 and phase 2. Incomplete antibodies occurred only in phase 2, which suggested that they occurred only as 7S molecules. By immunising pregnant heifers shortly before calving with formalin Killed Strain 19 vaccine, it was found that serum IgM may be secreted in colostrum and in this manner transferred to the calf on suckling. It is considered that the immunoglobulins of importance in protecting the young calf from Br. abortus, and also in neutralising Strain 19 vaccination, are of the IgG incomplete (7S) class. These antibodies appear to be less heat-labile than 7S agglutinins.

Animals↗
PubMed1977

The effect of immaturity of the calf on immunological responses to strain 19 and killed 45/20 adjuvant vaccines.

Thirty brucellosis free calves with zero titres to the serum agglutination test (SAT), complement fixation test (CFT) and antiglobulin test (ABGT) were vaccinated with strain 19 at ages from seven hours to 198 days. Calves 75 days of age and older responded with normal serological patterns, developing high titres to all three tests. At 45 days and younger most calves responded with much reduced titres, some were negative to the SAT and CFT but all develped titres to the ABGT. Two of the younger group were subjected to an anamnestic test at about a year old and gave a positive response, indicating that the calf may be effectively primed with S19 as early as the first day of life. Three of the group were colostrumdeprived yet the patterns of their responses were similar to those of the colostrum-fed calves. Seventy-four zero titres calves were vaccinated with killed 45/20 adjuvant vaccine at ages from 60 to 320 days. Up to 200 days of age only seven of 33 calves gave positive response. From 200 to 280 days 18 of 29 responded and from 280 days of age all calves a positive response. The late development of competence to respond to this adjuvant vaccine is somewhat unusual and is discussed. It is suggested that the rough strain 45/20 may be a very weak antigen in cattle.

Age Factors↗