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Biomedical subjects

R Cotton

Publications and source records attributed to R Cotton.

At least 37 records · Page 2Linked to original sources
PubMed1995

One-year follow-up of 273 infants with birth weights of 700 to 1100 grams after prophylactic treatment of respiratory distress syndrome with synthetic surfactant or air placebo. American Exosurf Neonatal Study Group I.

A single dose of synthetic surfactant was administered prophylactically to premature neonates with birth weights between 700 and 1100 gm. The effects of this treatment on neurodevelopmental, neurologic, and ophthalmologic outcomes, impairments, and general health status were examined during a follow-up evaluation at 1-year adjusted age. The study was a multicenter, parallel, randomized, double-blind comparison of 446 infants who received either air placebo (n = 222) or synthetic surfactant (n = 224). Follow-up evaluations were completed for 82% of surviving infants in both treatment groups. Neurodevelopmental outcome and growth were equivalent in the infants treated with synthetic surfactant and in the infants given air placebo. Impairments occurred in 38% of the infants treated with air placebo compared with 31% of those given synthetic surfactant; the difference was not statistically significant (relative risk 0.809, 95% confidence interval 0.585, 1.119). The incidence of asthma was significantly higher in the group of infants given air placebo (4% vs 10% for surfactant and air placebo, respectively, relative risk 0.391, 95% confidence intervals 0.157, 0.972). Other outcomes, including retinopathy of prematurity, hospital readmissions, surgery, and evidence of chronic lung disease, were not different. Administration of a single prophylactic dose of synthetic surfactant increases survival in infants with birth weights between 700 and 110 gm without increasing the number or proportion of impaired survivors.

Air↗
PubMed1994

Chemo-enzymic backbone engineering of proteins. Site-specific incorporation of synthetic peptides that mimic the 64-74 disulfide loop of granulocyte colony-stimulating factor.

We present the concept of chemo-enzymic backbone engineering of proteins. Recombinant DNA techniques are used to produce appropriate proteins that are enzymically fragmented to give the starting materials. These fragments are modified specifically at their chain termini either enzymically (coupling of a hydrazide to the C terminus) or chemically (periodate oxidation of N-terminal serine to a glyoxylyl function). The modified fragments, which need no side protection whatever, are mixed together and religate themselves spontaneously under mild conditions. The hydrazone bond thus formed can be reduced if desired, which stabilizes the linkage and enhances the flexibility of the local conformation. In this way biologically or chemically derived structures can be incorporated into the protein, and the choice of the chemical ones is free of all of the constraints of the genetic code. We believe that this combined approach gives access to constructions that could not be derived by either recombinant or chemical methods alone. We illustrate the particularity of this concept by the engineered modifications of the 64-74 disulfide loop region of human granulocyte colony-stimulating factor. Analogs constructed include one which, in spite of having a nonpeptide link in its backbone, has full biological activity.

Amino Acid Sequence↗
PubMed1994

Economic outcomes of colfosceril palmitate rescue therapy in infants weighing 1250g or more with respiratory distress syndrome: results from a randomised trial.

An analysis of the economic data from a multicentre, randomised, placebo-controlled clinical trial of colfosceril palmitate in infants with neonatal respiratory distress syndrome (NRDS) and birthweights of 1250g or more is presented. Two 5 ml/kg (67.5 mg/kg) doses of a synthetic surfactant (colfosceril palmitate) or air placebo were administered to 1237 infants who were receiving mechanical ventilation and had an arterial/alveolar oxygen tension ratio of less than 0.22. In addition to the clinical end-points for safety and efficacy, data were collected on length of hospital stay, days in the neonatal intensive care unit, days on mechanical ventilation, days on oxygen, and hospital charges until the child reached 1-year adjusted age. One-year adjusted age is attained when the time elapsed since birth is equal to 365 days plus the number of days of prematurity. Rescue treatment with synthetic surfactant therapy has been shown to reduce the incidence of complications of NRDS. Growth and development of infants who received colfosceril palmitate therapy in the study and survived to 1-year adjusted age were equivalent to those of the survivors in the air placebo group. For the cohort of treated infants, colfosceril palmitate reduced the average length of stay at 2 levels of care needed during both the initial hospitalisation (a reduction of 8 days overall and 5 days in intensive care) and all first year hospitalisations (a reduction of 9 days overall and 5 days in intensive care). Total hospital charges for the initial hospitalisation and through 1-year adjusted age for a hypothetical cohort of 100 infants treated with colfosceril palmitate were less than those for a comparable cohort in the air placebo group. The results would, therefore, suggest that rescue therapy with colfosceril palmitate in infants with NRDS and birthweights over 1250g can result in substantial reductions in hospital resource utilisation and charges in addition to the clinical benefits associated with its use.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1991

A controlled trial of synthetic surfactant in infants weighing 1250 g or more with respiratory distress syndrome. The American Exosurf Neonatal Study Group I, and the Canadian Exosurf Neonatal Study Group.

BACKGROUND: Surfactant-replacement therapy is now recognized as a life-saving and safe intervention in small premature infants, but there is little evidence concerning its risks and benefits in larger premature infants. METHODS: We conducted a placebo-controlled, blinded trial in 1237 infants with respiratory distress who were enrolled at 23 hospitals in the United States and 13 hospitals in Canada. At entry all the infants weighed at least 1250 g, were receiving mechanical ventilation, and had a ratio of arterial to alveolar oxygen tension below 0.22. The initial dose of either the synthetic surfactant (Exosurf, 5 ml per kilogram of body weight) or air (the placebo) was administered less than 24 hours after birth, with a second dose given 12 hours later. A total of 614 infants were assigned to receive surfactant, and 623 to receive placebo. RESULTS: Fewer infants in the surfactant group than in the placebo group died before 28 days of age or survived at 28 days with bronchopulmonary dysplasia (7 percent vs. 12 percent, P = 0.002). In the first 28 days of life, there were fewer deaths due to respiratory distress syndrome in the surfactant group (1 percent vs. 3 percent, P = 0.043), lower overall neonatal mortality (4 percent vs. 7 percent, P = 0.04), and a lower incidence of bronchopulmonary dysplasia (3 percent vs. 6 percent, P = 0.008). There was also a significantly lower incidence of pulmonary air leaks, intraventricular hemorrhage, patent ductus arteriosus, seizures, hypotension, and pulmonary hypertension in the surfactant group. The infants treated with surfactant were weaned from oxygen and mechanical ventilation significantly sooner than those given placebo, and they less often required high-frequency ventilation or extracorporeal membrane oxygenation. The primary side effect observed more frequently among the infants who received surfactant treatment was pulmonary hemorrhage (six infants vs. one infant, P = 0.055). CONCLUSIONS: In infants weighing at least 1250 g at birth who have respiratory distress syndrome, treatment with two doses of synthetic surfactant improves survival and reduces perinatal morbidity.

Birth Weight↗
PubMed1990

Structural similarities among enzyme pterin binding sites as demonstrated by a monoclonal anti-idiotypic antibody.

BALB/c mice were immunized with a synthetic co-factor of the aromatic amino acid hydroxylases, 6,7-dimethyl-5,6,7,8-tetrahydropterin, conjugated to albumin. Hybridoma cell lines isolated from the immunized mice secreted monoclonal antibodies reacting specifically with the pterin molecule and monoclonal antibodies which were found to bind phenylalanine hydroxylase. Several lines of evidence were consistent with the anti-phenylalanine hydroxylase antibodies being anti-idiotype antibodies mimicking the pterin molecule and binding to the pterin binding site of phenylalanine hydroxylase. (a) An anti-idiotype monoclonal antibody, NS7, when reimmunized into mice produced anti-pterin antibodies consistent with NS7 being an internal image anti-idiotypic antibody. (b) NS7 antibody was prevented from binding to phenylalanine hydroxylase when a competitive inhibitor of phenylalanine hydroxylase enzyme activity, 6,7-dimethyl-7,8-dihydropterin, was bound to phenylalanine hydroxylase. (c) NS7 antibody was shown to bind to a wide range of pterin-requiring enzymes: phenylalanine, tyrosine and tryptophan hydroxylases, dihydropteridine reductase, dihydrofolate reductase, and sepiapterin reductase. Thus the NS7 antibody has successfully mimicked a common portion of the pterin cofactors utilized by these enzymes and demonstrated structure homology in their pterin binding sites despite their diverse function and little amino acid sequence homology except among the three aromatic amino acid hydroxylases.

Adrenal Glands↗
PubMed1990

Subglottic cysts in the premature infant.

Supraglottic cysts in the newborn are a well-recognized entity, but subglottic cysts have been rarely reported. Over the past 6 years we have observed subglottic cysts in nine patients with relatively long intubations from the neonatal intensive care unit of two university hospitals. Most frequently the patients were extubated and did well for weeks or months, but then they had progressive biphasic stridor. On endoscopy the patients had a subglottic stenosis that was irregular but with a smooth mucosal lining. Usually the cysts were apparent, but in two patients the mucosa was thickened and the patients were treated as a subglottic stenosis with tracheostomy. These subglottic cysts were recognized at the time of laryngotracheoplasty. In six patients the cysts were managed either by marsupialization with cup forceps, endoscopic diathermy, or carbon dioxide laser without recurrence. It is our belief that this condition is most likely due to scarring and obstruction of mucus glands of the subglottic area from prolonged intubation. This entity should be recognized and looked for in the neonate who has an acquired subglottic stenosis and should first be treated conservatively with endoscopic marsupialization.

Child, Preschool↗
PubMed1990

Identification of Pneumocystis carinii chromosomes and mapping of five genes.

Pulsed field gel electrophoresis was used to identify the chromosome-size DNA of Pneumocystis carinii, a major pathogen of immunocompromised patients. Thirteen chromosomes of rodent Pneumocystis carinii, ranging in size from 300 to 700 kilobases (kb), were identified. The minimum genome size for P. carinii, estimated on the basis of the sizes of chromosomes, is 7,000 kb. Genetic heterogeneity among different P. carinii isolates was documented by demonstration of chromosomal size variability. By hybridization studies, the genes for topoisomerase I, dihydrofolate reductase, rRNA, actin, and thymidylate synthase were mapped to single chromosomes of approximately 650, 590, 550, 460, and 350 kb, respectively. Hybridization studies further confirmed the genetic heterogeneity of P. carinii.

Actins↗
PubMed1990

Antagonists of bombesin/gastrin releasing peptide based on [D-Ala24]GRP(20-26)-heptapeptide. Modifications leading to potent analogues with prolonged duration of action.

Analogues of gastrin releasing peptide (GRP) and bombesin based on His-Trp-Ala-Val-D-Ala-His-Leu, the 20-26 heptapeptide sequence of [D-Ala24]GRP, have been synthesized and tested in vitro for their ability to inhibit GRP (18-27)-induced mitogenesis in Swiss 3T3 cells. Compounds identified as potent antagonists in this test system were also tested in vivo for their ability to inhibit bombesin-induced amylase secretion in rats. The Trp-Ala-Val sequence was found to be a very important feature of the antagonist activity; most substitutions in this region led either to much less potent or inactive analogues. In contrast, amino acid replacements in other parts of the molecule were more tolerated and sometimes led to marked increases in the in vitro and in vivo activity. The most potent analogues were obtained by replacing Leu26 by MeLeu and His25 by Lys(X) where X = Z, PhCO, PhCH2CO or Ph(CH2)2CO. Thus 4-pyridylcarbonyl-His-Trp-Ala-Val-D-Ala-Lys(CO-CH2-CH2-Ph)-Leu- NHMe (86) and 4-pyridylcarbonyl-His-Trp-Ala-Val-D-Ala-Lys(Z)-MeLeu-OMe (87) had IC50 values of less than 20 micrograms/kg s.c. in vivo, and their effects lasted for more than 3 hr.

Amino Acid Sequence↗
PubMed1989

N-isobutyryl-His-Trp-Ala-Val-D-Ala-His-Leu-NHMe (ICI 216140) a potent in vivo antaconist analogue of bombesin/gastrin releasing peptide (BN/GRP) derived from the C-terminal sequence lacking the final methionine residue.

The GRP receptor mediated growth response in Swiss 3T3 cells has been used to identify BN/GRP antagonists. Analysis of bombesin antagonism by substance P analogues and by truncated GRP analogues revealed that deletion of the C-terminal methionine residue was important for antagonism. Des-Met analogues showing potent antagonist activity in the in vitro 3T3 system (IC50 approximately 2nM) were synthesized. Further structural modification of these peptides led to the identification of (CH3)2CHCO-His-Trp-Ala-Val-D-Ala-His-Leu-NHCH3 (ICI 216140) which reduced bombesin-stimulated rat pancreatic amylase secretion to basal levels when administered subcutaneously at 2.0 mg per kg.

Amino Acid Sequence↗