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Biomedical subjects

L Cook

Publications and source records attributed to L Cook.

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

Insulinotropic action of methyl pyruvate: enzymatic and metabolic aspects.

The metabolism of methyl pyruvate was compared to that of pyruvate in isolated rat pancreatic islets. Methyl pyruvate was found to be more efficient than pyruvate in supporting the intramitochondrial conversion of pyruvate metabolites to amino acids, inhibiting D-[5-3H]glucose utilization, maintaining a high ratio between D-[3,4-14C]glucose or D-[6-14C]glucose oxidation and D-[5-3H]glucose utilization, inhibiting the intramitochondrial conversion of glucose-derived 2-keto acids to their corresponding amino acids, and augmenting 14CO2 output from islets prelabeled with L-[U-14C]glutamine. Methyl pyruvate also apparently caused a more marked mitochondrial alkalinization than pyruvate, as judged from comparisons of pH measurements based on the use of either a fluorescein probe or 14C-labeled 5,5-dimethyl-oxazolidine-2,4-dione. Inversely, pyruvate was more efficient than methyl pyruvate in increasing lactate output and generating L-alanine. These converging findings indicate that, by comparison with exogenous pyruvate, its methyl ester is preferentially metabolized in the mitochondrial, rather than cytosolic, domain of islet cells. It is proposed that both the positive and the negative components of methyl pyruvate insulinotropic action are linked to changes in the net generation of reducing equivalents, ATP and H+.

Alanine Transaminase↗
PubMed1996

The safety of calcium channel blockers in human pregnancy: a prospective, multicenter cohort study.

OBJECTIVE: Our purpose was to examine the potential teratogenicity of calcium channel blockers. STUDY DESIGN: Six teratogen information services prospectively collected and followed up 78 women with first-trimester exposure to calcium channel blockers. Pregnancy outcome was compared (by paired t text of chi2 analysis) with that of a control group matched for maternal age and smoking. RESULTS: There was no increase in major malformation (2/66=3.0% [calcium channel blockers] vs 0% [nonteratogenic controls], p=0.27); a fivefold increase was ruled out (baseline 2%, alpha = 0.05, beta = 0.20). The defects reported were attributable to maternal diabetes or coingestion of teratogens. The increase in preterm delivery 28% [calcium channel blockers] vs 9% [nonteratogenic controls], p=0.003), attributed to maternal disease by stepwise regression, was the most important factor responsible for the observed decrease in birth weight (mean -334 gm vs nonteratogenic controls, p=0.08). CONCLUSION: This study suggests that calcium channel blockers do not represent a major teratogenic risk.

Abnormalities, Drug-Induced↗
PubMed1996

Kinetic characterisation of alpha-1-antitrypsin F as an inhibitor of human neutrophil elastase.

Patients homozygous for the Z allele of alpha-1-antitrypsin (alpha 1AT) have very low serum levels and are predisposed to emphysema. There have also been reports of emphysema being associated with the heterozygous phenotype FZ. To investigate whether F alpha 1AT was dysfunctional, the inhibitory activity of F alpha 1AT against human neutrophil elastase (HNE) was compared with that of common alpha 1AT phenotypes. Time-dependent inhibition of HNE by alpha 1AT was used to calculate the association rate constant (k assoc) for M, MZ, FM, FZ, F (partially purified from FZ or FS), Z and S alpha 1AT phenotypes in human sera. The results for k assoc at 25 degrees C were 9.1 (SD 0.9), 9.7 (SD 0.9), 8.0 (SD 0.8), 4.0 (SD 0.4), 4.2 (SD 0.8), 5.1 (SD 0.6) and 8.6 (SD 0.6) x 10(6) M-1s-1 respectively. F was found to have reduced activity much like that of Z, the alpha 1AT most commonly associated with emphysema. MZ (low risk for disease) and FZ heterozygotes had similar intermediate alpha 1AT levels. However the in vivo inhibition time for FZ was almost three times longer than for MZ, indicating greater exposure to proteolytic damage from free elastase for FZ than MZ individuals. In conclusion, F alpha 1AT is expressed in serum at low normal levels but is dysfunctional in its ability to inhibit HNE. Individuals who coinherit the F and a deficiency allele such as Z or Null, are likely to have a high risk for the development of emphysema. The disease risk for F homozygotes remains to be determined.

Adult↗
PubMed1995

Health and neurodevelopmental outcome at 1-year adjusted age in 508 infants weighing 700 to 1100 grams who received prophylaxis with one versus three doses of synthetic surfactant. American Exosurf Neonatal Study Groups I and II.

A three-dose prophylactic regimen of synthetic surfactant replacement has been shown to improve neonatal and 1-year survival rates in infants of 700 to 1100 gm birth weight when compared with a single prophylactic dose. The purpose of this study was to evaluate the growth, development, and late morbidity at 1 year adjusted age among the survivors of the 826 patients enrolled in the protocol. Complete follow-up data were obtained for 75% of the survivors in both groups. Chronic lung disease, need for respiratory support, neurologic disease requiring medication, visual or auditory impairments, and the incidence and severity of retinopathy of prematurity were equivalent in the two groups. The frequency of neurodevelopmental impairment was also comparable in the groups that received one dose versus three doses: moderate to severe cerebral palsy was found in 9% versus 6%, mental retardation assessed by Bayley Scales of Infant Development scores less than 69 was found in 16% vs 14%, and moderate to severe impairments of any kind were found in 33% vs 24%, respectively. Furthermore, the absolute number of impaired survivors was 92 in the three-dose group versus 106 in the one-dose group, despite a higher survival rate in the three-dose group. This study demonstrates that developmental outcomes of infants weighing 700 to 1100 gm who received three prophylactic doses of synthetic surfactant are at least as good as those of infants receiving a single dose, and that improving survival rates of very premature infants with synthetic surfactant does not result in increased numbers of infants with impairments.

Child Development↗
PubMed1995

Double-blind, randomized trial of one versus three prophylactic doses of synthetic surfactant in 826 neonates weighing 700 to 1100 grams: effects on mortality rate. American Exosurf Neonatal Study Groups I and IIa.

At 33 hospitals in the United States, a double-blind, randomized clinical trial was performed to compare one versus three prophylactic doses of synthetic surfactant in 700 to 1100 gm inborn infants. All 826 infants received an initial prophylactic dose of surfactant within 30 minutes of birth. Subsequently 410 infants received two doses of placebo (air) 12 and 24 hours later, and 416 infants received two additional doses of surfactant. By the age of 28 days, 70 infants who received one dose of surfactant and 40 infants who received three doses were dead, a 43% relative reduction in the mortality rate (30 fewer deaths; p = 0.002). By the age of 1 year after term, 87 infants who received one dose and 62 infants who received three doses were dead: a 29% relative reduction in the mortality rate (25 fewer deaths; p = 0.027). Infants who received three doses of surfactant required significantly less oxygen and less mean airway pressure for the first week of life. Necrotizing enterocolitis (9 vs 25 infants; p = 0.005), and use of high-frequency ventilation (13 vs 26 infants; p = 0.037); pancuronium (43 vs 62 infants; p = 0.045); and leukocyte transfusions (0 vs 4 infants; p = 0.042) were less frequent in the three-dose group, but air leak, bronchopulmonary dysplasia, intraventricular hemorrhage, patent ductus arteriosus, pulmonary hemorrhage, and infections were not different. These results indicate that physiologic findings, mortality rates, and probably morbidity rates are improved by two additional prophylactic doses of synthetic surfactant.

Bronchopulmonary Dysplasia↗
PubMed1995

Randomized double-blind crossover ondansetron-dexamethasone versus ondansetron-placebo study for the treatment of chemotherapy-induced nausea and vomiting in pediatric patients with malignancies.

PURPOSE: To determine whether the addition of dexamethasone to ondansetron (OND + DEX) is a more effective antiemetic regimen than ondansetron (OND) alone in children receiving chemotherapy. PATIENTS AND METHODS: Children who had solid tumors and who were receiving highly emetogenic chemotherapy, including cisplatin, carboplatin, cyclophosphamide, and ifosfamide, were randomized (1:1) in a double-blind fashion to receive either OND 0.15 mg/kg intravenously (i.v.) 30 min before and 4 and 8 h after chemotherapy and placebo, or OND + DEX (same OND doses plus DEX 8 mg/m2 i.v. 30 min before chemotherapy, followed by 16 mg/m2 in divided doses) as antiemetics. The patients were crossed over to the other antiemetic regimen when receiving an identical course of chemotherapy. Patients were monitored for emetic episodes, nausea, appetite, sense of well-being, and antiemetic adverse events. RESULTS: A total of 33 patients were evaluated. Sixty-one percent of the patients receiving OND + DEX regimens had a complete response for emetic episodes as compared with 23% with OND alone. Combined complete and major responses (two or less emetic episodes) were 86% for OND + DEX and 67% for OND. Failure for emetic episodes (more than five vomitings/day) were seen only in 7-10% of the total population. Minimal or no nausea was experienced in 74% of OND + DEX courses and in 52% of the OND courses. Appetite was better in OND + DEX courses (p = 0.006). Both antiemetic arms had similar adverse events. Mild to moderate sedation occurred in about half of the courses, followed by restlessness (29%), headache (17%), diarrhea (17%), and hiccups (2%). CONCLUSION: The combination of ondansetron and dexamethasone is superior to ondansetron alone to control emetic episodes in children receiving highly emetogenic chemotherapy (p = 0.04).

Adolescent↗
PubMed1995

Alpha 1-antitrypsin deficiency and anti-proteinase 3 antibodies in anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis.

alpha 1-antitrypsin (alpha 1-AT) is a naturally occurring inhibitor of proteinase 3 (PR3) and elastase, two of the target antigens of anti-neutrophil cytoplasmic antibodies (ANCA). An increased incidence of alpha 1-AT phenotypes associated with dysfunctional alpha 1-AT or low serum levels has been reported in patients with anti-PR3 antibodies. We have studied the relationship between ANCA, and phenotypes and serum levels of alpha 1-AT. Phenotypes usually associated with a moderate or severe reduction in alpha 1-AT serum levels or in dysfunctional activity were found more often in individuals with anti-PR3 antibodies than in the general population: four of the 31 patients (13%) with anti-PR3 antibodies had phenotypes MZ (n = 2), S (n = 1) or Z (n = 1) (P < 0.05). However, the corresponding alpha 1-AT serum levels were normal (n = 3) or elevated (n = 1). None of the 31 sera with anti-PR3 antibodies had low levels of alpha 1-AT. No abnormal alpha 1-AT phenotype was demonstrated in seven patients with anti-elastase antibodies, despite a low level of alpha 1-AT in one serum. Anti-myeloperoxidase antibodies are common in patients with ANCA, but no abnormal phenotype or low serum alpha 1-AT level was demonstrated in any of 29 sera containing these antibodies. Finally anti-glomerular basement membrane (GBM) antibodies occur occasionally in patients with ANCA-associated diseases, but again none of 10 sera had an abnormal alpha 1-AT phenotype or low serum level. ANCA were not demonstrated by indirect immunofluorescence in any serum from 73 patients with abnormal alpha 1-AT phenotypes. These results confirm that patients with anti-PR3 antibodies often have alpha 1-AT phenotypes that are usually associated with low serum levels of alpha 1-AT or with dysfunctional protein. Nevertheless, the incidence of anti-PR3 antibodies in patients with abnormal alpha 1-AT phenotypes is very low. This probably reflects the rarity of Wegener's granulomatosis, the major disease associated with anti-PR3 antibodies, and the relative frequency of abnormal alpha 1-AT phenotypes. The mechanism for the development of anti-PR3 antibodies in patients with abnormal alpha 1-AT phenotypes is not clear, but may relate to the increased propensity of unbound and uninhibited PR3 to stimulate autoantibody production.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1995

Alpha-1-antitrypsin PLowell: a normally functioning variant present in low concentration.

BACKGROUND: Alpha-1-antitrypsin deficiency is associated with a high risk for the development of emphysema, particularly for phenotype Pi ZZ, which is both deficient and an abnormal inhibitor of the powerful proteolytic enzyme, human neutrophil elastase. The rare variant PLowell is also expressed at abnormally low levels, but its anti-elastase activity has not been described. AIM: To study the anti-elastase activity of alpha-1-antitrypsin PLowell and compare it to the common M, S and Z proteins. METHOD: Alpha-1-antitrypsin from a female patient aged 75 years with the rare genotype PLowell NullBellingham was studied for its ability to inhibit human neutrophil elastase in a time dependent manner. RESULTS: PLowell has near normal function as an inhibitor of human neutrophil elastase with an association rate constant of 7.4 x 10(6) M-1 S-1 at 25 degrees C, similar to that of M and S. CONCLUSION: Alpha-1-antitrypsin PLowell is associated with a severe deficiency of alpha-1-antitrypsin similar to Z, but unlike that protein it has near normal function as an anti-elastase.

Aged↗
PubMed1994

Using Functional Independence Measure profiles as an index of outcome in the rehabilitation of brain-injured patients.

Rehabilitation preserves and restores everyday functions in people who have disabilities. Functional change for patients undergoing a rehabilitation program is the best measure of the effectiveness of the rehabilitation program. One tool used for measuring function is the Functional Independence Measure (FIM). However, there are problems with the psychometric properties of FIM. This article presents a method for using FIM with median patient profiles. We show the method with data from 53 patients. The results show a relationship between the pattern of recovery and the length of stay in the unit. Spearman's rank order correlation coefficients confirm this observation. Median patient profiles prove to be a useful method of displaying data as outcome measures of the effectiveness of a rehabilitation program.

Activities of Daily Living↗
PubMed1994

Daidzein is a more bioavailable soymilk isoflavone than is genistein in adult women.

Soybean isoflavones are proposed to be anticarcinogenic, but their effective doses have not been established. To study the bioavailability of soybean isoflavones for humans, 12 young adult women received single doses of 0.7, 1.3 and 2.0 mg isoflavones/kg body wt in soybean milk as part of a liquid diet. Plasma, urine and fecal isoflavones were measured by reverse-phase HPLC. Average 24-h urinary recoveries of daidzein and genistein were approximately 21% and 9%, respectively, at all three doses. Urinary recovery of daidzein was significantly greater than that of genistein (P < 0.001). Total fecal excretion of isoflavones was only 1-2% of the ingested amount. Plasma total isoflavone concentration was significantly increased to 4.4 +/- 2.5 mumol/L at 6.5 h after a dose of 2.0 mg/kg. The plasma concentrations of daidzein and genisten were approximately equal. Twenty-four hours after dosing, both plasma and urine isoflavone concentrations were nearly nil. Although soybean milk isoflavones seem to be 85% degraded in the intestine, the bioavailability, especially of daidzein, may be sufficient to exert some health-protective effects.

Administration, Oral↗
PubMed1994

Passively transferable protection against Schistosoma japonicum induced in the mouse by multiple vaccination with attenuated larvae: the development of immunity, antibody isotype responses and antigen recognition.

Vaccination of mice with attenuated S. japonicum cercariae induces protection against secondary infection which can be transferred to naive mice with serum (VMS). The presence of antibody does not per se impart protection as serum from mice carrying non-attenuated infections (CIS), contains high levels of specific antibody, but confers no protection. Here we describe the increased protection transferred (20 to 68%) with increased number of vaccinations (one to five) given to the donors, and its decline with time after the final vaccination. We also describe the development of IgM, IgA, IgE, total IgG and IgG subclass responses in VMS, giving different levels of protection and CIS, directed against sodium periodate-sensitive and -resistant epitopes in 'skin-stage', 'lung-stage' and 'liver-stage' schistosomula, adult worms and eggs. In addition, antibody affinity maturation, development of S. japonicum species-specific responses, and vaccination-specific responses were examined. No response developed in parallel with serum-mediated immunity, suggesting immunity may be due to responses against individual antigens. Preliminary examination of antigens recognized in Western blot showed that two schistosomal membrane antigens, of 13 and 40 kDa, were recognized by VMS from mice vaccinated five times (68% protection), but not by twice vaccinated VMS (27% protection). Neither antigen was recognized by non-protective CIS.

Animals↗
PubMed1994

Absence of alpha-1-antitrypsin (Pi Null Bellingham) and the early onset of emphysema.

BACKGROUND: Alpha-1-antitrypsin is the body's major inhibitor of human neutrophil elastase, a powerful proteolytic enzyme capable of degrading the common tissue components. There are over 70 genetic variants of alpha-1-antitrypsin, with the Z allele being of greatest clinical relevance. Individuals homozygous for this allele (approximately one in 2500 in Caucasians) have low serum alpha-1-antitrypsin levels (10-20% of normal) and are predisposed to emphysema, especially if they smoke. Much rarer are mutations which result in the complete or almost complete absence of alpha-1-antitrypsin in the serum. AIM: To determine the cause of complete absence of alpha-1-antitrypsin in a patient who at age 27 years had both emphysema and idiopathic cardiomyopathy. METHODS: Molecular biology techniques were used to sequence the alpha-1-antitrypsin gene. Allele specific amplification was used to show the presence of the mutations in other family members. RESULTS: Investigation showed that the proband was homozygous for the Pi Null Bellingham variant of alpha-1-antitrypsin due to the mutation Lys 217 (AAG) to Stop (TAG). His grandmother was heterozygous for Pi Null Bellingham and the additional rare variant P Lowell, Asp 256 (GAT) to Val (GTT), a variant that also results in alpha-1-antitrypsin deficiency. CONCLUSION: Patients with complete absence of alpha-1-antitrypsin develop premature emphysema not having smoked or after only minimal exposure, and much earlier than the more common Pi Z individuals who have the usual form of alpha-1-antitrypsin deficiency.

Adult↗
PubMed1994

Evaluation of defined antigen vaccines against Schistosoma bovis and S. japonicum in bovines.

Our objective is to contribute to the development of defined antigen vaccines for schistosomiasis by evaluating the protective efficacy of Schistosoma bovis and S. japonicum antigens in their natural bovine hosts. Antigens under evaluation include some already identified as vaccine candidates: glutathione S-transferases (GSTs); KLH, which shares protective epitopes with the protective antigen GP38 of S. mansoni; and Sj23, the analogue of the vaccine candidate Sm23 antigen. In another approach, since crude freeze/thaw schistosomular antigen plus BCG(F/T vaccine) has proved protective against S. japonicum in bovines, as it was against S. mansoni in mice, we are carrying out further evaluations both of this crude antigen and of recombinant-derived paramyosins. In a third line of work, novel vaccine candidate antigens identified by screening our cDNA libraries with various passively protective animal sera are being evaluated in animal experiments. In the Sudan we have shown that vaccination of calves with either native S. bovis GSTs or KLH induces high levels of fecundity-suppression without causing a significant reduction in adult worm recoveries. Therefore, recombinant-derived S. bovis 28kD GST is now being evaluated, as are the effects of combined GST/KLH vaccination. In China, sheep have been vaccinated with either S. japonicum GSTs, with KLH, or with the F/T vaccine, as a prelude to trials in bovines. As judged by adult worm recoveries, each type of vaccine induced significant protection, and there was also evidence, particularly with the GST and F/T vaccines, of fecundity-suppressive effects. As with the S. bovis/cattle system therefore, both GST and KLH showed protective effects against S. japonicum in sheep.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Occurrence and characterization of a dehydratase enzyme in the leek icosanoyl-CoA synthase complex.

The presence of a beta-hydroxyacyl-CoA dehydratase involved in the icosanoyl-CoA synthase (EC 2.3.1.119) complex of leek epidermis has been demonstrated using antibodies raised against the purified beta-hydroxyacyl-CoA dehydratase from rat liver. In a first step the leek icosanoyl-CoA synthase activity was measured in the presence of different amounts of this antibody, the results obtained showed a 75% inhibition of the activity using a 8:1 IgG/microsomal protein ratio, whereas only a weak diminution of the activity occurred using pre-immune IgG. The analysis of the reaction products after incubation in the presence of increasing IgG amounts showed a decrease of the fatty acids (the final product) and an accumulation of beta-hydroxy fatty acids using immune IgG, whereas no change occurred in the presence of pre-immune IgG. Moreover, the beta-hydroxyacyl-CoA dehydratase activity was strongly inhibited, whereas in the same conditions, the beta-ketoacyl-CoA reductase and the (trans-2-3) enoyl-CoA reductase activities were not affected. The protein fractions that eluted from the DEAE and Ultrogel columns containing the leek icosanoyl-CoA synthase activity were able to specifically bind the anti beta-hydroxyacyl-CoA dehydratase from rat liver. The cross-reactivity was demonstrated. In immunoblotting experiments using the same antiserum after SDS-PAGE of the purified leek icosanoyl-CoA synthase, only one of the four protein bands constituting the leek icosanoyl-CoA synthase was detected. This protein, having an apparent molecular mass of 65 kDa, could be the dehydratase component of the elongation complex.

Allium↗