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Biomedical subjects

G Dover

Publications and source records attributed to G Dover.

At least 19 recordsLinked to original sources
PubMed2000

How genomic and developmental dynamics affect evolutionary processes.

Evolutionary genetics is concerned with natural selection and neutral drift, to the virtual exclusion of almost everything else. In its current focus on DNA variation, it reduces phenotypes to symbols. Varying phenotypes, however, are the units of evolution, and, if we want a comprehensive theory of evolution, we need to consider both the internal and external evolutionary forces that shape the development of phenotypes. Genetic systems are redundant, modular and subject to a variety of genomic mechanisms of "turnover" (transposition, gene conversion, unequal crossingover, slippage and so on). As such the construction and spread of novel combinations of modules by turnover, in particular within gene promoters, contributes significantly to the evolution of phenotypes. Furthermore, redundancy, turnover and modularity lead to ever more complex networks of genetic interactions and ever more functions for a given module. The significant interaction between genomic turnover and natural selection leads to a molecular coevolution between interacting modules and hence facilitates the establishment of biological novelties.

Animals↗
PubMed1998

Phase I study of the orally administered butyrate prodrug, tributyrin, in patients with solid tumors.

Butyrates have been studied as cancer differentiation agents in vitro and as a treatment for hemoglobinopathies. Tributyrin, a triglyceride with butyrate molecules esterified at the 1, 2, and 3 positions, induces differentiation and/or growth inhibition of a number of cell lines in vitro. When given p.o. to rodents, tributyrin produces substantial plasma butyrate concentrations. We treated 13 patients with escalating doses of tributyrin from 50 to 400 mg/kg/day. Doses were administered p.o. after an overnight fast, once daily for 3 weeks, followed by a 1-week rest. Intrapatient dose escalation occurred after two courses without toxicity greater than grade 2. The time course of butyrate in plasma was assessed on days 1 and 15 and after any dose escalation. Grade 3 toxicities consisted of nausea, vomiting, and myalgia. Grades 1 and 2 toxicities included diarrhea, headache, abdominal cramping, nausea, anemia, constipation, azotemia, lightheadedness, fatigue, rash, alopecia, odor, dysphoria, and clumsiness. There was no consistent increase in hemoglobin F with tributyrin treatment. Peak plasma butyrate concentrations occurred between 0.25 and 3 h after dose, increased with dose, and ranged from 0 to 0.45 mM. Peak concentrations did not increase in three patients who had dose escalation. Butyrate pharmacokinetics were not different on days 1 and 15. Because peak plasma concentrations near those effective in vitro (0.5-1 mM) were achieved, but butyrate disappeared from plasma by 5 h after dose, we are now pursuing dose escalation with dosing three times daily, beginning at a dose of 450 mg/kg/day.

Administration, Oral↗
PubMed1996

A multiparameter analysis of sickle erythrocytes in patients undergoing hydroxyurea therapy.

During 24 weeks of hydroxyurea treatment, we monitored red blood cell (RBC) parameters in three patients with sickle cell disease, including F-cell and F-reticulocyte profiles, distributions of delay times for intracellular polymerization, sickle erythrocyte adherence to human umbilical vein endothelial cells in a laminar flow chamber, RBC phthalate density profiles, mean corpuscular hemoglobin concentration and cation content, reticulocyte mean corpuscular hemoglobin concentration, 1H-nuclear magnetic resonance transverse relaxation rates of packed RBCs, and plasma membrane lateral and rotational mobilities of band 3 and glycophorins. Hydroxyurea increases the fraction of cells with sufficiently long delay times to escape the microcirculation before polymerization begins. Furthermore, high pretreatment adherence to human umbilical vein endothelial cells of sickle RBCs decreased to normal after only 2 weeks of hydroxyurea treatment, preceding the increase in fetal hemoglobin levels. The lower adhesion of sickle RBCs to endothelium would facilitate escape from the microcirculation before polymerization begins. Hydroxyurea shifted several biochemical and biophysical parameters of sickle erythrocytes toward values observed with hemoglobin SC disease, suggesting that hydroxyurea moderates sickle cell disease toward the milder, but still clinically significant, hemoglobin SC disease. The 50% reduction in sickle crises documented in the Multicenter Study of Hydroxyurea in Sickle Cell Disease is consistent with this degree of erythrocyte improvement.

Adult↗
PubMed1996

Factors affecting prepubertal growth in homozygous sickle cell disease.

OBJECTIVE: To investigate the role of haematological indices, socioeconomic status, and morbidity in prepubertal growth in homozygous sickle cell (SS) disease. METHOD: Height, weight, and haematology were serially recorded in a cohort study of 315 children with SS disease from birth to 9 years at the sickle cell clinic of the University Hospital of the West Indies, Kingston, Jamaica. RESULTS: Height increment between 3 and 9 years correlated positively with total haemoglobin at age 7 years in boys but not girls. Attained height and weight at age 7 years correlated positively with haemoglobin and fetal haemoglobin in boys but not girls. Only the correlation between haemoglobin and weight showed a significant gender difference. Partial correlation analysis suggested that the effect of haemoglobin was accounted for by the effect of fetal haemolglobin and further analysis indicated that height correlated with F reticulocyte count (a measure of fetal haemoglobin production) in both sexes but not with the ratio of F cells to F reticulocytes (a measure of F cell enrichment). Growth was not significantly related to mean red cell volume, proportional reticulocyte count, alpha thalassaemia, socioeconomic status, or morbidity. CONCLUSION: A high concentration of fetal haemoglobin in boys with SS disease is associated with greater linear growth. It is postulated that in boys, low concentrations of fetal haemoglobin increase haemolysis and hence metabolic requirements for erythropoiesis, putting them at greater risk of poor growth. Differences in the relationship of haematology and growth between boys and girls with SS disease dictate that future analyses of growth take gender into account.

Anemia, Sickle Cell↗
PubMed1995

Stimulation of fetal hemoglobin production by short chain fatty acids.

Butyrate, a four-carbon fatty acid, and its two-carbon metabolic product, acetate, are inducers of gamma-globin synthesis. To test whether other short-chain fatty acids share this property, we first examined whether propionic acid, a three-carbon fatty acid that is not catabolized to acetate, induces gamma-globin expression. Sodium propionate increased the frequency of fetal hemoglobin containing erythroblasts and the gamma/gamma + beta mRNA ratios in adult erythroid cell cultures and F reticulocyte production in a nonanemic juvenile baboon. Short-chain fatty acids containing five (pentanoic), six (hexanoic), seven (heptanoic), eight (octanoic), and nine (nonanoic) carbons induced gamma-globin expression (as measured by increase in gamma-positive erythroblasts and gamma/gamma + beta mRNA ratios) in adult erythroid burst-forming unit cultures. There was a clear-cut relationship between the concentration of fatty acids in culture and the degree of induction of gamma-globin expression. Three-, four-, and five-carbon fatty acids were better inducers of gamma globin in culture as compared with six- to nine-carbon fatty acids. These results suggest that all short-chain fatty acids share the property of gamma-globin gene inducibility. The fact that valproic acid, a derivative of pentanoic acid, also induces gamma-globin expression suggests that short-chain fatty acid derivatives that are already approved for human use may possess the property of gamma-globin inducibility and may be of therapeutic relevance to the beta-chain hemoglobinopathies.

Adult↗
PubMed1995

Sustained increase in haemoglobin and RBC following long-term administration of recombinant human erythropoietin to patients with homozygous beta-thalassaemia.

Recombinant human erythropoietin (rHuEPO) was given subcutaneously three times per week in an escalating dose from 500 u/kg to 950 u/kg together with ferrous fumarate 305 mg and folic acid 5 mg/d, to 10 patients from four unrelated Arab families with homozygous beta-thalassaemia. Six splenectomized patients showed a mean (+/- standard error) increase in haemoglobin from 7.1 +/- 0.1 to 9.3 +/- 0.1 g/dl (P = 0.0001), in RBC from 4.0 to 5.0 x 10(12)/l (P = 0.0001) and in nucleated RBC from 32 +/- 7 x 10(10)/l to 82 +/- 6 x 10(10)/l while receiving 750 u/kg three times per week which persisted for 4-11 months. In two patients there was no need for further blood transfusions. In three out of four unsplenectomized patients there were no changes in Hb and RBC despite dose escalation. There were no significant changes in MVC, MCH and reticulocyte count, serum bilirubin, LDH, malonyldialdehyde (MDA) and vitamin E levels. After 13 weeks of rHuEPO there was a mean increase in the percentage of F cells from 31 +/- 10% to 86 +/- 6% (P < 0.003) in three splenectomized patients and in one unsplenectomized patient from 56.4% to 80% without changes in the levels of Hb F. Globin chain synthesis ratios did not change in four responding patients. Mean serum iron and transferrin saturation index did not change, whereas mean serum ferritin increased from 299 +/- 45 micrograms/l to 480 +/- 20 micrograms/l (P < 0.001). In seven responding patients an accelerated linear growth was indicated by positive changes in height standard deviation score for chronological age. Side-effects were minimal throughout the treatment period.

Administration, Cutaneous↗
PubMed1994

Fetal hemoglobin induction by acetate, a product of butyrate catabolism.

Butyrate induces fetal hemoglobin (HbF) synthesis in cultures of erythroid progenitors, in primates, and in man. The mechanism by which this compound stimulates gamma-globin synthesis is unknown. In the course of butyrate catabolism, beta oxidation by mitochondrial enzymes results in the formation of two acetate molecules from each molecule of butyrate. Studies were performed to determine whether acetate itself induces HbF synthesis. In erythroid burst-forming unit (BFU-E) cultures from normal persons, and individuals with sickle cell disease and umbilical-cord blood, dose-dependent increases in gamma-globin protein and gamma mRNA were consistently observed in response to increasing acetate concentrations. In BFU-E cultures from normal adults and patients with sickle cell disease, the ratio of gamma/gamma + beta mRNA increased twofold to fivefold in response to acetate, whereas the percentage of BFU-E progeny staining with an anti-gamma monoclonal antibody (MoAb) increased approximately twofold. Acetate-induced increases in gamma-gene expression were also noted in the progeny of umbilical cord blood BFU-E, although the magnitude of change in response to acetate was less because of a higher baseline of gamma-chain production. The effect of acetate on HbF induction in vivo was evaluated using transgenic mouse and primate models. A transgenic mouse bearing a 2.5-kb mu locus control region (mu LCR) cassette linked to a 3.3-kb A gamma gene displayed a near twofold increase in gamma mRNA during a 10-day infusion of sodium acetate at a dose of 1.5 g/kg/d. Sodium acetate administration in baboons, in doses ranging from 1.5 to 6 g/kg/d by continuous intravenous infusion, also resulted in the stimulation of gamma-globin synthesis, with the percentage of HbF-containing reticulocytes (F reticulocytes) approaching 30%. Surprisingly, a dose-response effect of acetate on HbF induction was not observed in the baboons, and HbF induction was not sustained with prolonged acetate administration. These results suggest that both two-carbon fatty acids (acetate) and four-carbon fatty acids (butyrate) stimulate synthesis of HbF in vivo.

Acetates↗
PubMed1994

Epidural analgesia in the management of severe vaso-occlusive sickle cell crisis.

OBJECTIVES: To determine whether continuous epidural analgesia could effectively decrease pain and thereby improve the management of severe vaso-occlusive crisis in children with sickle cell disease who were unresponsive to conventional analgesic therapy. DESIGN: Retrospective observational study. SETTING: A tertiary care hospital with a large pediatric sickle cell patient referral population. PATIENTS: The study describes nine children in 11 painful vaso-occlusive crises, unresponsive to high-dose systemic opioids, nonsteroidal anti-inflammatory drugs, and adjunctive measures, who underwent continuous epidural analgesia to control pain. OUTCOME MEASURES: Subjective pain scores, arterial oxygen saturation monitoring, and plasma lidocaine levels. METHODS: Placement of an epidural catheter for the administration of a continuous infusion of local anesthetic, alone, or in combination with fentanyl, in the management of vaso-occlusive crisis. RESULTS: An initiation of epidural analgesic therapy, 8 of 9 patients reported severe pain (8 to 10 on a scale of 0 to 10, 0 = no pain, 10 = the worst pain they ever experienced). Analgesic was immediate (pain score 0 to 2) in 8 of 9 patients, and continuously effective in 9 of 11 crises. Five patients required either the addition of fentanyl or changing the local anesthetic from lidocaine to bupivacaine to maintain analgesia for 2 to 5 days. In 7 of 9 patients, oxygen saturation dramatically increased from 87 to 95% to 99 to 100% after epidural analgesia was initiated. In all patients, plasma lidocaine levels ranged from 1.1 to 4.6 mg/L and dose-related toxicity did not occur. One patient developed hypotension secondary to high sympathetic blockade (T-4), one had an inadvertent dural puncture during insertion of the catheter, one had the epidural catheter removed for fever, and one achieved analgesia only transiently. There were no other complications, and epidural analgesia was not associated with sedation, respiratory depression, or limitation of movement. All epidural catheters were cultured on removal, and colonization did not occur. CONCLUSIONS: Epidural analgesia with local anesthetics administered alone or in combination with fentanyl effectively and safely treats the pain of sickle cell vaso-occlusive crisis unresponsive to conventional pain management and does so without causing sedation, respiratory depression, or significant limitation on ambulation. Furthermore, early treatment of painful crisis with this technique may improve oxygenation, a critical factor in the evolution of further sickling.

Analgesia, Epidural↗
PubMed1993

The antagonist actions of WAY-100135 and its enantiomers on 5-HT1A receptor-mediated hyperpolarization of the rat isolated superior cervical ganglion.

A grease-gap extracellular recording technique was used to detect 5-HT1A receptor-mediated hyperpolarizing responses to 5-hydroxytryptamine (5-HT) in the rat isolated superior cervical ganglion. In the presence of the novel 5-HT1A receptor antagonist, WAY-100135 [N-tert-butyl-3-(4-(2-methoxyphenyl)piperazin-1-yl)-2-phenylpropan amide], the responses to 5-HT were antagonised in a competitive manner with a pA2 value of 7.2 (6.9-8.5) and Schild plot slope of 1.0 (0.4-1.6), n = 20. The antagonist activity was greater in the (+) than the (-)enantiomer of WAY-100135. The pA2 value of the (+)enantiomer was 7.5 (7.2-8.0), Schild plot slope 1.2 (0.8-1.6), n = 17. In contrast the (-)enantiomer had weak antagonist activity (pA2 6.3 +/- 0.25, n = 3). No agonist activity of WAY-100135 or its enantiomers were observed in this study.

Animals↗
PubMed1992

Chorionic villus sampling for fetal Rh typing: clinical implications.

OBJECTIVE: The prenatal Rh typing of red blood cells obtained by chorionic villus sampling was performed with an immune rosette technique. STUDY DESIGN: Ten Rh-negative pregnant women undergoing chorionic villus sampling at 9 to 11 weeks' gestation were studied at a large referral hospital. RESULTS: Accurate Rh phenotyping may be done on red blood cells obtained from chorionic villi weighing 2 to 8 mg. The preparations were shown to be greater than 90% fetal in origin as demonstrated by radial immunodiffusion quantitation of fetal hemoglobin-containing cells. Of the 10 fetuses typed in the first trimester nine of the pregnancies were carried to term. In all cases typing of red blood cells confirmed the antenatal fetal red cell typing. CONCLUSIONS: This study shows that antenatal Rh phenotyping may be performed as early as 9 to 11 weeks' gestation. This technique may be used in the management of pregnancies complicated by Rh incompatibility.

Blood Grouping and Crossmatching↗
PubMed1987

Influence of hydroxyurea on fetal hemoglobin production in vitro.

Cytotoxic drugs increase circulating fetal hemoglobin levels. We examined the mechanism by measuring the fetal hemoglobin produced per BFU-E-derived erythroblast following hydroxyurea treatment in vivo and in vitro. Treatment of four sickle cell patients increased the percentage of circulating F reticulocytes. The frequencies of bone marrow or peripheral blood BFU-E or CFU-E-derived colonies and their fetal hemoglobin content were unaffected. In all cases, the number of erythroid cells/progenitor-derived colony increased. To explore further the effect of hydroxyurea on fetal hemoglobin production, we added 50 mumol/L hydroxyurea to cultures of peripheral blood BFU-E-derived erythroblasts on 1 of 9 days (day 5 through 13) to nine samples. These BFU-E were derived from the peripheral blood of normal donors, sickle trait donors, and sickle cell anemia patients and from the bone marrows of monkeys. This concentration of hydroxyurea was selected so that the frequency of BFU-E and their size was moderately decreased. Addition of hydroxyurea to these progenitor-derived erythroid cells had no effect on fetal hemoglobin content per cell. Neither did transient exposure of progenitors to hydroxyurea prior to culture in nontoxic concentrations (0 to 500 mumol/L) result in a significant increase in fetal hemoglobin content in progenitor-derived erythroblasts. These data suggest that hydroxyurea does not directly alter the HbF program expressed by progenitor-derived erythroid cells. Instead, it enhances hemoglobin F content secondarily, possibly by inducing alterations in erythropoiesis.

Anemia, Sickle Cell↗