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Biomedical subjects

D V Devine

Publications and source records attributed to D V Devine.

At least 19 recordsLinked to original sources
PubMed2003

Genetic polymorphisms in the Renin-Angiotensin system in high-altitude and low-altitude Native American populations.

Cardiovascular disease (CVD) is reportedly less common in high-altitude native populations than in lowlanders. To some extent, this is due to cultural and demographic factors; however, increased cardiovascular efficiency contributing to hypoxia adaptation may also be involved. Numerous genetic variants have been associated with cardiovascular health. If the decreased incidence of CVD in modern high-altitude populations reflects selective pressures having favoured the transmission of these alleles in their antecedents, it would be expected that these alleles would be more common in highlanders than in lowlanders. We tested this hypothesis by determining the allele frequencies of five polymorphic loci in genes encoding components of the renin-angiotensin system (RAS) that have alleles associated with hypertension and cardiovascular disease in a high-altitude native Andean population, Quechua from the Peruvian altiplano, and in a lowland Amerindian population, Maya from the Yucatan peninsula. The polymorphisms examined were 1) the insertion/deletion polymorphism in intron 16 of the angiotensin converting enzyme (ACE) gene; 2) the A/G2350 transition (ACE-8) in intron 17 of the ACE gene; 3) the A/C1166 transversion in the 3' untranslated region of the angiotensin II receptor (type 1) gene (AGTR1); 4) the G/AI9-83 transition in intron 8 of the renin gene (REN); and 5) the T/C704 (Met235Thr) transition mutation in angiotensinogen (AGT). There was no evidence for an over-representation of the RAS alleles associated with cardiovascular fitness in the high-altitude Amerindian population when compared to the lowland Amerindian population.

Altitude↗
PubMed2003

Methylenetetrahydrofolate reductase (MTHFR) allele frequencies in Amerindians.

Neural tube defects (NTDs) have been associated with abnormalities of folate metabolism. Methylenetetrahydrofolate reductase (MTHFR) is the regulatory enzyme for the conversion of homocysteine to methionine. The C677T mutation in the MTHFR gene affects folate distribution, and homozygosity for the T allele may be associated with an increased risk of NTDs. A second mutation, an A1298C transversion in this same gene, is also associated with an increased risk for NTDs but only in conjunction with the 677T allele. A low incidence of NTDs has been observed in high-altitude populations; however, these studies did not provide information about the allele distribution of genes involved in folate metabolism. This investigation compares allele frequencies of the C677T and A1298C polymorphisms between Quechua people living at 3200-4200 m in the Peruvian Central Andes and an Aché group living at low altitude. Allele frequencies at both loci were not significantly different between the two populations. The absence of the 677T/677T genotypes and of the 677T/1298C arrangement in both groups may indicate a genetic contribution to reduced risk for NTDs; however, factors other than altitude are likely responsible for the low variant allele frequencies in these populations.

Altitude↗
PubMed2003

Selective pressure has not acted against hypercoagulability alleles in high-altitude Amerindians.

Elevated hematocrit increases blood oxygen carrying capacity in high-altitude populations, but blood viscosity and coaguability may increase concomitantly. Alleles of the beta-fibrinogen gene (FGB) associated with lower fibrinogen levels are more common in highland Amerindians (Quechua) than lowland Amerindians (Na-Dene). Although genetic drift could account for this, selection may have acted against transmission of hypercoagulability alleles at high altitude. To test this hypothesis, we compared allele frequencies between Quechua and more closely related lowlanders (Maya) at loci in the genes encoding beta-fibrinogen (FGB), factors V (F5), VII (F7) and XIII (F13), alpha2-integrin (ITGA2) and plasminogen activator inhibitor type 1 (PAI-1; SERPINE1). No significant differences in allele frequencies were found except 485arg in the gene encoding factor V, which was more common in the Quechua. These data do not support the hypothesis that selection has acted to eliminate alleles associated with hypercoagulability in Andean highlanders.

Altitude↗
PubMed2001

Room temperature activates human blood platelets.

Temperatures ranging from room temperature (20 degrees C) to 42 degrees C are generally not considered to have an activating effect on platelets. However, this assumption is not supported by clinical phenomena that result in hemostatic failure related to hypothermia. In this study, we investigated the effect of temperatures between room temperature (20 degrees C) and 42 degrees C on human blood platelets and found that room temperature causes marked activation of platelets. Major changes in platelet morphology were seen at 20 degrees C compared to resting platelets at 37 degrees C. Platelet morphology was investigated with noninvasive live cell techniques (light microscopy and dynamic and static light scattering), as well as with transmission and scanning electron microscopy. The changes in platelet morphology correlated with the expression of the activation marker, activated glycoprotein (GP) IIb-IIIa, measured by flow cytometry. Twenty-five percent to 30% of platelets expressed activated GPIIb-IIIa after exposure to 20 degrees C for 10 minutes. In the presence of serotonin re-uptake inhibitors, the serotonin content of platelets at 20 degrees C was twice that of resting platelets. In comparison, moderate heat shock conditions (42 degrees C for 10 minutes) caused no signs of platelet activation as indicated by the absence of morphological alterations, no expression of activated GPIIb-IIIa, and no changes in serotonin content. These results show that room temperature by itself significantly activates platelets and has an effect on the platelet serotonin content. This may contribute to both the functional lesion associated with 22 degrees C storage of platelets for transfusion and the in vivo hemostatic failure after hypothermia.

Blood Platelets↗
PubMed2001

Platelet aggregation is not initiated by platelet shape change.

Because the initial decrease in light transmission in platelet aggregometry is attributed to platelet shape change, it is widely held that platelet shape change is a prerequisite for platelet aggregation. We conducted this study to determine the basis of this initial optical effect in aggregometry. Platelets were activated with ADP, thrombin, or the thrombin receptor agonist peptide SFLLRN (TRAP(1-6)). In every case the initial decrease in light transmission occurred with the concomitant formation of microaggregates. This was also seen when preactivated platelets, which cannot undergo further morphological changes, were used, and when platelets were activated in the presence of shape-change inhibitors such as cytochalasin D and vincristine. Microscopy analysis of samples fixed at minimum light transmission in the aggregometer, which is generally assumed to signal shape change, always showed the presence of microaggregates. Microaggregation appeared to be distinct from full aggregation, as it was not inhibited by the addition of CD61, an antibody to the beta(3) integrin. To model these findings, fibrinogen-coated latex spheres, which cannot change shape, were aggregated with thrombin; the initial decrease in light transmission was still seen, and microaggregates formed at this time. These results indicate that platelet shape change is not a prerequisite for aggregation and that the signal widely believed to represent shape change reflects platelet microaggregation instead. We conclude that platelet aggregation occurs independently of shape change and that shape change is not necessarily followed by aggregation. These observations suggest an alternative role for platelet shape change of single platelets.

Adenosine Diphosphate↗
PubMed2001

Generation of reticulated platelets in response to whole blood donation or plateletpheresis.

BACKGROUND: There are few reports about thrombopoietic responses in whole blood (WB) and platelet-pheresis donors. This study compares the thrombopoietic responses of such donors and their platelet values. STUDY DESIGN AND METHODS: The effect of WB donation or selective platelet loss (plateletpheresis) was evaluated prospectively. WB and platelet donor samples before donation and for 7 days thereafter were assessed for platelet count, mean platelet volume, and platelet reticulocytes. RESULTS: Reticulated platelets appeared in the circulation of plateletpheresis donors by 24 hours. The proportion of reticulated platelets was highest on Day 2, and above-normal levels of reticulated platelets persisted until Day 7. The mean platelet volume was high on Days 2 and 3, which corresponded with the appearance of reticulated platelets. After plateletpheresis, platelet counts were higher than could be accounted for by new platelets, which suggested the release of sequestered platelets. WB donors manifested no changes in platelet counts but had a peak of circulating platelet reticulocytes 2 days after the donation. CONCLUSION: The thrombopoietic peak in WB and plateletpheresis donors occurs 2 days after donation, and the response level is related to the amount of platelets lost. The impact of platelet loss on the number of circulating platelets is modulated by the release of platelets from the spleen.

Benzothiazoles↗
PubMed2001

Toxicity and toxicokinetics of a phosphorothioate oligonucleotide against the c-myc oncogene in cynomolgus monkeys.

A 2-week toxicity and toxicokinetic study of a 15-mer phosphorothioate oligonucleotide, INX-3280, against the c-myc oncogene was performed in cynomolgus monkeys. As this oligonucleotide readily adopts an aggregate structure, a quadruplex, which may be associated with adverse physiologic effects, this study was performed using INX-3280 that had been converted to its monomeric form. Animals received intravenous (i.v.) infusions of monomeric INX-3280 three times per week for 2 weeks at doses of 3 or 15 mg/kg per administration. The monkeys were examined for clinical signs: changes in hematology, serum chemistry, coagulation, and urinalysis parameters; complement activation; macroscopic findings at necropsy; and histopathologic alterations. In addition, the toxicokinetics of INX-3280 were evaluated, using a validated HPLC assay, after the first and last (sixth) doses. No treatment-related clinical signs of any adverse effects were observed, and there were no test article-related changes in hematology, serum chemistry, or complement activation parameters. The only alteration in clinical pathology parameters was a minor (30%) prolongation of the activated partial thromboplastin time (aPTT), reflecting slight inhibition of the intrinsic coagulation pathway, which was less than that reported with other oligonucleotides given at similar doses. Treatment-related histopathologic alterations consisted of characteristic accumulation of basophilic material in the cytoplasm of tubular epithelial cells in the kidney, resident macrophages in the lymph nodes, and Kupffer cells in the liver. These changes were graded as minimal in all cases. The basophilic material is believed to reflect accumulation of the oligonucleotide or metabolites or both. The pharmacokinetic parameters of INX-3280 were identical on the first and sixth administrations and were similar to those reported for other phosphorothioate oligonucleotides. Maximum concentration (Cmax) values for INX-3280 (101-119 microg/ml) were in excess of the threshold plasma concentrations reported to trigger complement activation by phosphorothioate oligonucleotides. It is concluded that the safety profile of monomeric INX-3280 in cynomolgus monkeys is quite favorable relative to the known effects of other phosphorothioate oligonucleotides, particularly with respect to the blood level-related toxicities of this class of compounds, including complement activation and inhibition of coagulation. This study found no toxicities that were expected to be clinically significant.

Animals↗
PubMed2000

Incorporation of an Asp-Ser sequence to form an RGDS-like motif in hirutonin: the effect on in vitro platelet function.

We investigated the effect on in vitro platelet function of hirutonin, a modified hirutonin with an RGD-like motif, a pseudo-RGDS peptide and a linear RGDS peptide. Inhibition of expression of surface fibrinogen on ADP-activated platelets with 40 microM of the peptide was as follows: hirutonin 10+/-3%, modified chimeric peptide 26+/-5%, pseudo-RGDS 66+/-11% and linear RGDS 93+/-13%. Both hirutonin and the chimeric peptide significantly inhibited ADP-induced platelet activation as detected by CD62 expression. Unlike the RGDS and pseudo-RGDS controls, neither the chimeric peptide nor the parent hirutonin inhibited ADP-induced platelet aggregation even at 140 microM. The chimeric hirutonin peptide reduced ATP release from ADP-stimulated platelets by 40+/-4%. This inhibition was stronger than that caused by hirutonin (23+/-13%), but less than the RGDS (90+/-2%) and pseudo RGDS-peptides (59+/-11%). Primary platelet haemostasis was slightly but not significantly affected by the peptide at 40 and 80 microM. However, shear-induced platelet adhesion to vWF and especially subsequent aggregate formation was interrupted after the addition of the chimeric peptide. Similar results were obtained with hirutonin. This inhibition was not as marked as with the RGDS- and pseudo-RGDS peptides. Both the parent hirutonin and the chimeric peptide caused prolongation of the clinical coagulation assays aPTT and TT. In conclusion, the chimeric hirutonin peptide with introduction of the RGD motif retained its anticoagulant effect but had little formal disintegrin activity. Instead, it appeared to have novel anti-platelet effects that may be of therapeutic use.

Adenosine Triphosphate↗
PubMed2000

Beta-globin gene cluster haplotypes in two North American indigenous populations.

Haplotypes derived from five polymorphic restriction sites were determined in 50 Carrier-Sekani and 70 Mvskoke chromosomes, and the results were integrated with those previously obtained for 11 South American Indian populations. Eleven haplotypes were identified in the Mvskokes, while five were observed in the Carrier-Sekani. As in South American natives, haplotype 2 (+----) and 6 (-++ -+) were the most prevalent among the Mvskoke (46% and 30%, respectively). In the Carrier-Sekani, haplotype 2 was also the most common, but haplotype 5 (-+ -++) was somewhat more frequent (18%) than 6 (12%). High heterozygosities, as well as genetic differentiation, were observed among these two North American and two other South American groups (Mapuche and Xavante). They could be due to non-Indian admixture in the Mvskoke and Mapuche, but the findings in the other two populations require some other type of explanation.

Gene Frequency↗
PubMed2000

Beta2-adrenergic receptor allele frequencies in the Quechua, a high altitude native population.

The beta2-adrenergic receptor is involved in the control of numerous physiological processes and, as the primary catecholamine receptor in the lungs, is of particular importance in the regulation of pulmonary function. There are several polymorphic loci in the beta2-adrenergic receptor gene that have alleles that alter receptor function, including two (A/G46, G/C79) that increase agonist sensitivity. As such a phenotype may increase vaso and bronchial dilation, thereby facilitating air and blood flow through the lungs, we hypothesized that selection may have favoured these alleles in high altitude populations as part of an adaptive strategy to deal with the hypoxic conditions characteristic of such environments. We tested this hypothesis by determining the allele frequencies for these two polymorphisms, as well one additional missense mutation (C/T491) and two silent mutations (G/A252 and C/A523) in 63 Quechua speaking natives from communities located between 3200 and 4200 m on the Peruvian altiplano. These frequencies were compared with those of two lowland populations, one native American (Na-Dene from the west coast of Canada) and one Caucasian of Western European descent. The Quechua manifest many of the pulmonary characteristics of high altitude populations and differences in allele frequencies between the Quechua and lowlanders could be indicative of a selective advantage conferred by certain genotypes in high altitude environments. Allele frequencies varied between populations at some loci and patterns of linkage disequilibrium differed between the old-world and new-world samples; however, as these populations are not closely related, significant variation would be expected due to stochastic effects alone. Neither of the alleles associated with increased receptor sensitivity (A46, G79) was significantly over-represented in the Quechua compared with either lowland group. The Quechua were monomorphic for the C allele at base 79. This variant has been associated with body mass index; however no clearly defined metabolic phenotype has been established. In addition, we sequenced the coding region of the gene in three unrelated Quechua to determine if there were any other polymorphisms common in this population. None were detected.

Alleles↗
PubMed2000

Hemostatic parameters and platelet activation marker expression in cyanotic and acyanotic pediatric patients undergoing cardiac surgery in the presence of tranexamic acid.

We have investigated hemostatic parameters including platelet activation in 56 pediatric patients with or without cyanosis undergoing cardiopulmonary bypass (CPB) and cardiac surgery to repair congenital defects. Patients were participants in a study assessing the effects of tranexamic acid on surgery-related blood loss. Parameters monitored included blood loss, prothrombin F1.2, thrombin-antithrombin complexes, t-PA, PAI-1, plasminogen, fibrin D-dimer, and plasma factor XIII. Additionally, flow cytometry monitored platelet degranulation (P-selectin or CD63), as well as surface-bound fibrinogen, von Willebrand factor and factor XIIIa. Cyanotic patients had evidence of supranormal coagulation activation as both fibrin D-dimer and PAI-1 levels were elevated prior to surgery. While the extent of expression of P-selectin or CD63 was not informative, platelet-associated factor XIIIa was elevated in cyanotic patients at baseline. In both patient groups, CPB altered platelet activation state and coagulation status irrespective of the use of tranexamic acid.

Antifibrinolytic Agents↗
PubMed1999

Languages, geography and HLA haplotypes in native American and Asian populations.

A number of studies based on linguistic, dental and genetic data have proposed that the colonization of the New World took place in three separate waves of migration from North-East Asia. Recently, other studies have suggested that only one major migration occurred. It is the aim of this study to assess these opposing migration hypotheses using molecular-typed HLA class II alleles to compare the relationships between linguistic and genetic data in contemporary Native American populations. Our results suggest that gene flow and genetic drift have been important factors in shaping the genetic landscape of Native American populations. We report significant correlations between genetic and geographical distances in Native American and East Asian populations. In contrast, a less clear-cut relationship seems to exist between genetic distances and linguistic affiliation. In particular, the close genetic relationship of the neighbouring Na-Dene Athabaskans and Amerindian Salishans suggests that geography is the more important factor. Overall, our results are most congruent with the single migration model.

Alleles↗
PubMed1999

Unusual electrostatic effects on binding of C1q to anionic liposomes: role of anionic phospholipid domains and their line tension.

The binding of 125I-C1q to anionic liposomes was studied as a function of protein concentration, pH, ionic strength, and anionic lipid composition. The maximum amount of protein bound per micromole of lipid was very sensitive to electrostatic factors, increasing strongly with decreased pH and ionic strength or increased anionic lipid content. The apparent association constant was independent of these electrostatic factors, however, in marked contrast to studies on basic peptide binding to anionic lipid vesicles. Microscopic observations of large unilamellar liposomes containing fluorescently labeled C1q or phosphatidylglycerol demonstrated, under conditions causing strong electrostatic interactions, that C1q and anionic lipids colocalized into domains whose radii of curvature were higher than that of the surrounding lipid. These domains were observed to bud and pinch off into brightly fluorescent vesicles. We propose a model for all of these observations in which the line tension or edge energy at the boundary of the domain resists its increase in circumference as the domain grows by electrostatic effects on binding, eventually resulting in vesiculation. We propose that under favorable electrostatic conditions, as larger domains form the edge energy balances the increases in the electrostatic contribution to binding, resulting in a net binding energy independent of electrostatic factors.

Anions↗
PubMed1999

C1q binding to liposomes is surface charge dependent and is inhibited by peptides consisting of residues 14-26 of the human C1qA chain in a sequence independent manner.

Complement activation by anionic liposomes proceeds by antibody-independent, C1q-initiated activation of the classical pathway. Purified C1q bound to anionic liposomes in an acidic lipid concentration-dependent manner. Saturation binding, but not the apparent association constant, was enhanced by increasing the cardiolipin content of the liposomes or decreasing either the pH or ionic strength of the reaction mixture. These observations indicate the involvement of electrostatic factors in the binding. A highly cationic region in the collagen-like domain of C1q comprised of residues 14-26 of the C1qA polypeptide chain was assessed for involvement in liposome binding. This region has previously been shown to mediate C1q binding to other immunoglobulin-independent activators of the classical pathway of complement. Peptides containing residues 14-26 of C1qA, denoted C1qA14-26, inhibited C1q binding to and complement activation by anionic liposomes. The inhibitory capacity of these cationic peptides had no sequence or conformation specificity. Rather, the amount of positive charge on the peptides was the determining factor. When present in excess, peptides with five cationic residues inhibited C1q binding and complement activation; however, C1q peptides with only two cationic residues did not. In addition to the C1qA14-26 region, other parts of C1q that contain cationic residues may also be involved in C1q binding to anionic liposomes.

Complement Activation↗
PubMed1999

Beta-fibrinogen allele frequencies in Peruvian Quechua, a high-altitude native population.

Elevated hematocrits, which are found in many high-altitude populations, increase the oxygen-carrying capacity of blood and may represent an adaptation to hypoxic environments. However, as high hematocrit increases blood viscosity, which in turn is associated with hypertension and heart disease, it may be advantageous for high-altitude populations to limit other factors that contribute to increased blood viscosity. One such factor is the plasma concentration of the coagulation protein fibrinogen. Several common polymorphisms in the beta-fibrinogen gene have been identified that affect fibrinogen concentrations. We determined the allele frequencies of three of these polymorphisms (G/A-455(HaeIII), C/T-148(HindIII), and G/A+448(MnlI)) in sample groups drawn from three populations: Quechua-speaking natives living at over 3,200 m in the Peruvian Andes, North American natives (Na-Dene) from coastal British Columbia, and Caucasian North Americans. The frequencies of the alleles previously shown to be associated with increased fibrinogen levels were so low in the Quechuas that their presence could be accounted for solely by genetic admixture with Caucasians. Frequencies in the Na-Dene, a Native American group unrelated to the Quechua, were not significantly different from those in Caucasians.

Alleles↗
PubMed1999

Idiopathic immune-mediated acquired von Willebrand's disease in a patient with angiodysplasia: demonstration of an unusual inhibitor causing a functional defect and rapid clearance of von Willebrand factor.

A case of idiopathic immune-mediated von Willebrand's disease (AvWD) associated angiodysplasia and recurrent lower gastrointestinal bleeding is reported. Coagulation parameters at presentation were activated partial thromboplastin time of 41 sec, bleeding time >15 min, factor VIII procoagulant activity, 5%; von Willebrand factor antigen (WF:Ag) 5%, and vWF:ristocetirn cofactor activity 11% sodium dodecyl sulfate-agarose gel electrophoresis pattern of plasma vWF showed a pattern similar to type II vWD. An in vitro inhibitor against vWF in the immunoglobulin (Ig)G fraction of the patient's plasma was demonstrated vWF parameters showed a short-lived increase after 1-deamino-8-D-arginine vasopressin (DDAVP) administration. The patient's bleeding episodes were initially managed adequately with cryoprecipitate replacement therapy and DDAVP, to which she became refractory. No significant improvement was achieved following the institution of immunosuppressive therapy in the form of high-dose steroids and cyclophosphamide. She was then treated with intravenous immunoglobulin (IvIg) to which she showed an adequate response in terms of her clinical situation and her hemostatic parameters. The patient is on maintenance treatment with repeated courses of IvIg based on vWF parameter monitoring. To our knowledge, this is the third reported association between idiopathic immune-mediated AvWD and angiodysplasia.

Aged↗
PubMed1999

Effects of prestorage white cell reduction on platelet aggregate formation and the activation state of platelets and plasma enzyme systems.

BACKGROUND: The introduction of prestorage white cell (WBC) reduction in random-donor platelet concentrates in Canada has increased the occurrence of particulate material in PCs. The effects of filtration on platelet activation state and the activation of plasma enzyme systems were assessed. STUDY DESIGN AND METHODS: Particulate material was examined by light microscopy, electron microscopy, protein electrophoresis, and biochemical analysis. Thirty PCs (10 unfiltered, 20 filtered) were examined during processing and 5-day storage for pH, platelet count and mean volume, morphology, activation marker expression, and hypotonic shock response. Complement activation, thrombin generation, and fibrinolysis were assessed by using specific enzyme immunoassays or chromogenic assays. RESULTS: By all analyses, the particulate material appeared to be platelet aggregates. Platelets exposed to WBC-reduction filters expressed a significantly higher level of activation markers CD62 and CD63, altered morphology, and increased platelet microparticles throughout the storage period than did unfiltered platelets. Complement activation at the C3 level was significantly increased in filtered units with little evidence of coagulation or fibrinolytic system activation. CONCLUSION: Exposure of platelets to filters during prestorage WBC reduction increased platelet activation and mildly increased complement activation over the levels during the storage period. These alterations can contribute to the formation of irreversible platelet aggregates during processing.

Antigens, CD↗