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Biomedical subjects

J P Evans

Publications and source records attributed to J P Evans.

At least 19 recordsLinked to original sources
PubMed2006

Polymorphisms in the VKORC1 gene are strongly associated with warfarin dosage requirements in patients receiving anticoagulation.

BACKGROUND: Warfarin is a mainstay of therapy for conditions associated with an increased risk of thromboembolic events. However, the use of this common agent is fraught with complications and little is known regarding inter-individual variation in warfarin response. OBJECTIVE: We tested for association between single nucleotide polymorphisms (SNPs) in VKORC1 and CYP2C9 and average weekly warfarin dose required to maintain patients at their desired anticoagulation target. METHODS: The sample consisted of 93 European-American patients from anticoagulation clinics at the University of North Carolina at Chapel Hill. Data on mean weekly warfarin dose were collected over a mean treatment period of 20.6 months. ANCOVA models were used and haplotype analysis was performed. RESULTS: Three of six VKORC1 SNPs were found to be very strongly associated with the average warfarin dose required to achieve the target international normalised ratio (INR; p<0.0001). The mean weekly dose by genotype ranged from approximately 27 to 47 mg. There was no evidence for an association between either of the two CYP2C9 polymorphisms studied, CYP2C9*2 and CYP2C9*3. CYP2C9*3 was significantly (p = 0.05) associated with average warfarin dosage after adjustment for VKORC1*1173. CONCLUSIONS: These results are of considerable clinical interest and confirm recently published results regarding the role of these two genes in modifying warfarin metabolism and maintenance dosage. The consistent findings regarding the role of VKORC1 and CYP2C9 in warfarin metabolism and maintenance dosage represent a clinically useful proof of principal for the use of pharmacogenomic information in medicine and may lead to improved understanding of warfarin's actions.

Adult↗
PubMed2006

Colourful male guppies produce faster and more viable sperm.

In guppies (Poecilia reticulata) precopulatory sexual selection (via female choice) and post-copulatory selection (via sperm competition) both favour males with relatively high levels of carotenoid (orange) pigmentation, suggesting that colourful males produce more competitive ejaculates. Here we test whether there is a positive association between male orange pigmentation and sperm quality. Our analysis of sperm quality focused on sperm swimming speeds (using CASA: computer-assisted sperm analysis to estimate three parameters of sperm velocity in vitro), sperm viability (proportion of live sperm per stripped ejaculate) and sperm lengths. We found that males with relatively large areas of orange pigmentation had significantly faster and more viable sperm than their less ornamented counterparts, suggesting a possible link between dietary carotenoid intake and sperm quality. By contrast, we found no relationship between sperm length (head length and total sperm length) and male phenotype. These findings, in conjunction with previous work showing that highly ornamented male guppies sire higher quality offspring, suggest that female preference for colourful males and sperm competition work in concert to favour intrinsically higher quality males.

Animal Communication↗
PubMed2005

The benefits of polyandry in the free-spawning polychaete Galeolaria caespitosa.

In many species, females are thought to benefit from polyandry due to the reduced risks of fertilization by genetically incompatible sperm. However, few studies that have reported such benefits have directly attributed variation in female reproductive success to the interacting effects of males and females at fertilization. In this paper, we determine whether male x female interactions influence fertilization in vitro in the free-spawning, sessile polychaete Galeolaria caespitosa. Furthermore, we determined whether polyandry results in direct fertilization benefits for females by experimentally manipulating the number of males contributing towards staged spawning events. To test for male x female interaction effects we performed an initial experiment that crossed seven males with six females (in all 42 combinations), enabling us to assess fertilization rates for each specific male-female pairing and attribute variation in fertilization success to males, females and their interaction. This initial experiment revealed a strong interaction between males and females at fertilization, confirming that certain male-female combinations were more compatible than others. A second experiment tested the hypothesis that polyandry enhances female reproductive success by exposing each female's eggs to either a single male's sperm (monandry) or the sperm from three males simultaneously (polyandry). We performed this second experiment at two ecologically relevant sperm concentrations. This latter experiment revealed a strong fertilization benefit of polyandry, independent of the effects of sperm concentration (which were also significant). We suggest that these direct fertilization gains arising from polyandry will constitute an important source of selection on females to mate multiply in nature.

Analysis of Variance↗
PubMed2005

Does egg competition occur in marine broadcast-spawners?

When the availability of sperm limits female reproductive success, competition for sperm, may be an important broker of sexual selection. This is because sperm limitation can increase the variance in female reproductive success, resulting in strong selection on females to compete for limited fertilization opportunities. Sperm limitation is probably common in broadcast-spawning marine invertebrates, making these excellent candidates for investigating scramble competition between broods of eggs and its consequences for female reproductive success. Here, we report our findings from a series of experiments that investigate egg competition in the sessile, broadcast-spawning polychaete Galeolaria caespitosa. We initially tested whether the order in which eggs encounter sperm affects their fertilization success at two ecologically relevant current regimes. We used a split-clutch-split--ejaculate technique to compare the fertilization success of eggs from individual females that had either first access (competition-free treatment) or second access (egg competition treatment) to a batch of sperm. We found that fertilization success depended on the order in which eggs accessed sperm; eggs that were assigned to the competition-free treatment exhibited significantly higher fertilization rates than those assigned to the egg competition treatment at both current speeds. In subsequent experiments we found that prior exposure of sperm to eggs significantly reduced both the quantity and quality of sperm available to fertilize a second clutch of eggs, resulting in reductions in fertilization success at high and low sperm concentrations. These findings suggest that female traits that increase the likelihood of sperm-egg interactions (e.g. egg size) will respond to selection imposed by egg competition.

Animals↗
PubMed2003

Revising the troublesome stoma: combined abdominal wall recontouring and revision of stomas.

PURPOSE: Despite preoperative siting and maturation of stomas, some patients may have poor stoma function because of redundant pannus, scars, creases, and parastomal or incisional hernias. In these patients, a combined abdominoplasty and stoma revision may be helpful. The object of this manuscript is to report our preliminary results. METHODS: Eight patients (mean age, 48 years; female/male ratio, 7/1) undergoing this procedure are reported. Five patients had inflammatory bowel disease, two had malignancies, and one had multiple sclerosis with bladder and bowel involvement. Patients were contacted at two months to two years follow-up to assess functional outcome and satisfaction with the procedure. RESULTS: Indications for surgery were difficulty maintaining an appliance (n = 7), frequent stool leakage (n = 6), and skin irritation (n = 4). Multiple surgeries (n = 4), skin creases (n = 3), scarring (n = 2), large weight loss (n = 4), and hernias (n = 5) were contributing factors. At surgery five patients had hernias repaired (3 parastomal, 2 incisional), three had stomas resited, and three underwent resections for Crohn's disease. One patient developed a seroma postoperatively. At follow-up six patients were able to maintain an appliance for at least four days, whereas one changed the appliance every three days because of personal preference. None experience stool leakage. All reported a dramatic improvement in body image. CONCLUSION: Combined stoma revision and abdominoplasty can be performed safely and leads to improved functional results and outcome.

Abdominal Muscles↗
PubMed2001

Disrupted sperm function and fertilin beta processing in mice deficient in the inositol polyphosphate 5-phosphatase Inpp5b.

Inpp5b is an ubiquitously expressed type II inositol polyphosphate 5-phosphatase. We have disrupted the Inpp5b gene in mice and found that homozygous mutant males are infertile. Here we examine the causes for the infertility in detail. We demonstrate that sperm from Inpp5b(-/-) males have reduced motility and reduced ability to fertilize eggs, although capacitation and acrosome exocytosis appear to be normal. In addition, fertilin beta, a sperm surface protein involved in sperm-egg membrane interactions that is normally proteolytically processed during sperm transit through the epididymis, showed reduced levels of processing in the Inpp5b(-/-) animals. Inpp5b was expressed in the Sertoli cells and epididymis and at low levels in the developing germ cells; however, mice lacking Inpp5b in spermatids and not in other cell types generated by conditional gene targeting, were fully fertile. The abnormalities in mutant sperm function and maturation appear to arise from defects in the functioning of Sertoli and epididymal epithelial cells. Our results directly demonstrate a previously unknown role for phosphoinositides in normal sperm maturation beyond their previously characterized involvement in the acrosome reaction. Inpp5b(-/-) mice provide an excellent model to study the role of Sertoli and epididymal epithelial cells in the differentiation and maturation of sperm.

ADAM Proteins↗
PubMed2001

Nocturnal hypoxaemia and central-nervous-system events in sickle-cell disease.

BACKGROUND: Central-nervous-system (CNS) events, including strokes, transient ischaemic attacks, and seizures are common in sickle-cell disease. Stroke can be predicted by high velocities in the internal-carotid or middle-cerebral arteries on transcranial doppler ultrasonography. We tested the hypothesis that nocturnal hypoxaemia can predict CNS events better than clinical or haematological features, or transcranial doppler sonography. METHODS: We screened 95 hospital-based patients with sickle-cell disease (median age 7.7 years [range 1.0-23.1]), but without previous stroke, with transcranial doppler and overnight pulse oximetry. Follow-up continued for a median of 6.01 (0.11-8.54) years. FINDINGS: 19 patients had CNS events (six ischaemic and one haemorrhagic stroke, eight transient ischaemic attacks, and four seizures). Mean overnight oxygen saturation ([SaO(2)] hazard ratio 0.82 per 1% increase [95% CI 0.71-0.93]; p=0.003) and higher internal-carotid or middle-cerebral artery velocity (1.02 for every increase of 1 cm/s [1.004-1.03]; p=0.009) were independently associated with time to CNS event. After accounting for mean SaO(2), artery velocity, and haemoglobinopathy, high haemoglobin concentration was also associated with an increased risk of CNS event (1.7 per g/dL, [1.18-2.43]; p=0.004). Dips suggestive of obstructive sleep apnoea did not predict CNS events, and adenotonsillectomy seemed to have no effect, although the CI were wide and clinically important effects cannot be excluded. INTERPRETATION: Screening for, and appropriate management of, nocturnal hypoxaemia might be a safe and effective alternative to prophylactic blood transfusion for primary prevention of CNS events in sickle-cell disease.

Adolescent↗
PubMed2001

Analysis of fertilin alpha (ADAM1)-mediated sperm-egg cell adhesion during fertilization and identification of an adhesion-mediating sequence in the disintegrin-like domain.

Fertilin alpha (also known as ADAM1) is a member of the ADAM (A disintegrin and A metalloprotease domain) family of proteins. In this study, we examine the mechanism of mouse fertilin alpha's in adhesion of sperm to the egg plasma membrane during fertilization. We find that recombinant forms of fertilin alpha corresponding to either the disintegrin-like domain or the cysteine-rich domain and the EGF-like repeat can perturb sperm-egg binding, suggesting that both of these domains can participate in fertilin alpha-mediated adhesion events. In further examination of the fertilin alpha disintegrin-like domain, we find that a subdomain of disintegrin-like domain with the sequence DLEECDCG outside the putative disintegrin loop but with homology to the fertilin beta disintegrin loop can inhibit the binding of both sperm and recombinant fertilin alpha to eggs, suggesting that this is an adhesion-mediating motif of the fertilin alpha disintegrin-like domain. This sequence also inhibits the binding of recombinant fertilin beta to eggs and thus is the first peptide sequence found to block two different sperm ligands. Finally, a monoclonal antibody to the tetraspanin protein CD9, KMC.8, inhibited the binding of recombinant fertilin alpha to eggs in one type of binding assay, suggesting that, under certain conditions, fertilin alpha may interact with a KMC.8-sensitive binding site on the egg plasma membrane.

ADAM Proteins↗
PubMed2001

Patterns of sperm precedence and predictors of paternity in the Trinidadian guppy.

Despite its widespread occurrence in animals, sperm competition has been studied in a limited range of taxa. Among the most neglected groups in this respect are internally fertilizing fish in which virtually nothing is known about the dynamics of sperm competition. In this study, we examined the outcome of sperm competition when virgin female guppies mated with two males. Behavioural cues were used to ensure that each male mated once (with female cooperation) and that sperm were successfully inseminated at copulation. Two polymorphic microsatellite loci were used to estimate the proportion of offspring sired by the second male (P2) and the results revealed a bimodal distribution with either first or (more often) second male priority The observed P2 distribution differed from that expected under the 'fair raffle' model of sperm competition. Random sperm mixing is therefore unlikely to account for the observed variance in P2 in this study. A further aim of our study was to identify predictors of male reproductive success. Using logistic linear modelling, we found that the best predictors of paternity were time to remating and the difference in courtship display rate between first and second males. Males that mated quickly and performed relatively high numbers of sigmoid displays obtained greater parentage than their slower and less vigorous counterparts. Since females are attracted to high-displaying males, our results suggest that female choice may facilitate sperm competition and/or sperm choice in guppies.

Animals↗
PubMed2001

Fertilin beta and other ADAMs as integrin ligands: insights into cell adhesion and fertilization.

One of the most important cell-cell interactions is that of the sperm with the egg. This interaction, which begins with cell adhesion and culminates with membrane fusion, is mediated by multiple molecules on the gametes. One of the best-characterized of these molecules is fertilin beta, a ligand on mammalian sperm and one of the first ADAMs (A Disintegrin and A Metalloprotease domain) to be identified. Fertilin beta (also known as ADAM2) participates in sperm-egg membrane binding, and it has long been hypothesized that this function is achieved through the interaction of the disintegrin domain of fertilin beta with an integrin on the egg surface. There are now approximately 30 members of the ADAM family and, to date, five different ADAMs (fertilin beta, ADAM9, ADAM12, ADAM15, ADAM23) have been described to interact with integrins (specifically alpha(6)beta(1), alpha(v)beta(3), alpha(9)beta(1), alpha(v)beta(5), and/or alpha(5)beta(1)). This field will be discussed with respect to what is known about specific ADAMs and the integrins with which they interact, and what the implications are for sperm-egg interactions and for integrin function. These data will also be discussed in the context of recent knockout studies, which show that eggs lacking the alpha(6) integrin subunit can be fertilized, and eggs lacking the integrin-associated tetraspanin protein CD9 fail to fertilize. Key issues in cell adhesion that pertain to gametes and fertilization will also be highlighted.

ADAM Proteins↗
PubMed2001

Perfusion magnetic resonance abnormalities in patients with sickle cell disease.

Neurological complications are common in sickle cell disease (SCD). However, it is often difficult to relate the clinical presentation to conventional neuroimaging, because subclinical infarction is common and stroke has been described in the absence of large-vessel disease. We studied 48 patients with SCD aged 4-34 (median 13) years with T2-weighted, diffusion and perfusion magnetic resonance imaging (MRI) and with MR angiography. Forty-four underwent transcranial Doppler (TCD). Abnormalities on perfusion imaging were seen in 25 cases, 24 of whom had been symptomatic. The remaining patient had evidence of executive dysfunction and reduced perfusion in the frontal lobes. The perfusion abnormality was larger than the area of infarction in 9 patients and was seen in an arterial distribution with no infarction in a further 9. In 3 patients with transient ischemic attacks, perfusion abnormalities were demonstrated in the absence of any other neuroimaging abnormalities, and perfusion changes were seen in 3 others despite normal MR angiography and TCD. Perfusion abnormalities are associated with neurological symptoms in patients with SCD, whether or not MRI, MR angiography, and TCD are abnormal. It is likely that this technique will guide management in individual patients.

Adolescent↗
PubMed2000

Multiple benefits of multiple mating in guppies.

The rewards of promiscuity for males are undisputed. But why should a female mate promiscuously, particularly when her partners offer no resources other than sperm and increase her chances of succumbing to predation or disease? This question has been hotly debated but at present remains largely unresolved [Jennions, M. D. & Petrie, M. (2000) Biol. Rev. 75, 21-64]. One possibility is that females exploit postcopulatory mechanisms, such as sperm competition, to increase both the quality and quantity of their offspring. In this paper, we use the Trinidadian guppy, a species with a resource-free mating system, to test the hypothesis that females gain multiple benefits from multiple mating. Our results indicate that multiply mated females secure substantive advantages: They have shorter gestation times and larger broods, and they produce offspring with better developed schooling abilities and escape responses than their singly mated counterparts.

Animals↗
PubMed2000

Identification of key functional amino acids of the mouse fertilin beta (ADAM2) disintegrin loop for cell-cell adhesion during fertilization.

Fertilin beta (also known as ADAM2) is a cell adhesion molecule on the surface of mammalian sperm that participates in sperm-egg membrane binding. Fertilin beta is a member of the molecular family known as ADAMs or MDCs. These proteins have a disintegrin domain with homology to integrin ligands found in snake venoms; several of these snake proteins have an RGD tripeptide presented on an extended "disintegrin loop." However, fertilin beta lacks an RGD tripeptide and instead has the consensus sequence X(D/E)ECD (QDECD in mouse fertilin beta) in its putative disintegrin loop, and there is controversy over which amino acids comprise the active site of the fertilin beta disintegrin loop. We have used point-mutated versions of the sequence AQDECDVT and two bioassays to identify the key functional amino acids of this sequence from the mouse fertilin beta disintegrin domain. Amino acid substitutions for the terminal aspartic acid residue of the QDECD sequence result in dramatically reduced activities in the two assays for protein function, implicating the terminal aspartic acid residue as critical for protein function. Substitutions for the glutamic acid and the cysteine residues in the QDECD sequence result in slight reductions in activity, whereas substitution of the first aspartic acid has virtually no effect. These data suggest that the conserved ECD sequence of the mouse fertilin beta disintegrin loop, especially the terminal D residue, contributes more to the protein's activity than does the QDE sequence that aligns with the RGD tripeptide in other disintegrins.

ADAM Proteins↗
PubMed2000

Platelet and leucocyte activation in childhood sickle cell disease: association with nocturnal hypoxaemia.

We hypothesized that vaso-occlusive events in childhood sickle cell disease (SCD) may relate to inflammatory cell activation as well as interactions between sickle erythrocytes and vascular endothelium. Peripheral blood was examined from 24 children with SCD, of whom 12 had neurological sequelae and seven had frequent painful crises, and 10 control subjects. Platelet (CD62P and CD40L expression) and granulocyte (CD11b expression) activation and levels of platelet-erythrocyte and platelet-granulocyte complexes were determined by flow cytometry. Platelets (P = 0.019), neutrophils (P = 0.02) and monocytes (P = 0.001) were more activated and there were increased platelet-erythrocyte complexes (P = 0.026) in SCD patients compared with controls. Platelet-granulocyte complexes were not raised. There were no differences between the different groups of SCD. As hypoxia activates monocytes, platelets and endothelial cells and causes sickling of SCD erythrocytes, we also investigated 20 SCD patients with overnight pulse oximetry. Minimum overnight saturation correlated with the level of platelet-erythrocyte complexes (Spearman's rho -0.668, P < 0.02), neutrophil CD11b (Spearman's rho -0.466, P = 0.038) and monocyte CD11b (Spearman's rho -0.652, P = 0. 002). These findings provide important clues about the mechanism by which SCD patients may become predisposed to vaso-occlusive events.

Adolescent↗
PubMed2000

Effects of perturbation of cell polarity on molecular markers of sperm-egg binding sites on mouse eggs.

The mouse germinal vesicle (GV)-intact oocyte is a symmetric cell, with the GV centrally localized and with components of the plasma membrane and cortex symmetrically distributed around the periphery of the oocyte. During oocyte maturation, two distinct regions of the egg plasma membrane and cortex develop: the amicrovillar region overlying the meiotic spindle and the microvillar region. The development of this polarity is significant, since sperm bind to and fuse with the microvillar region. We are interested in the development of egg polarity and have characterized the localizations of several markers for egg polarity in normal metaphase II eggs and GV-intact oocytes. The asymmetric distributions of these markers (including actin, cortical granules, binding sites for the sperm proteins fertilin alpha and fertilin beta, and two different beta(1) integrin epitopes) develop during oocyte maturation in vitro, and this polarity can be perturbed by treatments that disrupt the actin microfilaments or microtubules. In addition, immunoelectron microscopy reveals that binding sites for recombinant fertilin beta are specifically localized to the microvillar region, suggesting that the binding sites for this sperm ligand are either specifically localized or activated in this region. These results indicate that structural remodeling of the mouse egg plasma membrane is accompanied by molecular remodeling, resulting in the localization or activation of specific molecules in subdomains of the plasma membrane.

ADAM Proteins↗
PubMed2000

Getting sperm and egg together: things conserved and things diverged.

Sperm-egg interactions occur at multiple levels on the egg surface, first with the egg's extracellular matrix and then with the egg's plasma membrane. The BioPore minisymposium on "The Egg Surface" at the 1999 annual meeting of the Society for the Study of Reproduction highlighted a series of events underlying successful interactions of the sperm with the egg: 1) composition, synthesis, and assembly of the mouse egg's extracellular matrix, the zona pellucida, during oogenesis; 2) oocyte maturation and development of the sperm-binding domain of mouse eggs; and 3) characterization of functional domains in different sperm ligands (fertilin-alpha and fertilin-beta in the mouse and lysin in the abalone) that recognize cognate binding sites on the egg surface. Data that were presented are reviewed here and discussed with respect to conserved and divergent features of gamete functions.

Animals↗
PubMed1999

Sperm disintegrins, egg integrins, and other cell adhesion molecules of mammalian gamete plasma membrane interactions.

The cell-cell interactions that occur between sperm and egg involve not only the binding but also the fusion of the gamete plasma membranes. Numerous studies, carried out decades ago and more recently, have implicated several different molecules on both the sperm and egg as being involved in gamete membrane interactions. The sperm proteins that have received the most attention recently have homology to disintegrins, which are proteins in snake venoms that can interact with integrins. These sperm disintegrin-like proteins are members of a molecular family, known as ADAM's (for A Disintegrin and A Metalloprotease) or MDC's (for Metalloprotease, Disintegrin, Cysteine-rich). This review will focus on the molecules that have been implicated in mediating mammalian sperm-egg binding or the fusion of the gamete membranes. The molecules that will be discussed include three members of the ADAM/MDC family on sperm (fertilin alpha, fertilin beta, and cyritestin), integrins on eggs (alpha-6/beta-1 and others), and a number of other egg and sperm molecules, novel and characterized in other systems, that have been implicated in these processes.

ADAM Proteins↗