Botox injections and monitoring neuromuscular blockade.
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Adult↗
Biomedical subjects
S J Ward
Publications and source records attributed to S J Ward.
The role of CB1 receptors in sweet versus fat reinforcement: effect of CB1 receptor deletion, CB1 receptor antagonism (SR141716A) and CB1 receptor agonism (CP-55940).
It is well established that Cannabis sativa can increase appetite, particularly for sweet and palatable foods. In laboratory animals, cannabinoid CB1 receptor antagonism decreases motivation for palatable foods, and most recently, the CB1 receptor antagonist SR141716A, or rimonabant (Acomplia), was reported to produce weight loss in obese human subjects. Indeed, the endocannabinoid system plays a select role in the rewarding properties of palatable foods, and this is well characterized in laboratory animals with sweet sucrose solutions. In the present study, CB1 knockout mice (CB1 KO) and wild-type littermate mice (WT) were trained to respond for a complex sweet as well as a pure fat reinforcer under a progressive ratio (PR) schedule, to determine whether motivation to consume different palatable foods is tonically regulated by CB1 receptors. To assess sweet reinforcement, several concentrations of the liquid nutritional drink, Ensure, were presented under the PR schedule. For fat reinforcement, several concentrations of corn oil (emulsified in 3% xanthan gum) were made available. Additionally, to compare the result of genetic invalidation of the CB1 receptor to antagonism of the CB1 receptor system, the effect of SR141716A (3.0 mg/kg) on responding for Ensure and corn oil were also assessed using the PR schedule. We also assessed the effect of the CB1 agonist CP-55940 (30 microg/kg) on responding for Ensure and corn oil. CB1 KOs took significantly longer to acquire operant responding maintained by Ensure, and responding for Ensure under the PR schedule was significantly reduced in CB1 KOs as well as in WTs pretreated with SR141716A, as compared to WT controls. Additionally, pretreatment with the CB1 agonist CP-55940 increased responding for Ensure. In contrast, responding for corn oil during acquisition and under the PR schedule was not significantly different in CB1 KOs versus wild-type mice. However, SR141716A did reduce responding for corn oil in WTs, and CP-55940 significantly increased responding for corn oil. Taken together, these results suggest that CB1 receptors are preferentially involved in the reinforcing effects of a complex sweet, as compared to a pure fat, reinforcer. These data also suggest, however, that antagonism of CB1 receptors with SR141716A is sufficient to attenuate the reinforcing effect of Ensure and corn oil, while activation of the central CB1 system is sufficient to enhance Ensure and corn oil reinforcement.
Animals↗
The effects of habitat fragmentation via forestry plantation establishment on spatial genotypic structure in the small marsupial carnivore, Antechinus agilis.
Dispersal is an important influence on species' distributions, patch colonization and population persistence in fragmented habitat. We studied the impacts of habitat fragmentation resulting from establishment of an exotic pine plantation on dispersal of the marsupial carnivore, Antechinus agilis. We applied spatial analyses of individual multilocus microsatellite genotypes and mitochondrial haplotypes to study patterns of gene flow in fragmented habitat and natural habitat 'control' areas, and how this is affected by the spatial dispersion of habitat patches, the presence of corridors and a 'mainland' source of migrants. Spatial analysis of molecular variance and partial Mantel tests confirmed the absence of cryptic barriers to gene flow in continuous habitat, which if present would confound the comparison of genetic structures in fragmented vs. unfragmented habitats. Spatial genotypic structure suggested that although dispersal was male-biased in both habitat types, fragmentation restricted dispersal of males more than that of females and the degree of restriction of male dispersal was dependent on the geographical isolation of the patch. The scale of positive genotypic structure in fragmented habitat was restricted to the two closest patches for females and the three closest patches for males. Our results provide evidence for significantly increased gene flow through habitat corridors relative to that across the matrix and for significantly lower gene flow between 'mainland' unfragmented habitat and habitat patches relative to that within either habitat type, suggesting a behavioural barrier to crossing habitat interfaces.
Animals↗
The effects of habitat fragmentation on the social kin structure and mating system of the agile antechinus, Antechinus agilis.
Habitat fragmentation is one of the major contributors to the loss of biodiversity worldwide. However, relatively little is known about its more immediate impacts on within-patch population processes such as social structure and mating systems, whose alteration may play an important role in extinction risk. We investigated the impacts of habitat fragmentation due to the establishment of an exotic softwood plantation on the social kin structure and breeding system of the Australian marsupial carnivore, Antechinus agilis. Restricted dispersal by males in fragmented habitat resulted in elevated relatedness among potential mates in populations in fragments, potentially increasing the risk of inbreeding. Antechinus agilis nests communally in tree hollows; these nests are important points for social contact between males and females in the mating season. In response to elevated relatedness among potential mates in fragmented habitat, A. agilis significantly avoided sharing nests with opposite-sex relatives in large fragment sites (but not in small ones, possibly due to limited nest locations and small population sizes). Because opposite-sex individuals shared nests randomly with respect to relatedness in unfragmented habitat, we interpreted the phenomenon in fragmented habitat as a precursor to inbreeding avoidance via mate choice. Despite evidence that female A. agilis at high inbreeding risk selected relatively unrelated mates, there was no overall increased avoidance of related mates by females in fragmented habitats compared to unfragmented habitats. Simulations indicated that only dispersal, and not nonrandom mating, contributed to inbreeding avoidance in either habitat context. However, habitat fragmentation did influence the mating system in that the degree of multiple paternity was reduced due to the reduction in population sizes and population connectivity. This, in turn, reduced the number of males available to females in the breeding season. This suggests that in addition to the obvious impacts of reduced recruitment, patch recolonization and increased genetic drift, the isolation of populations in habitat patches may cause changes in breeding behaviour that contribute to the negative impacts of habitat fragmentation.
Animals↗
Genetic association between an AACC insertion in the 3'UTR of the stratum corneum chymotryptic enzyme gene and atopic dermatitis.
Atopic dermatitis is a disease with an impaired skin barrier that affects 15%-20% of children. In the normal epidermis, the stratum corneum chymotryptic enzyme (SCCE) thought to play a central role in desquamation by cleaving proteins of the stratum corneum (e.g., corneodesmosin and plakoglobin). Genetic variations within the SCCE gene could be associated with dysregulation of SCCE activity leading to an abnormal skin barrier. We screened the SCCE gene for variations and performed a case-control study on 103 atopic dermatitis patients and 261 matched controls. 16 synonymous single nucleotide polymorphisms (SNPs) have been identified and a 4 bp (AACC) insertion has been found in the 3'UTR. We performed an association study of the SCCE AACC insertion in the 3'UTR, and found a significant trend between the AACC allele with the two insertions and disease in the overall data set [odds ratio (OR)=2.31; p=0.0007]. The AACC insertion in the SCCE gene may result in a change to SCCE activity within the skin barrier. These findings suggest that SCCE could have an important role in the development of atopic dermatitis.
3' Untranslated Regions↗
A cluster randomised, controlled trial of the value of dental health educators in general dental practice.
AIM: To test the effectiveness of dental health educators in general dental practice. OBJECTIVE: To evaluate the effectiveness and cost of primary care trusts seconding dental health educators free of charge to suitable general dental practices to provide dental health counselling to mothers of regularly attending pre-school children at risk to caries. METHOD: Two-cell, parallel group, cluster randomised, controlled clinical trial of two years' duration. CLINICAL SETTING: 30 general dental practices in North-West England. PARTICIPANTS: 269 mothers of 334 pre-school children. INTERVENTIONS: Those in the test group were given visits to a dental health educator over a 2-year period to counsel mothers of at-risk, pre-school children. The rest were held as a control. MAIN OUTCOME MEASURES: Caries prevalence of the children and dental health knowledge, attitudes and toothbrushing skills of the parents. The full costs of the exercise were kept throughout. The statistical analysis controlled for the clustering of children within practices. RESULTS: After 2 years, 271 (81%) children and 248 (92%) mothers remained in the study. There was an 18% difference in mean dmft between the groups in favour of the test group children but this was not statistically significant. At the end of the study there was an 18% difference in mean dmft between the groups in favour of the test group children but this was not statistically significant. No difference in plaque levels was found. The mothers in the test group were more knowledgeable, had better attitudes towards the dental health of their offspring and better toothbrushing skills than those in the control. Each 2-hour session to counsel ten parents cost pound 40. CONCLUSION: Primary care trusts should carefully consider the cost value of seconding dental health educators to counsel parents of regularly attending, at-risk, pre-school children when considering such an option.
Attitude to Health↗
Paternity success and the direction of sexual selection in a field population of a semelparous marsupial, Antechinus agilis.
Antechinus agilis is a small sexually size dimorphic marsupial with a brief annual mating period of 2-3 weeks. All males die after this period, and females give birth to up to 10 young. Mating is thought to be promiscuous, however, there is no field data to confirm this. Using microsatellites, we investigated paternity patterns over two seasons in a wild population. Male weight was significantly positively related to the number of females fertilized and with the number of offspring sired, in both years. Furthermore, selection gradients indicated selection for larger males. Both results suggest that size dimorphism in A. agilis can be explained by sexual selection for larger males. The proportion of offspring sired within litters, did not relate to male size. Therefore, larger males are more successful through higher mating access, not through their sperm outcompeting that of smaller males. As expected from their known ranging behaviour, the number of offspring within litters left unassigned to a father did not depend on the grid location of the mother. Female size did not differ between successful reproducing and unsuccessful females. However, females that weaned offspring had larger heads than females that did not wean offspring. Males did not 'prefer' mating with larger females, nor did assortative mating occur. From our results, the mating system of A. agilis is clearly promiscuous. Selection for larger males occurred in both years, even though in one year the operational sex ratio was highly female biased, suggesting that the potential reproductive rate is a better predictor of the direction of sexual selection in A. agilis.
Animals↗
Training of Doctors project.
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Education, Medical, Continuing↗
Genomic organization of the mouse plunc gene and expression in the developing airways and thymus.
Few genes have been isolated which display specific expression in the proximal airways. A recently identified mouse cDNA, plunc, appears to be confined to the upper airways and nasopharyngeal epithelium, and may prove a useful marker for these regions. We now report the genomic cloning and characterization of the mouse plunc gene as well as its developmental expression in the nasal and airway epithelium. We also report the novel finding that plunc is also expressed in the medullary compartment of the murine thymus. The mouse gene contains nine exons and the intron-exon boundaries are conserved with those in the human homologue. At e14.5 plunc is expressed in the nasal epithelium and several days later is seen in the thymic lobes, but not in the lining of the tracheobronchial tree. Expression in the trachea and main-stem bronchi first appears at 1--2 days after birth. Tracheobronchial expression persists at high levels throughout adulthood, as do regional areas of nasal and thymic expression. Finally, we show that the human homologue is expressed in bronchial epithelium, suggesting a transcript that is evolutionarily conserved in the mammalian airway.
Animals↗
Use of transgenic mice model for understanding the placentation: towards clinical applications in human obstetrical pathologies?
The mammalian embryo and fetus are unable to develop without a well-established, functional placenta. This transitory yet indispensable structure attaches the conceptus to the uterus and establishes the vascular connections necessary for nutrient and gaseous exchange between maternal and fetal compartments. Genetic targeting strategy allows the generation of mice lacking a specific gene. Such approaches reveal: (i) the high incidence of mutant embryonic or fetal death in utero, and (ii) the extraembryonic (placental) causes of these deaths. Due to the similarities presented between mouse and human placenta, we propose to use the potential of mouse targeting experiments as a model in order to understand human obstetrical pathologies. In this paper, we first review genes that have been demonstrated to be required in mice for implantation, choriovitelline and chorioallantoic placentation. Using examples (integrins, homeoboxs, hepatocyte growth factor or epidermal growth factor receptor...) we demonstrate the reality and efficiency of such an approach. Other candidate genes (receptor of leukemia inhibitory factor, Wnt2 or retinoic acid receptor alpha...) in order to understand, prevent and treat human obstetrical pathologies.
Animals↗
Association analysis of IL1A and IL1B variants in alopecia areata.
Alopecia areata is an inflammatory hair loss disease with a major genetic component. The disease is characterized by focal inflammatory lesions with perifollicular T-cell infiltrates, reflecting the role of local cytokine production in the development of patchy hair loss. IL-1 alpha and IL-1 beta are important inhibitors of hair growth in vitro. Their effect is opposed by the interleukin-1 receptor antagonist, IL-1ra. Genes of the IL-1 cluster are candidate genes in the pathogenesis of alopecia areata. To investigate the role of the IL-1 system in alopecia areata we examined three biallelic polymorphisms within the IL-1 gene cluster (IL1A+4845, IL1B+3954 and IL1B-511) in 165 patients and a large number of matched controls (n=1150). There was no significant association of IL1B-511 or IL1B+3954 genotypes with the overall dataset, or with disease severity or age at onset, in contrast with a previous report. The results suggested the possibility of an association with IL1A+4845 in the overall dataset [OR 1.39 (95% CI 1.00, 1.93)] although this was not statistically significant. This was due mainly to the contribution from mild cases of alopecia areata [OR 1.48 (0.96, 2.29)], suggesting that IL-1 alpha may have a particular role in the pathogenesis of this subgroup.
Adult↗
Impact of genomics in drug discovery.
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Animals↗
Tissue-specific expression of retinoic acid receptor isoform transcripts in the mouse embryo.
The three murine retinoic acid receptor (RAR) genes each contain two distinct promoters which give rise to protein isoforms differing in their N-terminal regions. This study used in situ hybridization to describe the expression patterns of RARalpha1, RARalpha2, RARbeta1/3, RARbeta2/4, RARgamma1 and RARgamma2 isoform transcripts during mouse embryogenesis. RARalpha1 transcripts are widely distributed, with the exception of the central nervous system. Highest expression is found in developing muscle, pituitary gland and various epithelia. On the other hand, RARalpha2 is essentially expressed along the spinal cord up to the hindbrain 7th rhombomere and in the 4th rhombomere, pons and developing basal ganglia (corpus striatum and pallidum). RARbeta2/4 transcripts account for most of the previously described RARbeta expression features being expressed specifically, or more prominently than RARbeta1/3, in foregut endoderm and its derivatives, olfactory and periocular mesenchyme, urogenital region, proximal limb bud mesenchyme and later within interdigital regions. RARbeta1/3 is more prominently expressed in the developing heart outflow tract mesenchyme, intervertebral disks, midgut loop mesenchyme and umbilical vessel walls. RARbeta1/3 and RARbeta2/4 are coexpressed in the developing corpus striatum. They exhibit, however, distinct dorsoventral distributions along the spinal cord and caudal hindbrain. RARgamma2 is the RARgamma isoform expressed at high levels in the caudal neural groove at embryonic day 8.5. At later stages, both RARgamma isoforms are essentially coexpressed, although the progressive restriction of RARgamma1 transcripts to craniofacial or limb precartilaginous condensations appears to precede that of RARgamma2.
Animals↗
Helicobacter pylori possesses two CheY response regulators and a histidine kinase sensor, CheA, which are essential for chemotaxis and colonization of the gastric mucosa.
Infection of the mucous layer of the human stomach by Helicobacter pylori requires the bacterium to be motile and presumably chemotactic. Previous studies have shown that fully functional flagella are essential for motility and colonization, but the role of chemotaxis remains unclear. The two-component regulatory system CheA/CheY has been shown to play a major role in chemotaxis in other enteric bacteria. Scrutiny of the 26695 genome sequence suggests that H. pylori has two CheY response regulators: one a separate protein (CheY1) and the other (CheY2) fused to the histidine kinase sensor CheA. Defined deletion mutations were introduced into cheY1, cheY2, and cheA in H. pylori strains N6 and SS1. Video tracking revealed that the wild-type H. pylori strain moves in short runs with frequent direction changes, in contrast to movement of cheY2, cheAY2, and cheAY2 cheY1 mutants, whose motion was more linear. The cheY1 mutant demonstrated a different motility phenotype of rapid tumbling. All mutants had impaired swarming and greatly reduced chemotactic responses to hog gastric mucin. Neither cheY1 nor cheAY2 mutants were able to colonize mice, but they generated a significant antibody response, suggesting that despite impaired chemotaxis, these mutants were able to survive in the stomach long enough to induce an immune response before being removed by gastric flow. Additionally, we demonstrated that cheY1 failed to colonize gnotobiotic piglets. This study demonstrates the importance of the roles of cheY1, cheY2, and cheA in motility and virulence of H. pylori.
Animals↗
Development of a gonadotrophin-releasing hormone and prostaglandin regimen for the planned breeding of dairy cows.
Four studies were carried out to determine the ovarian responses of dairy cows undergoing natural oestrous cycles to sequential injections of gonadotrophin-releasing hormone (GnRH), followed seven days later by prostaglandin and, 48 to 72 hours later, by a second injection of GnRH. In study 1, of 60 cows so treated, 47 were in the intended periovulatory phase when a fixed-time insemination was given 72 hours after the prostaglandin. In study 2, detailed observations were made in 32 cows treated as in study 1, using ultrasound to determine the optimum time to administer the second dose of GnRH. Ovulation was most effectively synchronised by giving GnRH 56 to 60 hours after the prostaglandin. Study 3 investigated the timing of ovulation when no initial dose of GnRH was given. Six cows were injected with prostaglandin on day 12 of the oestrous cycle, followed by GnRH 60 hours later. Five of the six cows ovulated 24 to 36 hours after GnRH, an equivalent timing and synchrony to that in study 2, in which a dose of GnRH had been given seven days before prostaglandin. In study 4, an initial dose of GnRH was given to six cows late (day 17) in the oestrous cycle, and prostaglandin seven days later. The GnRH treatment delayed luteolysis in five of the cows so that they were responsive to the prostaglandin and ovulated 24 to 36 hours after the second dose of GnRH. The use of GnRH (day 0) - prostaglandin (day 7) - GnRH (day 9.5) appears to be an effective means of synchronising ovulation in most cows.
Animal Husbandry↗
Oesophageal atresia, related malformations, and medical problems: a family study.
Oesophageal atresia (OA) and tracheo-oesophageal fistula (TOF) are life-threatening malformations of generally undefined cause. Previous reports of familial cases suggest a genetic contribution. The pattern of inheritance appears non-Mendelian, i.e., multifactorial. Individuals with OA/TOF often have other malformations and medical problems. The aim of this study was to determine the association in OA/TOF cases and healthy control subjects of associated malformations, midline defects, and medical conditions. We also investigate the relationships of these conditions in the relatives of the cases and controls. The results show that infants with OA/TOF frequently have VACTERL anomalies (vertebral, 17%; anal, 12%; cardiac, 20%; renal, 16%; limb, 10%) and other midline defects (cleft lip and palate, 2%; sacral dysgenesis, 2%; urogenital anomalies, 5%). The following medical problems were also reported: oesophageal dysmotility, 21%; gastro-oesophageal reflux, 22%; chest infections, 6%; and autonomic dysfunction, 0.5%. The first-degree relatives of children with OA are much more likely to have one of the aforementioned malformations or medical conditions when compared with the control group: one or more VACTERL anomalies (P < 0.01), gastro-oesophageal reflux (P < 0.05), recurrent respiratory infections (P < 0.05), and autonomic dysfunction (P < 0.001). The more distant relatives also show an increased incidence of such problems although in this case the data must be viewed with caution. The results confirm that the associated malformations and related medical problems occur significantly more frequently in the relatives of individuals with OA/TOF. These families may prove valuable for linkage analysis in an attempt to determine the genetics of OA/TOF.
Abnormalities, Multiple↗
Functional analysis of the roles of FliQ and FlhB in flagellar expression in Helicobacter pylori.
Expression of the two Helicobacter pylori flagellin proteins FlaA and FlaB is required for full motility and persistent infection of the gastric mucosa. The mechanisms and regulation of the biosynthesis and export of flagella in H. pylori are still poorly understood. Scrutiny of the H. pylori 26695 genome sequence revealed homologues of FliQ and FlhB. The roles of the fliQ and flhB genes in H. pylori were investigated by the construction and characterisation of defined isogenic mutants. The results indicate that these genes are involved in the flagellar expression, adhesion to and colonisation of the gastric mucosa.
Animals↗
Ovarian and hormonal responses of cows to treatment with an analogue of gonadotrophin releasing hormone and prostaglandin F2 alpha.
Blood samples were taken from 11 cows and their ovaries were scanned by ultrasound at least daily. Around day 5 of an induced cycle, they were injected with 10 micrograms buserelin, an analogue of gonadotrophin releasing hormone, and on day 12 they received 0.5 mg cloprostenol, an analogue of prostaglandin F2 alpha (PGF2 alpha). Two days later six of the cows (the treated group) received a second injection of 10 micrograms buserelin, but the remaining five received no further treatment (control group). The dominant, that is, the largest follicle in each cow disappeared after the first buserelin injection and was replaced by a new one which grew synchronously in all the cows until after the treatment with PGF2 alpha. Ovulation occurred significantly earlier after PGF2 alpha in the treated group than in the control group (72 to 96 hours v 96 to 120 hours; P < 0.05). Plasma progesterone concentrations then increased more rapidly in the treated group than in the control group and were significantly higher on days 3 and 4 after ovulation (P < 0.05).
Animals↗